DNA TEST - ANDRO SENSOR 40 + -English Version by DNA Medic

Fem/Andro Sensor 40+ Dr. John Smith DEMO5

COVER LETTER

Dear Mr. Dr. Muster Mustermann, Your sample for the analysis arrived on 01/06/2014 in the laboratory and was evaluated according to the highest laboratory quality standards (ISO 15189 and ISO 17025). The results were evaluated by two independent geneticists and molecular biologists and personally approved by me, the laboratory manager. After obtaining the results, your personal report was compiled. I would like to send this to you in the format of your choice. I would like to thank you for your trust and I hope that you are satisfied with our service. If you have any problems or complaints, please do not hesitate to contact us. This is the only way we can continuously improve our services. I hope the analysis meets your expectations. Kind regards,

Dr. Daniel Wallerstorfer, B.Sc. Laboratory director

Andro Sensor 40+

Personal analysis results for:

Dr. Muster Mustermann | Date of birth: 01/01/1985 Order number:

DEMO_DNAMEDIC

This report contains personal genetic data and is to be treated confidentially.

Table of contents Grayed-out sections are optional elements that were not ordered and are not included in the brochure. GENERAL INFORMATION How genes influence our health

PHARMACO GENETICS Pharmaco Sensor (Drug side effects)

$*$

HIV Sensor (HIV resistance)

$*$

ONCOLOGY Breast Health Sensor (Breast Cancer)

$*$

ANDROLOGY Prostate Health Sensor (Prostate Cancer)

CARDIOVASCULAR SYSTEM Cardiovascular sensor (cardiovascular disease)

Thrombo Sensor (Thrombosis)

Hypertension Sensor (Hypertonia)

$*$

METABOLISM Toxo Sensor (Detoxification of toxins)

Diabetes Sensor (Diabetes Type 2)

$*$

Alzheimer Sensor (Alzheimer's Disease)

$*$

Iron Sensor (Hemochromatosis)

$*$

MOBILITY Bone Health Sensor (Osteoporosis)

Joint Sensor (Rheumatoid Arthritis)

$*$

DIGESTION Gluten Sensor (Celiac Disease)

$*$

Lactose Sensor (Lactose Intolerance)

$*$

IBD Sensor (Inflammatory Bowel Disease)

$*$

OPHTHALMOLOGY Glaucoma Sensor (Glaucoma)

$*$

AMD Sensor (Macular Degeneration)

$*$

ODONTOLOGY Periodontitis Sensor (Periodontitis)

$*$

GENERAL INFORMATION Technical details

References

GENETICS

How genes influence our health The human body consists of about 50 trillion individual cells. Most of these cells have a nucleus which contains 46 chromosomes. A chromosome consists of a very closely wound thread, the DNA "double helix." Chromosome

Cells Body (50 trillion cells)

DNA double helix

Lactose gene (LCT)

A = healthy G = risk

DNA, the genetic code, is the blueprint of the human body. This genetic code consists of approximately 3.1 billion molecules, which are each represented by a letter. About 1% of this code makes up the genes. Each gene is an instruction for the body, usually with a single function. For example, some genes tell the body how to generate the iris. Differences in these genes produce different eye colors. Every function of the body is controlled by one or more genes, including the way we process food and medicine.

Thrombosis gene (FV)

Our genes are not completely error-free. The genes of each person are changed slightly by environmental effects. Most of these changes have no effect. A small number have a harmful effect. An even tinier number can produce a beneficial effect. Parents pass these changes, including defects, to their children. Thus most of our genetic defects are inherited from our parents. In addition, our genes developed to help us live in the primitive world, and some of the traits in our genes can interact with our modern environment to create negative effects on our world. For example, the genetic predisposition to build up fat quickly and lose it slowly is beneficial for people who go through times when food is scarce: they will have a better chance of

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surviving because their bodies use fat efficiently. However, in the modern world, this trait is harmful because it programs the body to gain weight quickly and lose weight slowly. Genes increase our risk of heart attacks, trigger asthma and allergies, cause lactose intolerance, and many other disorders. Genetic traits can affect our health. While some genetic defects always cause disease, most genetic traits just increase our risk of getting a disease. For example, a person may have genes that increase their risk for diabetes. However, not everyone at risk for diabetes actually develops the disease. Furthermore, even people with a high risk of diabetes can lower their risk with the right diet and exercise plan. Other genetic traits only cause illness when they are triggered by a specific environmental feature. For example, lactose intolerance is a genetic condition that causes a person who drinks milk to become ill. However, a lactose-intolerant person who never drinks milk will not have any symptoms. Thanks to the latest technologies, it is now possible to test specific genes to determine if you have genetic traits that are linked to various diseases. Based on the results of the analysis, we can develop a prevention program that significantly reduces your personal disease risk and helps you stay healthy. A healthy lifestyle will decrease your risk of many diseases whether or not you have specific information about your genetic traits. However, DNA Plus provides you with additional information that may point out other changes to your lifestyle that are not part of standard medical advice. There are many examples, but one of the traits we test for is a gene that impairs your bodyâ&#x20AC;&#x2122;s ability to absorb iron. If you have this trait, we will recommend that you take iron supplements beyond the general recommendations so that your body absorbs all the iron you need. Experts estimate that every person carries about 2,000 genetic defects, which may affect their health, and, in some cases, cause illnesses. A variety of factors can cause changes in our genes (also called mutations). In a few cases, these mutations can benefit us. However, the vast majority either have no effect or have a negative impact on our health. The best-known cause of mutations, as depicted in the media and Hollywood, is radioactivity. Radioactive rays and particles actually impact the DNA in our cells and physically alter our genes. In the movies, these changes or mutations often lead to the creation of monsters like Godzilla, or characters with supernatural powers, as in X-Men. In reality, they mostly go unnoticed or cause deadly diseases, such as cancer, or congenital abnormality for newborns. Mutations are also caused by substances such as carbon, which can be ingested from burnt food. Carbon enters the cells and damages our genes, which can lead to colon cancer, among other form of cancer. UV radiation from the sun can also damage our genes and cause diseases such as skin cancer. External influences can affect individual genes and disrupt their function, but the majority of our defective genes are inherited from our parents. Each embryo receives half of its genes from the father and half of its genes from the mother, resulting in a new human being with some of the characteristics of each parent. The genetic defects are unfortunately passed together with these genes; for example, a genetic defect that causes heart attack may pass from the father to the child and further to the grandchild and so on, leading to passing the same disease to each generation. Whether the genetic defect is passed, however, is determined randomly, and it may be that some of the grandchildren carry the defective gene and others do not.

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Each person is the unique product of generations of accumulation and combination of different genetic traits. Some of those traits have negative effects on our health. With the latest technology, it is now finally possible to examine one's genes and determine his personal health risks and strengths. In many cases, taking advantage of this knowledge, and following some precautionary measures, the diseases may even be prevented. This is the next step in preventive medicine and a new generation of health care.

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PHARMACO GENETICS

How drugs operate in our body Each person reacts differently to drugs. Some people benefit significant from a particular medication, while others experience side effects with symptoms that can range from mild to fatal. According to estimates, approximately 7% of patients suffer from severe adverse reactions and about 0.4% suffer fatal consequences. Adverse reactions to drugs are the fifth most frequent cause of death in the Western world. In most cases, these reactions are determined by inherited genetic variations or interactions between certain drugs.

The path of drugs through our body

drug is taken Drug shows effect

enzyme gene

drug is prepared for breakdown by enzyme

If a drug is taken or injected with a needle, it first enters the bloodstream, through which it reaches the target organ. The drug is recognised by certain enzymes which break it down and remove it from the bloodstream. This causes most drugs to lose their effect. The deactivated drug is then filtered out of the blood with the help of the kidney and finally excreted with urine.

drug enters urine

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Long-term Drug Treatment Due to the fact that many drugs operate over a long period of time, they need to be taken in regular intervals to ensure that the amount of the drug in the bloodstream is kept in the correct range.

administration

Drug in blood active range of drug

16h

24h

32h

Time (hours) This is how the drug always remains at the right concentration and shows its intended effect.

Genetic defects inhibit the break down of the drug Unfortunately, many people carry a defect in one of the enzyme-producing genes that are crucial in this process.

drug is taken

Drug shows effect

enzyme gene

drug is not filtered out of bloodstream

The drug still enters the blood circulation and has its effect, but enzymes do not break it down and it remains in the body for a significantly longer period of time. This is only a minor problem after only one dose, but when a person takes warfarin three times a day, the level of warfarin in the blood gradually increases until it leads to toxic side effects.

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The problem with regular administration of a drug when there is a genetic defect In the case of blood thinners, drug action is at the right level in the beginning of therapy, but the concentration of the drug rises constantly with every administration until it reaches to the point of causing uncontrolled bleeding.

genetic defect slows breakdown of drug

toxic concentration >>> adverse reactions

administration Drug in blood

active range of drug

16h Time (hours)

24h

32h

This means that the 20% of the population that carry a genetic defect need a significantly lower dose of warfarin because the usual dose could lead to serious adverse reactions.

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Prodrugs, the precursors of active drugs Some drugs, so-called "prodrugs", are taken in an inactive form and are only activated by the enzymes of the body. Examples for this kind of drugs include the cancerprevention drug tamoxifen and the painkiller codeine. A prodrug enters the bloodstream in its inactive form. Enzymes in the blood transform it into its active form, and then it takes effect. For example, the painkiller codeine is transformed into morphine in this way and then relieves pain.

drug is taken

enzyme gene

Drug is activated by enzyme Drug shows effect

drug enters urine

In some people, the enzyme that converts a specific prodrug into a drug does not function, so that the drug never has an effect on the body, other than potential side effects. In the case of codeine, there is no pain relief after taking the drug and an alternative drug needs to be chosen. In case of tamoxifen, a drug that prevents the emergence of breast cancer, the drug's ineffectiveness will only be discovered if cancer develops.

drug is taken Drug shows no effect

enzyme gene

Drug is not activated

drug is not filtered out of bloodstream

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Dosage instructions for the physician This genetic analysis provides information on the rate of absorption of various medications. This information is one factor among many that should be used to determine the optimal dosage of a medication. This data cannot replace your professional opinion and responsibility for proper dosage. With that in mind, the genetic analysis indicates that the following dosages would generally be appropriate for a patient with this genetic profile:

Recommended dosage: ~100% This is the normal state when the relevant genes do not contain any performance-reducing gene variations. Administrate the medication as usual.

Recommended dosage: ~20%, ~50%, ~70% etc. The enzymes involved in the absorption of this medication have limited function and the absorption rate is probably very low. Alternative compounds will most likely be more effective. If absolutely necessary, use this drug with close surveillance for effectiveness and side effects.

Recommended dosage: 0% The enzymes involved in the absorption of this medication have limited function and the absorption rate is probably very low. Alternative compounds will most likely be more effective. If absolutely necessary, use this drug with close surveillance for effectiveness and side effects.

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PHARMACO GENETICS

Pharmacogenetic genes The following genes and polymorphisms have an impact on the breakdown and effect of various drugs. You genetic analysis found the following: Pharmacogenetics Drug Category 1

polymorphism

condition of gene

drug metabolism

Cytochrome P-450 2D6

2549 A/del (Allele*3)

active

rapid

Cytochrome P-450 2D6

1846 G/A (Allele*4)

inactive

slow

Cytochrome P-450 2D6

1707 T/del (Allele*6)

active

rapid

Cytochrome P-450 2D6

2935 A/C (Allele*7)

active

rapid

Cytochrome P-450 2D6

1758 G/T (Allele*8/14)

active

rapid

ULTRA RAPID METABOLIZER

EXTENSIVE METABOLIZER

INTERMEDIATE METABOLIZER

POOR METABOLIZER Your result

Drug Category 2

polymorphism

condition of gene

drug metabolism

Cytochrome P-450 2C9

Arg144Cys (Allele*2)

active

rapid

Cytochrome P-450 2C9

Ile359Leu (Allele*3)

active

rapid

ULTRA RAPID METABOLIZER

EXTENSIVE METABOLIZER

INTERMEDIATE METABOLIZER

POOR METABOLIZER

Your result

Drug Category 3

polymorphism

condition of gene

drug metabolism

Cytochrome P-450 2C19

681 G/A (Allele*2)

active

rapid

ULTRA RAPID METABOLIZER

EXTENSIVE METABOLIZER

INTERMEDIATE METABOLIZER

POOR METABOLIZER

Your result

Drug Category 4

polymorphism

condition of gene

drug metabolism

NAT2

G191A

normal

NAT2

C282T

normal

NAT2

T341C

normal

NAT2

C481T

normal

NAT2

G590A

normal

NAT2

A803G

normal

NAT2

G857A

normal

ULTRA RAPID METABOLIZER

EXTENSIVE METABOLIZER

INTERMEDIATE METABOLIZER

Your result

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POOR METABOLIZER

Drug Category 5

polymorphism

condition of gene

drug metabolism

Cytochrome P-450 3A4

rs28371759 (Allele*18)

active

rapid

ULTRA RAPID METABOLIZER

EXTENSIVE METABOLIZER

INTERMEDIATE METABOLIZER

POOR METABOLIZER

Your result

Drug Category 6

polymorphism

condition of gene

drug metabolism

Cytochrome P-450 3A5

rs776746 (Allele*1)

inactive

slow

ULTRA RAPID METABOLIZER

RAPID METABOLIZER

EXTENSIVE METABOLIZER

POOR METABOLIZER

Your result

Drug Category 7

polymorphism

condition of gene

drug metabolism

Cytochrome P-450 2E1

rs72559710 (Allele*2)

active

rapid

ULTRA RAPID METABOLIZER

EXTENSIVE METABOLIZER

INTERMEDIATE METABOLIZER

POOR METABOLIZER

Your result

Drug Category 8

polymorphism

condition of gene

drug metabolism

Cytochrome P-450 1A2

rs2069514 (*1C)

inhibited

Cytochrome P-450 1A2

rs762551 (*1F)

active

very rapid

ULTRA RAPID METABOLIZER

EXTENSIVE METABOLIZER

INTERMEDIATE METABOLIZER

POOR METABOLIZER

Your result

Genetic variations SYMBOL

rs NCBI

POLYMORPH.

GENOTYPE

RESPOND

PROTECT.

RISK

NOS1AP

rs10494366

T>G

T/G

RESPOND

RISK

VKORC

rs9923231

C>T

C/C

LEGEND: ULTRA RAPID METABOLIZER = The enzymes for this group of drugs are too active and convert the medication too fast and remove it from the body. EXTENSIVE METABOLIZER = enzymes are functional and modify and break down certain drugs rapidly. INTERMEDIATE METABOLIZER = enzymes are inhibited or produced at a lower rate leading to a slower and break down of certain drugs. POOR METABOLIZER = no functional enzymes are being produced and so certain drugs are not broken down or metabolized correctly.

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SCIENCE

Pharmaco Sensor CYP2D6 - cytochrome P450, family 2, subfamily D, polypeptide 6 Cytochrome P450 2D6 (CYP2D6) is an enzyme that is involved in the metabolism of drugs through oxidation or hydrolysis of various substrates. This process is strongly influenced by the genetic variant of the CYP2D6 gene or allele. RES

Genotype

POP

URM

Result options Certain medications are metabolized too quickly, and the dosage has to be increased

70% Drugs are metabolized by this enzyme as normal Prodrugs are activated by this enzyme as normal

16% Drugs are metabolized by this enzyme at a slow rate Prodrugs can barely be activated by this enzyme

Drugs are metabolized by this enzyme at a very slow rate Prodrugs are activated by this enzyme as normal

References Zhou SF. et al. Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part I. Clin Pharmacokinet. 2009,48(11):689-723. St端ven et al. Rapid detection of CYP2D6 null alleles by long distance- and multiplex-polymerase chain reaction. Pharmacogenetics. 1996 Oct,6(5):417-21.

CYP2C9 - cytochrome P450, family 2, subfamily C, polypeptide 9 Cytochrome P450 2C9 (CYP2C9) enzyme is expressed mainly in the liver, where it is involved in the oxidation of xenobiotic and endogenous substances. CYP2C9 plays an important role in the metabolism of various drugs. Defects in the CYP2C6 gene are associated with a reduced enzyme activity. RES

Genotype

POP

Result options

77% Drugs are metabolized by this enzyme as normal Prodrugs are activated by this enzyme as normal

21% Drugs are metabolized by this enzyme at a slow rate Prodrugs can barely be activated by this enzyme

Drugs are metabolized by this enzyme at a very slow rate Prodrugs are activated by this enzyme as normal

References Van Booven D. et al. Cytochrome P450 2C9-CYP2C9 Pharmacogenetics and genomics (2010)

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VKORC - Vitamin K epoxide reductase complex (rs9923231) The vitamin K epoxide reductase-(VKOR) is a membrane protein in the ER (endoplasmic reticulum), and it is involved in the formation of blood clotting factors. The anticoagulant Warfarin inhibits the activity of the VKOR protein. This inhibition can be prevented by defects of the VKORC gene. RES

Genotype

POP

Result options

C/C

40% No dose adjustment for the blood thinner Warfarin

C/T

40% Dose adjustment (reduction) for the blood thinner Warfarin

T/T

20% Dose adjustment (reduction) for the blood thinner Warfarin

References Anderson J. L. et al. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation. 2007 Nov 27,116(22):2563-70 Flockhart D. A. et al. Pharmacogenetic testing of CYP2C9 and VKORC1 alleles for warfarin. Genet Med. 2008 Feb,10(2):139-50. International Warfarin Pharmacogenetics Consortium Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med. 2009 Feb 19,360(8):753-64.

CYP2C19 - cytochrome P450, family 2, subfamily C, polypeptide 19 The cytochrome P450 2C19 (CYP2C19) enzyme is involved in the oxidative metabolism of various drugs, such as: antidepressants, antipsychotics, tranquilizers and proton pump inhibitors. CYP2C19 provides an alternative metabolic pathway for CPY2D6. Defects in the CYP2C19 gene can increase, or decrease, the enzymatic activity. RES

Genotype

POP

Result options

69% Drugs are metabolized by this enzyme as normal Prodrugs are activated by this enzyme as normal

28% Drugs are metabolized by this enzyme at a slow rate Prodrugs can barely be activated by this enzyme

Drugs are metabolized by this enzyme at a very slow rate Prodrugs are activated by this enzyme as normal

References Sheffield L. J. et al. Clinical use of pharmacogenomic tests in 2009. Clin Biochem Rev. 2009 May,30(2):55-65. Hodgson K. et al. Genetic differences in cytochrome P450 enzymes and antidepressant treatment response. J Psychopharmacol. 2014 Feb,28(2):133-41.

NAT2 - N-acetyltransferase 2 (arylamine N-acetyltransferase) The arylamine N-acetyltransferase 2 (NAT2) is involved in the detoxification from drugs and endogenous substances through acetylation. Toxic and carcinogenic substances are converted and can be eliminated. The polymorphisms can alter the enzymatic activity of the NAT2 protein. RES

Genotype

POP

Result options

45% Drugs are metabolized by this enzyme as normal Prodrugs are activated by this enzyme as normal

30% Drugs are metabolized by this enzyme at a slow rate Prodrugs can barely be activated by this enzyme

25% Drugs are metabolized by this enzyme at a very slow rate Prodrugs are activated by this enzyme as normal

References Daly A. K. et al. Pharmacogenomics of adverse drug reactions. Genome Med. 2013 Jan 29,5(1):5. Barbieri R. B. et al. Genes of detoxification are important modulators of hereditary medullary thyroid carcinoma risk. Clin Endocrinol (Oxf). 2013 Aug,79(2):288-93. Int. braz j urol. vol.30 no.4 Rio de Janeiro Jul., Aug. 2004, Rama D. Mittal, Daya S.L. Srivastava, Anil Mandhani

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CYP3A4 - cytochrome P450, family 3, subfamily A, polypeptide 4 The cytochrome P450 3A4 (CYP3A4) is expressed in the liver, and it is involved in the activation, or hydroxylation, of various drugs and endogenous substances. RES

Genotype

POP

Result options

96% Drugs are metabolized by this enzyme as normal Prodrugs are activated by this enzyme as normal

Drugs are metabolized by this enzyme at a slow rate Prodrugs can barely be activated by this enzyme

Drugs are metabolized by this enzyme at a very slow rate Prodrugs are activated by this enzyme as normal

References Chiang TS et al. Enhancement of CYP3A4 Activity in Hep G2 Cells by Lentiviral Transfection of Hepatocyte Nuclear Factor-1 Alpha. PLoS One. 2014 Apr 14,9(4):e94885. Lee JS et al. Screening of Genetic Polymorphisms of CYP3A4 and CYP3A5 Genes. Korean J Physiol Pharmacol. 2013 Dec,17(6):479-84. Okubo M et al. CYP3A4 intron 6 C>T polymorphism (CYP3A4*22) is associated with reduced CYP3A4 protein level and function in human liver microsomes. J Toxicol Sci. 2013,38(3):349-54.

CYP3A5 - cytochrome P450, family 3, subfamily A, polypeptide 5 The cytochrome P450 3A5 (CYP3A5) is expressed in the liver, and it is involved in the activation, or hydroxylation, of various drugs and endogenous substances. RES

Genotype

POP

URM

Result options Certain medications are metabolized too quickly, and the dosage has to be increased

10% Certain medications are metabolized too quickly, and the dosage has to be increased

89% Affected drugs are metabolized as normal

References Lee JS et al. Screening of Genetic Polymorphisms of CYP3A4 and CYP3A5 Genes. Korean J Physiol Pharmacol. 2013 Dec,17(6):479-84. Roden Dan M et al. Pharmacogenomics: the genetics of variable drug responses Circulation (2011)

CYP2E1 - cytochrome P450, family 2, subfamily E, polypeptide 1 The cytochrome P450 2E1 (CYP2E1) is expressed in the liver, and it is involved in the activation, or hydroxylation, of various drugs and endogenous substances. RES

Genotype

POP

Result options

97% Drugs are metabolized by this enzyme as normal Prodrugs are activated by this enzyme as normal

Drugs are metabolized by this enzyme at a slow rate Prodrugs can barely be activated by this enzyme

Drugs are metabolized by this enzyme at a very slow rate Prodrugs are activated by this enzyme as normal

References Sheng YJ et al. The association between CYP2E1 polymorphisms and hepatotoxicity due to anti-tuberculosis drugs: A meta-analysis. Infect Genet Evol. 2014 Jun,24:34-40. De Bock L. et al. Quantification of cytochrome 2E1 in human liver microsomes using a validated indirect ELISA. J Pharm Biomed Anal. 2014 Jan 25,88:536-41.

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CYP1A2 - cytochrome P450, family 1, subfamily A, polypeptide 2 CYP1A2 (cytochrome P450 1A2) is a heme protein- enzyme involved in various metabolic processes. It metabolizes various xenobiotics such as caffeine, aflatoxin B1 and medications like paracetamol. RES

Genotype URM

POP

Result options

14% Certain medications are metabolized too quickly, and the dosage has to be increased

53% Drugs are metabolized by this enzyme as normal Prodrugs are activated by this enzyme as normal

28% Drugs are metabolized by this enzyme at a slow rate Prodrugs can barely be activated by this enzyme

Drugs are metabolized by this enzyme at a very slow rate Prodrugs are activated by this enzyme as normal

References Hubacek JA. et al. Drug metabolising enzyme polymorphisms in Middle- and Eastern-European Slavic populations. Drug Metabol Drug Interact. 2014,29(1):29-36.

NOS1AP - Nitric oxide synthase 1 (neuronal) adaptor protein (rs10494366) The nitric oxide synthase 1 adaptor protein (NOS1AP) is an adapter protein which binds the signal molecule nNOS (neuronal nitric oxide synthase) with other molecules, facilitating their interaction. This NOS1AP polymorphism decreases the glucose-reducing effect of different drugs and is associated with an increased mortality rate. RES

Genotype

POP

Result options

T/T

30% The drug Glibenclamide is effective The drug Sulfonyluria is effective The drug Tolbutamide is less effective/mortality rate is increased when using this drug The drug Glimepiride less effective/mortality rate is increased when using this drug

G/T

44% The drug Glibenclamide is less effective/mortality rate is increased when using this drug The drug Sulfonyluria is less effective/mortality rate is increased when using this drug The drug Tolbutamide is effective The drug Glimepiride is effective

G/G

26% The drug Glibenclamide is less effective/mortality rate is increased when using this drug The drug Sulfonyluria is less effective/mortality rate is increased when using this drug The drug Tolbutamide is effective The drug Glimepiride is effective

References Tomรกs M et al. Polymorphisms in the NOS1AP gene modulate QT interval duration and risk of arrhythmias in the long QT syndrome. JACC. 2010 Jun 15,55(24):2745-52. Treuer AV et al. NOS1AP modulates intracellular Ca(2+) in cardiac myocytes and is up-regulated in dystrophic cardiomyopathy. Int J Physiol Pathophysiol Pharmacol. 2014 Mar 13,6(1):37-46. eCollection 2014. Becker et al. Common variation in the NOS1AP gene is associated with reduced glucose-lowering effect and with increased mortality in users of sulfonylurea. Pharmacogenet Genomics. 2008 Jul,18(7):591-7.

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PROSTATE HEALTH SENSOR Effective prevention and treatment of prostate cancer • Genetic assessment of prostate cancer risk • Genetic assessment of the prostate hyperplasia risk • Extensive testing with more than 9 genetic variations • Analysis of 13 genetic variations, for the effect of 40 + relevant drugs • Effective preventive measures and timely early diagnosis • Better chances of recovery through optimal drug therapy • Change of lifestyle to reduce the risk of disease • Medical monitoring for optimal prevention

Prevention Early diagnosis Treatment

ANDROLOGY

Prostate The prostate is a sex gland. It lies below the bladder, near the beginning of the urethra, and is about the size and shape of a chestnut. It consists of several glands that produce a secretion that is discharged during ejaculation into the urethra, where it is mixed with the sperm. Thus, it plays an important role in reproduction. Unfortunately, the prostate is also associated with a number of diseases, some of which can be serious or even fatal. As a result, every man should undergo an annual examination of the prostate after the age of 45. Benign prostatic hyperplasia (BPH) is a noncancerous enlargement of the prostate gland caused by the abnormal proliferation of certain cells. The disease is very common and usually develops with age. The risk of an enlarged prostate depends on genetic and lifestyle factors. About 10-20% of men between age 50 and 59 have this condition, and 25-35% of men in between 60 and 69. In contrast to prostate cancer, the symptoms of prostate enlargement develop very rapidly. Typical symptoms are: pain during urination; frequent urination; difficult, long-lasting urination supported by abdominal pressure. If the bladder is significantly obstructed, urine may accumulate in the kidney, which can cause a life-threatening condition. An enlarged prostate can be treated either with medication, depending on the extent, or reduced surgically using a laser beam. However, the best option remains prevention. Since benign enlargement of the prostate is closely related to an unfortunate combination of genes and lifestyle, modifications in lifestyle can greatly reduce the risk of disease for genetically predisposed people. Prostate cancer is one of the most common cancers for men. About 15% of men will be diagnosed with prostate cancer at some point in life. In most cases, prostate cancer does

not produce symptoms until it has progressed, and so it is usually detected only at a later stage through symptoms such as urinary symptoms, bone pain, weight loss, and anemia. The main complaints arising are referring to urination disorders: delayed onset, a weak jet, drip or the interruption of the urinary stream during urination. Residual urine often remains in the bladder. Other frequently observed symptoms include: increased or predominantly nocturnal urination, frequent urination in small quantities, difficulty, or pain when urinating. Due to pressure damage to nerves of the sacrum area, erection problems may also occur. Visible blood in the urine or sperm is rare but significant. A prostate tumor does not cause discomfort, and so symptoms usually appear only after the tumor has spread to nearby lymph nodes or into the bones. At that point, the most common symptoms are pain in the spine and pelvis. In most cases, bone metastases are the predominant disease, and they are also the most common cause of death from prostate cancer. The advanced stage is often accompanied by anemia and weight loss. Prostate cancer can only be treated successfully before it has spread, so early detection is crucial for effective treatment. That is why men over the age of 45 should be tested annually for prostate cancer.

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Treatment options include surgery with complete removal of the prostate, radiation therapy, hormone therapy, and in some cases, chemotherapy. If the cancer is treated early, before spreading to other tissues, the 5-year survival rate is approximately 90%. After the cancer spreads, the 5-years survival rate is only around 35%, which is why early detection is so important. The lifetime risk for the diagnosis of "prostate cancer" is about 11%. It is estimated that approximately 20% of patients with prostate cancer die. About half of the cases of prostate cancer are caused by genetic variations. Now it is possible to test these genes and to determine the personal risk prior to the occurrence of prostate cancer. If the risk is significantly increased, a preventive program can significantly reduce the risk of developing of the disease. Additionally, you can detect potential diseases at an early stage through a more intensive monitoring program and allow for its timely treatment. More serious and unpleasant consequences can be prevented in most cases.

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ANDROLOGY

Relevant genes for prostate Several genetic variations have been identified, which taken individually slightly increase or decrease the risk of prostate cancer. Taken together, they have a significant impact on the risk probability. The analysis of relevant genetic variations came to the following conclusion:

Genetic risks and traits SYMBOL

rs NCBI

POLYMORPH.

GENOTYPE

RESPOND

PROTECTIV E

RISK

TCF2

rs4430796

G>A

G/G

LOC124685

rs1859962

T>G

T/T

8q24 region 2

rs16901979

C>A

C/C

8q24 region 3

rs6983267

T>G

T/T

8q24 Region 1

rs1447295

C>A

C/C

VDR

rs2107301

C>T

T/T

2.47

RISK

8q24

rs4242382

G>A

A/A

2.1

RISK

8q24

rs7837688

T>G

T/T

8q24

rs2011077

A>G

A/A

RNASEL

rs627928

G>T

G/G

LEGEND: rsNCBI = description of investigated genetic variation, polymorphism = form of genetic variation, ODDS RATIO = X-times risk of disease triggered by polymorphism, genotype = personal analysis result, RESPONDER = your body is particularly sensitive because of your genetic traits, PROTECTIVE = your genetic traits give you some protection against the disease, RISK = this genetic variation increases your risk of disease.

Page 18 of 81

Summary of effects Here you can see a summary of the impact your genetic variations have on your health and your body: ➤ Your risk of developing prostate cancer is lower than that of the general population. What is your risk of prostate cancer? LOW

AVERAGE RISK

HIGHER

▲

When are checkups recommended? FROM 45 YEARS

EARLIER

▲

Page 19 of 81

ANDROLOGY

Prevention Your disease risk is normal. You should follow the general rules of a healthy life and get a prostate exam every year from age 45 forward. In this way, the age-related (nongenetic) forms of prostate diseases can be recognized and treated in time.

Page 20 of 81

ANDROLOGY

Effect on relevant drugs Your genetic profile has an impact on the effect of drugs prescribed for prostate cancer and associated diseases. This information can help your doctor choose the correct dosage of the right medications to minimize side effects.

Painkillers (analgesics) Painkillers

effect

Breakdown

Adverse Reaction

recommended dose*

alternative?

alfentanil

Normal

~100%

Normal

~100%

Not neccessary

buprenorphine

Normal

~100%

Normal

~100%

Not neccessary

codeine (FDA!)

likely higher

~20%

common

~20%

Advisable

enflurane

Normal

~100%

Normal

~100%

Not neccessary

fentanyl

Normal

~100%

Normal

~100%

Not neccessary

halothane

Normal

~100%

Normal

~100%

Not neccessary

hydrocodone

Normal

~0%

common

Advisable

isoflurane

Normal

~100%

Normal

~100%

Not neccessary

levacetylmethadol

likely higher

~100%

Normal

~100%

Not neccessary

lidocaine

Normal

~100%

Normal

~100%

Not neccessary

methadone

Normal

~90%

Normal

~100%

Not neccessary

methoxyflurane

Normal

~100%

Normal

~100%

Not neccessary

oxycodone

Normal

~0%

common

Advisable

paracetamol

Normal

~100%

Normal

~100%

Not neccessary

phenacetin

Normal

~100%

Normal

~100%

Not neccessary

ropivacaine

Normal

~100%

Normal

~100%

Not neccessary

sevoflurane

Normal

~100%

Normal

~100%

Not neccessary

tramadol (FDA!)

likely higher

~40%

common

~50%

Advisable

zolmitriptan

Normal

~100%

Normal

~100%

Not neccessary

Adverse Reaction

recommended dose*

alternative?

Drugs for traveling sickness (antiemetic) Drugs for easing the feeling of sickness

effect

Breakdown

aprepitant

Normal

~100%

Normal

~100%

Not neccessary

dolasetron

Normal

~0%

common

Advisable

domperidone

Normal

~100%

Normal

~100%

Not neccessary

metoclopramide

Normal

~0%

common

Advisable

Page 21 of 81

Anti-cancer drugs (chemotherapy) Drugs for the treatment and prevention of cancer

effect

Breakdown

Adverse Reaction

recommended dose*

alternative?

anastrozole

Normal

~100%

Normal

~100%

Not neccessary

cyclophosphamide

likely higher

~100%

Normal

~100%

Not neccessary

docetaxel

Normal

~100%

Normal

~100%

Not neccessary

doxorubicin

Normal

~100%

Normal

~100%

Not neccessary

erlotinib

Normal

~100%

Normal

~100%

Not neccessary

etoposide

Normal

~100%

Normal

~100%

Not neccessary

gefitinib

Normal

~100%

Normal

~100%

Not neccessary

ifosfamide

likely higher

~100%

Normal

~100%

Not neccessary

imatinib

likely higher

~100%

Normal

~100%

Not neccessary

nilutamide

Normal

~100%

Normal

~100%

Not neccessary

paclitaxel

Normal

~100%

Normal

~100%

Not neccessary

sorafenib

Normal

~100%

Normal

~100%

Not neccessary

sunitinib

likely higher

~100%

Normal

~100%

Not neccessary

tamoxifen (FDA!)

likely higher

~10%

common

Advisable

temsirolimus

Normal

~100%

Normal

~100%

Not neccessary

teniposide

Normal

~100%

Normal

~100%

Not neccessary

vemurafenib

Normal

~100%

Normal

~100%

Not neccessary

vinblastine

Normal

~100%

Normal

~100%

Not neccessary

vincristine

Normal

~50%

common

~50%

Advisable

vindesine

Normal

~100%

Normal

~100%

Not neccessary

Recommended dosage for the doctor: ~ 100% (simply use the normal dosage), ~ 20% (start with a low dosage and if necessary increase it under supervision), 0% (if possible use an alternative drug), 200% (start normally at 100% dosage and if necessary increase up to 200%)

REMEMBER: Only your doctor can prescribe the correct drugs and dosage. NEVER stop taking a drug or change the dose: consult your doctor instead!

Page 22 of 81

SCIENCE

Prostate Health Sensor TCF2 - Transcription factor 2 (rs4430796) The transcription factor 2 (TCF-2 or HNF1B) forms a heterodimer with TCF1, and activates, or inhibits, the expression of different target genes. The polymorphism rs4430796 is associated with an increased risk of prostate cancer. RES

Genotype

POP

A/A

18%

A/G

56% No increased risk of prostate cancer

G/G

26% No increased risk of prostate cancer

Result options Increased risk of prostate cancer (OR: 1.4)

References Zheng et al. Cumulative association of five genetic variants with prostate cancer. N Engl J Med. 2008 Feb 28,358(9):910-9. Levin et al. Chromosome 17q12 variants contribute to risk of early-onset prostate cancer. Cancer Res. 2008 Aug 15,68(16):6492-5. Gudmundsson et al. Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes. Nat Genet. 2007 Aug,39(8):977-83.

LOC124685 - Myosin, light chain 6, alkali, smooth muscle and non-muscle pseudogene (rs1859962) A genome-wide association study has shown that the polymorphism rs1859962 on chromosome 17q24.3 is associated with an increased risk of prostate cancer. RES

Genotype

POP

Result options

T/T

24% No increased risk of prostate cancer

T/G

57% No increased risk of prostate cancer

G/G

19%

Increased risk of prostate cancer (OR: 1.28)

References Sun et al. Cumulative effect of five genetic variants on prostate cancer risk in multiple study populations. Prostate. 2008 Sep 1,68(12):1257-62. Levin et al. Chromosome 17q12 variants contribute to risk of early-onset prostate cancer. Cancer Res. 2008 Aug 15,68(16):6492-5. Zheng et al. Cumulative association of five genetic variants with prostate cancer. N Engl J Med. 2008 Feb 28,358(9):910-9

8q24 region 2 (rs16901979) Several studies have shown that different polymorphisms on 8q24 increase the risk of prostate cancer. RES

Genotype

POP

A/A

Increased risk of prostate cancer (OR: 1.53)

A/C

Increased risk of prostate cancer (OR: 1.53)

C/C

94% No increased risk of prostate cancer

Result options

References Zheng et al. Cumulative association of five genetic variants with prostate cancer. N Engl J Med. 2008 Feb 28,358(9):910-9 Cheng et al. 8q24 and prostate cancer: association with advanced disease and meta-analysis. Eur J Hum Genet. 2008 Apr,16(4):496-505. Levin et al. Chromosome 17q12 variants contribute to risk of early-onset prostate cancer. Cancer Res. 2008 Aug 15,68(16):6492-5.

Page 23 of 81

8q24 region 3 (rs6983267) Several studies have shown that different polymorphisms on 8q24 increase the risk of prostate cancer. RES

Genotype

POP

Result options

T/T

24% No increased risk of prostate cancer

T/G

55% Increased risk of prostate cancer (OR: 1.25)

G/G

21%

Increased risk of prostate cancer (OR: 1.25)

References Haiman et al. A common genetic risk factor for colorectal and prostate cancer. Nat Genet. 2007 Aug,39(8):954-6. Yeager et al. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat Genet. 2007 May,39(5):645-9. Epub 2007 Apr 1. Zheng et al. Cumulative association of five genetic variants with prostate cancer. N Engl J Med. 2008 Feb 28,358(9):910-9. Cheng et al. 8q24 and prostate cancer: association with advanced disease and meta-analysis. Eur J Hum Genet. 2008 Apr,16(4):496-505.

8q24 region 1 (rs1447295) Several studies have shown that different polymorphisms on 8q24 increase the risk of prostate cancer. RES

Genotype

POP

A/A

Increased risk of prostate cancer (OR: 1.22)

A/C

12%

Increased risk of prostate cancer (OR: 1.22)

C/C

87% No increased risk of prostate cancer

Result options

References Zheng et al. Association between two unlinked loci at 8q24 and prostate cancer risk among European Americans. J Natl Cancer Inst. 2007 Oct 17,99(20):1525-33. Epub 2007 Oct 9. Amundadottir et al. A common variant associated with prostate cancer in European and African populations. Nat Genet. 2006 Jun,38(6):652-8. Epub 2006 May 7. Freedman et al. Admixture mapping identifies 8q24 as a prostate cancer risk locus in African-American men. Proc Natl Acad Sci U S A. 2006 Sep 19,103(38):14068-73. Epub 2006 Aug 31.

VDR - vitamin D (1,25- dihydroxyvitamin D3) receptor (rs2107301) The VDR gene encodes the vitamin D receptor, part of the steroid receptors family. It is a transcription factor that regulates the activity of specific target genes, and thus affects the metabolism. The rs2107301 polymorphism is associated with an increased risk of prostate cancer. RES

Genotype

POP

Result options

T/T

T/C

36% Increased risk of prostate cancer (OR: 1.11)

C/C

56% No increased risk of prostate cancer

Increased risk of prostate cancer (OR: 2.47)

References Sch채fer et al. No association of vitamin D metabolism-related polymorphisms and melanoma risk as well as melanoma prognosis: a case-control study. Arch Dermatol Res. 2012 Jul,304(5):353-61. Holt et al. Vitamin D pathway gene variants and prostate cancer risk. Cancer Epidemiol Biomarkers Prev. 2009 Jun,18(6):1929-33. Holick et al. Comprehensive association analysis of the vitamin D pathway genes, VDR, CYP27B1, and CYP24A1, in prostate cancer. Cancer Epidemiol Biomarkers Prev. 2007 Oct,16(10):1990-9.

Page 24 of 81

8q24 (rs4242382) Several studies have shown that different polymorphisms on 8q24 increase the risk of prostate cancer. RES

Genotype

POP

Result options

A/A

Increased risk of prostate cancer (OR: 2.1)

A/G

14%

Increased risk of prostate cancer (OR: 1.91)

G/G

85% No increased risk of prostate cancer

References Zheng et al. Association between two unlinked loci at 8q24 and prostate cancer risk among European Americans. J Natl Cancer Inst. 2007 Oct 17,99(20):1525-33. Epub 2007 Oct 9. Zheng et al. Cumulative association of five genetic variants with prostate cancer. N Engl J Med. 2008 Feb 28,358(9):910-9. Fitzgerald et al. Analysis of recently identified prostate cancer susceptibility loci in a population-based study: associations with family history and clinical features. Clin Cancer Res. 2009 May 1,15(9):3231-7.

8q24 (rs7837688) Several studies have shown that different polymorphisms on 8q24 increase the risk of prostate cancer. RES

Genotype

POP

Result options

T/T

No increased risk of prostate cancer

T/G

14%

Increased risk of prostate cancer (OR: 1.91)

G/G

85% Increased risk of prostate cancer (OR: 1.67)

References Zheng et al. Association between two unlinked loci at 8q24 and prostate cancer risk among European Americans. J Natl Cancer Inst. 2007 Oct 17,99(20):1525-33. Epub 2007 Oct 9. Zheng et al. Cumulative association of five genetic variants with prostate cancer. N Engl J Med. 2008 Feb 28,358(9):910-9. Lindstrom et al. Characterizing associations and SNP-environment interactions for GWAS-identified prostate cancer risk markers--results from BPC3. PLoS One. 2011 Feb 24,6(2):e17142.

8q24 (rs2011077) Several studies have shown that different polymorphisms on 8q24 increase the risk of prostate cancer. RES

Genotype

POP

Result options

A/A

A/G

32% Increased risk of prostate cancer (OR: 2.4)

No increased risk of prostate cancer

G/G

64% Increased risk of prostate cancer (OR: 6.2)

References Ma et al. Polymorphisms of fibroblast growth factor receptor 4 have association with the development of prostate cancer and benign prostatic hyperplasia and the progression of prostate cancer in a Japanese population. Int J Cancer. 2008 Dec 1,123(11):2574-9.

Page 25 of 81

RNASEL - Ribonuclease L (2',5'-oligoisoadenylate synthetase-dependent) (rs627928) RNase L, encoded by the RNASEL gene, is a ribonuclease that metabolizes viral and cellular RNA. The rs627928 polymorphism is associated with an increased risk of prostate cancer. RES

Genotype

POP

T/T

15%

Increased risk of prostate cancer (OR: 1.4)

T/G

51%

Increased risk of prostate cancer (OR: 1.24)

G/G

34% No increased risk of prostate cancer

Result options

References Mi et al. An update analysis of two polymorphisms in encoding ribonuclease L gene and prostate cancer risk: involving 13,372 cases and 11,953 controls. Genes Nutr. 2011 Nov,6(4):397-402. Breyer et al. Genetic variants and prostate cancer risk: candidate replication and exploration of viral restriction genes. Cancer Epidemiol Biomarkers Prev. 2009 Jul,18(7):2137-44. Li et al. RNASEL gene polymorphisms and the risk of prostate cancer: a meta-analysis. Clin Cancer Res. 2006 Oct 1,12(19):5713-9.

Page 26 of 81

Prevention Early diagnosis Treatment

CARDIOVASCULAR SENSOR Prevention and treatment of lipid metabolism problems • Analysis of more than 18 genetic variations • Identify the predisposition to high cholesterol (HDL and LDL), homocysteine and triglyceride levels • Is Omega-3 beneficial for cholesterol? • Identify the predisposition to sudden cardiac death (long QT interval) • Suitable micronutrients and diet for prevention and treatment • Analysis of more than 17 genetic variations, for the effect of 26 + relevant drugs • Better chances of recovery through optimal drug therapy • Medical monitoring for optimal prevention

CARDIOVASCULAR SYSTEM

Cardiovascular Disease Cholesterol and triglycerides are vital fats our body uses to produce cell membranes, store energy, absorb fat-soluble vitamins and produce hormones. These fats are so essential that our body even produces cholesterol itself. This cholesterol is then transported and made available for cell growth all over the body via the bloodstream. In this manner, our body produces about 70% of the cholesterol it needs itself. The other 30% comes from what we eat. The amount of cholesterol in your bloodstream goes up after every meal. To control this, your body has strict regulatory processes that maintain your blood cholesterol at normal levels. If there is too much cholesterol in your bloodstream, your body transports HDL to your liver, which filters it from your blood, lowering your cholesterol level. However, the liver will release LDL cholesterol into your bloodstream, which increases your cholesterol level. High cholesterol levels may cause arteriosclerosis, and so a low cholesterol level helps you stay healthy. Because of this, HDL cholesterol--the kind transported to the liver--is called "good" cholesterol, whereas LDL cholesterol--which the liver emits into the bloodstream--is called "bad" cholesterol.

That is why it is important for your health to maintain a high HDL and a low LDL cholesterol level. A number of genes are responsible for regulating cholesterol and triglyceride levels or for increasing the risk of cardiovascular disease. If you carry an adverse trait in one or more of these genes, you should pay special attention to your fat intake and metabolism. Since diet is the most significant influence on your body's lipid metabolism, it is important to follow a diet tailored to your genes.

Page 28 of 81

Arrhythmia Long QT syndrome is a life-threatening disease that can lead to sudden cardiac death in people with otherwise perfect health. The heartbeat is triggered by a recurring electrical pulse, which propagates through the heart. The time to initiate a heartbeat up to the point at which the cells are ready for the next heartbeat, is called the QT interval. If this interval is particularly long, it increases the risk of symptoms such as paroxysmal tachycardia, arrhythmia, vertigo or loss of consciousness. In severe cases, such episodes end in cardiac arrest due to ventricular fibrillation. However, most people with this condition have no symptoms until a life-threatening condition develops. The symptoms usually occur during physical exertion or stressful situations. A resting ECG (a measurement of the heart rate in the resting state) and a gene analysis help to better identify the risk. A long QT interval is usually not noticeable: more than half of the patients with long QT syndrome experience no symptoms. When symptoms do occur, they are caused by potentially lifethreatening heart rhythm disorders that are signs of serious disease. Palpitations may be sustained (more than 30 seconds) or intermittent, and sometimes remain unnoticed depending on the following: the duration and pulse rate, body position and the general constitution, dizziness, loss of consciousness or even cardiac arrest. Thus, they may lead to sudden cardiac death. Since tachycardia occurs suddenly and usually during exercise or in stressful situations, the symptoms are often unexpected, and observed because they affect our general state of well-being. People with this genetic risk should take steps to minimize symptoms. The steps include medical heart rate monitoring in high-risk situations such as cardiovascular disease, diabetes, morbid obesity, age over 55 years, extreme physical activity, and taking certain medications. If a prolonged QT interval is diagnosed in these situations, medical treatment may be necessary. Thanks to genetic analysis, you can find out if you are in a risk group and take the necessary precautions. Serious consequences such as sudden death can usually be prevented. Page 29 of 81

CARDIOVASCULAR SYSTEM

Relevant genes for cardiovascular disease The scientific community has linked several genes and polymorphisms to a risk of various cardiovascular diseases. An analysis of these polymorphisms allows us to determine your genetic risk for these diseases as well as some other genetic traits linked to this disease.

Cardiovascular sensor (cardiovascular disease) SYMBOL

rs NCBI

POLYMORPH.

GENOTYPE

RESPOND

PROTECT.

RISK

CHD13

rs8055236

G>T

T/G

RISK

CHDS8

rs1333049

G>C

G/G

APOA5

rs662799

-1131T>C

A/A

PON1

rs662

Q192R

A/A

PON1

rs854560

L55M

T/T

APOB

rs5742904

R3500Q

A/G

RISK

SREBF2

rs2228314

Gly595Ala

G/G

RISK

NOS3

Ins/Del Int. 4

Ins/Del Intron 4

Ins/Ins

NOS3

rs2070744

-786 T/C

C/C

RISK

NOS3

rs1799983

Glu298Asp

G/G

APOA1

rs670

-75G > A

A/G

RESPOND

RISK

MTRR

rs1801394

Ile22Met

G/A

RISK

MMP3

rs3025058

5A/6A

T/T

RISK

GJA4

rs1764391

Pro319Ser

C/C

RISK

ITGB3

rs5918

Leu33Pro

T/T

RESPOND

CETP

rs708272

Taq1(B1>B2)

C/C

RISK

MTHFR

rs1801133

C>T

T/T

RESPOND

RISK

APOE

rs429358

T>C

T/T

APOE

rs7412

T>C

T/T

ApoE type

combination

E2/E3/E4

E2/E2

RESPOND

NOS1AP

rs16847548

T>C

T/T

NOS1AP

rs12567209

G>A

G/G

NOS1AP

rs10494366

T>G

T/G

RESPOND

RISK

Page 30 of 81

Summary of effects This analysis examines numerous genes that contribute to risks for several different cardiovascular conditions. Many of these risk variations are common, and almost everyone has some genes that increase the risk of cardiovascular disease. If you have an unusually small number of genes that increase risk, your genes may actually reduce your risk of developing cardiovascular disease. Here you can see a summary of the influence your genetic variations have on your health and body: ➤ ➤ ➤ ➤ ➤ ➤ ➤

Compared to the average person, you have a 3.6 -times higher risk of coronary heart disease You have a high predisposition for high LDL cholesterol levels You have a slight predisposition for high triglyceride levels Vitamin B2 lowers your homocysteine levels Omega-3 fatty acids improve your cholesterol levels Aspirin can be effective in preventing thrombosis in risk situations Predisposition for slightly lowered HDL cholesterol values

Your risk of coronary heart disease, atherosclerosis and heart attack PROTECTION

AVERAGE RISK

INCREASED

▲ Your LDL cholesterol levels are likely to be

The effect of omega-3 on HDL cholesterol

NORMAL

IMPROVEMENT

INCREASED

▲ Your HDL cholesterol levels are likely to be NORMAL

LOW

▲ Your triglyceride levels are likely to be NORMAL INCREASED

▲

Your homocysteine levels are likely to be NORMAL INCREASED

Effect of vitamin B2 on homocysteine REDUCTION

DETERIORATION

Effect of aspirin on thrombosis (blood clots) PROTECTION NO EFFECT

▲

Risk of sudden cardiac death (QT) NORMAL

▲

Page 31 of 81

INCREASED

CARDIOVASCULAR SYSTEM

Prevention You have an elevated risk for coronary disease, and so it is particularly important for you to take preventative measures to reduce your risk. You should take steps to keep your cholesterol and triglycerides within normal levels. Discuss this issue with your doctor, and start an observation program based on your doctor's recommendation. The preventive measures and treatment options for cholesterol and triglycerides are listed separately. Talk to your doctor about putting these measures into practice. Preventive measures ➤ Do sports or regular exercise. The best exercises are endurance sports (walking, Nordic walking, cycling, swimming, weight training, etc.), and watch your weight. Ideally, you should do at least 30 minutes of exercises, 5 days a week. ➤ Smoking greatly increases your risk for vascular disease along with its many other health effects. Quitting smoking is one of the most important ways to improve your health. ➤ Keep alcohol consumption low (no more than one alcoholic beverage per day). ➤ In general, eat low-fat meals (fish, poultry and lean meats are recommended, but fatty meats like sausages, bacon, and fat cheese should be reduced). ➤ You should also eat only low-fat dairy products, for example low-fat milk, low fat cheese and low-fat yogurt. ➤ Eat as little animal products as possible, and use mainly vegetable oils. ➤ Eat fruits and vegetables multiple times during the day.

Omega-3-fatty acids ➤ Omega-3 fatty acids are usually recommended for high cholesterol, but for certain genetic types it can also worsen HDL-cholesterol. Based on your genes, Omega-3 improves your cholesterol levels.

Medical treatment is recommended when changes to diet and exercise do not lower cholesterol and triglycerides to a normal level. There are multiple options: statins, bile acid binders, fibrates, niacin (vitamin B3), cholesterol synthesis and absorption inhibitors. Your doctor will decide which drug is suitable for you. It is particularly important to take action to prevent heart disease because treatments followed after symptoms develop can only slow down the progress of the disease.

QT interval and sudden cardiac death As you are predisposed to have a long QT interval, you should take the following precautions, to avoid more serious complications. For you, it is important to understand the situations that create risk and to monitor your heart closely.

If you are exposed to the following risk factors it is strongly recommended that you have a physician determine the length of the QT intervals: ➤ ➤ ➤ ➤

Ischemia (circulatory disorder) Diabetes type 2 (diabetes) Metabolic Syndrome (severe overweight) Age over 55

If you are engaged in vigorous or difficult physical labor, your electrolyte level will drop. During these Page 32 of 81

events, regular electrolyte level testing should be performed, to detect abnormalities and allow for timely treatment. Prior to the taking medication that can affect the QT interval, you should have a resting ECG should be performed. Talk to your doctor about your genetic risk and the medications you are taking. In the context of a possible pharmacogenetic investigation by our laboratory, due to a possible QT prolonging effect, these drugs may influence the results. Your doctor should assess this based on your QT interval.

The following drug groups might not be appropriate: ➤ ➤ ➤ ➤ ➤ ➤ ➤ ➤

Antiarrhythmics Antiasthmatic Aerosols Antidepressants Antimalarial drugs Fluoroquinolones Macrolides Tamoxifen

This includes the following active ingredients (arranged alphabetically): Albuterol, Albuterol, Alfuzosin, Amantadine, Amiodarone, Amiodarone, Amitriptyline, Amphetamine, Amphetamine, Arsenic trioxide, Astemizole, Atazanavir, Atomoxetine, Azithromycin, Bepridil, Chloral hydrate, Chloroquine, Chlorpromazine, Ciprofloxacin, Cisapride, Citalopram, Clarithromycin, Clomipramine, Clozapine, Desipramine, Dexmethylphenidate, Diphenhydramine, Diphenhydramine, Disopyramide, Dobutamine, Dofetilide, Dolasetron, Domperidone, Dopamine, Doxepin, Dronedarone, Droperidol, Ephedrine, Ephedrine, Epinephrine, Epinephrine, Erythromycin, Erythromycin, Felbamate, Fenfluramine, Flecainide, Fluconazole, Fluoxetine, Fluoxetine, Foscarnet, Fosphenytoin, Galantamine, Gatifloxacin, Gemifloxacin, Granisetron, Halofantrine, Haloperidol, Ibutilide, Imipramine, Indapamide, Isoproterenol, Isoproterenol, Isradipine, Itraconazole, Ketoconazole, Lapatinib, Lapatinib, Levalbuterol, Levofloxacin, Levomethadyl, Lisdexamfetamine, Lithium, Lithium, Mesoridazine, Metaproterenol, Metaproterenol, Methadone, Methadone, Methylphenidate, Methylphenidate, Mexiletine, Midodrine, Moexipril/HCTZ, Moxifloxacin, Nicardipine, Nilotinib, Norepinephrine, Nortriptyline, Octreotide, Ofloxacin, Ondansetron, Oxytocin, Paliperidone, Paroxetine, Pentamidine, Pentamidine, Perflutren lipid microspheres, Phentermine, Phentermine, Phenylephrine, Phenylpropanolamine, Phenylpropanolamine, Pimozide, Probucol, Procainamide, Procainamide, Protriptyline, Pseudoephedrine, Pseudoephedrine, Quetiapine, Quinidine, Quinidine, Ranolazine, Risperidone, Ritodrine, Ritonavir, Roxithromycin, Salmeterol, Sertindole, Sertindole, Sertraline, Sibutramine, Solifenacin, Sotalol, Sparfloxacin, Sunitinib, Tacrolimus, Tamoxifen, Telithromycin, Terbutaline, Terfenadine, Thioridazine, Tizanidine, Tolterodine, Tolterodine, Trazodone, Trimethoprim-Sulfa, TrimethoprimSulfa, Trimipramine, Vardenafil, Venlafaxine, Voriconazole, Ziprasidone

Attention: Never decide by yourself to discontinue a medically prescribed medication. Only a doctor can decide this.

Page 33 of 81

CARDIOVASCULAR SYSTEM

Effect on relevant drugs Your genetic profile has an impact on the effect of drugs prescribed for cardiovascular disease. This information can help your doctor choose the correct dosage of the right medications to minimize side effects.

Drugs for heart problems (anti-arrhythmic) Drugs for the treatment of heart problems

effect

Breakdown

Adverse Reaction

recommended dose*

alternative?

amiodarone

Normal

~100%

Normal

~100%

Not neccessary

dronedarone

Normal

~100%

Normal

~100%

Not neccessary

encainide

Normal

~0%

common

Advisable

flecainide

Normal

~0%

common

Advisable

mexiletine

Normal

~0%

common

Advisable

procainamide

Normal

~100%

Normal

~100%

Not neccessary

propafenone (FDA!)

likely higher

~40%

common

~50%

Advisable

quinidine (FDA!)

Normal

~33%

common

~20%

Advisable

sparteine

Normal

~0%

common

Advisable

Drugs for the treatment of high blood pressure, cardiac insufficiency and cardiac arrhythmia

effect

Breakdown

Adverse Reaction

recommended dose*

alternative?

alprenolol

Normal

~0%

common

Advisable

carvedilol (FDA!)

Normal

~20%

common

~20%

Advisable

cilostazol

Normal

~100%

Normal

~100%

Not neccessary

debrisoquine

Normal

~0%

common

Advisable

eplerenone

Normal

~100%

Normal

~100%

Not neccessary

hydralazine (FDA!)

Normal

~100%

Normal

~100%

Not neccessary

isosorbide-dinitrate (FDA!)

Normal

~100%

Normal

~100%

Not neccessary

metoprolol (FDA!)

Normal

~0%

common

Advisable

nebivolol

Normal

~0%

common

Advisable

perhexiline

Normal

~0%

common

Advisable

propranolol (FDA!)

Normal

~20%

common

~20%

Advisable

s-metoprolol

Normal

~0%

common

Advisable

timolol

Normal

~0%

common

Advisable

Beta blockers

Page 34 of 81

Cholesterol-lowering drugs (Statins) Drugs for lowering cholesterol

effect

Breakdown

Adverse Reaction

recommended dose*

alternative?

atorvastatin

Normal

~100%

Normal

~100%

Not neccessary

cerivastatin

Normal

~100%

Normal

~100%

Not neccessary

fluvastatin

Normal

~100%

Normal

~100%

Not neccessary

lescol

Normal

~100%

Normal

~100%

Not neccessary

lovastatin

likely higher

~100%

Normal

~100%

Not neccessary

REMEMBER: Only your doctor can prescribe the correct drugs and dosage. NEVER stop taking a drug or change the dose: consult your doctor instead!

Page 35 of 81

SCIENCE

Cardiovascular Sensor CDH13 - Cadherin 13 (rs8055236) The CDH13 gene encodes a protein of the cadherin superfamily. The protein is localized on the cell membrane, and it is expressed, inter alia, in the heart, in the aortic wall, in neurons, and in the spinal cord. The polymorphism rs8055236 is associated with an increased risk of heart diseases. RES

Genotype

POP

T/T

T/G

34% Increased risk of coronary heart disease (OR: 1.91)

G/G

64% Increased risk of coronary heart disease (OR: 2.23)

Result options No increased risk of disease

References The Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Linnea M. Baudhuin. Genetics of coronary artery disease: focus on genome-wide association studies. Am J Transl Res. 2009, 1(3): 221â&#x20AC;&#x201C;234.

CHDS8 - Coronary heart disease, susceptibility to, 8 (rs1333049) The polymorphism rs1333049 on gene CHDS8 (Coronary heart disease, susceptibility to, 8) has been repeatedly associated with an increased risk of heart diseases. RES

Genotype

POP

Result options

G/G

30% No increased risk of disease

G/C

50% Increased risk of coronary heart disease (OR: 1.47)

C/C

20% Increased risk of coronary heart disease (OR: 1.9)

References Bilguvar K. et al. Susceptibility loci for intracranial aneurysm in European and Japanese populations. Nat Genet. 2008 Dec,40(12):1472-7. Helgadottir A. et al. The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm. Nat Genet. 2008 Feb,40(2):217-24. Helgadottir A. et al. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science. 2007 Jun 8,316(5830):1491-3. Karvanen J. et al. The impact of newly identified loci on coronary heart disease, stroke and total mortality in the MORGAM prospective cohorts. Genet Epidemiol. 2009 Apr,33(3):237-46.

Page 36 of 81

APOA5 - Apolipoprotein A-V (rs662799) The protein encoded by this gene is an apolipoprotein and an important determinant of plasma triglyceride levels, a major risk factor for coronary artery disease. It is a component of several lipoprotein fractions including VLDL, HDL, chylomicrons. It is believed that apoA-V affects lipoprotein metabolism by interacting with LDL-R gene family receptors. Studies have shown, that carriers of the G-Allele experience low weight gain when eating a fatty diet. RES

Genotype

POP

Result options

A/A

96% No increased risk of disease

A/G

Increased risk of coronary heart disease (OR: 1.98)/atherosclerosis/heart attack Predisposition to low HDL cholesterol (the good cholesterol) Predisposition to elevated triglyceride levels

G/G

Increased risk of coronary heart disease (OR: 1.98)/atherosclerosis/heart attack Predisposition to low HDL cholesterol (the good cholesterol) Predisposition to elevated triglyceride levels

References Aberle J. et al. A polymorphism in the apolipoprotein A5 gene is associated with weight loss after short-term diet. Clin Genet. 2005 Aug,68(2):152-4. Aouizerat B. E. et al. Genetic analysis of a polymorphism in the human apoA-V gene: effect on plasma lipids. J Lipid Res. 2003 Jun,44(6):1167-73. Dorfmeister B. et al. The effect of APOA5 and APOC3 variants on lipid parameters in European Whites, Indian Asians and Afro-Caribbeans with type 2 diabetes. Biochim Biophys Acta. 2007 Mar,1772(3):355-63.

PON1 - Paraoxonase 1 (rs662) Paraoxonase (PON1) is an antioxidant enzyme involved in the radical elimination and in the lipometabolism. The polymorphisms rs854560 and rs662 lead to a reduced catalytic activity, and an increased risk of cardiovascular diseases. RES

Genotype

POP

Result options

A/A

43% No increased risk of disease

G/A

47% Increased risk of coronary heart disease/atherosclerosis/heart attack

G/G

10% Increased risk of coronary heart disease/atherosclerosis/heart attack

References Regieli et al. Paraoxonase variants relate to 10-year risk in coronary artery disease: impact of a high-density lipoprotein-bound antioxidant in secondary prevention. J Am Coll Cardiol. 2009 Sep 29,54(14):1238-45. Hassan et al. The Q192R polymorphism of the paraoxonase 1 gene is a risk factor for coronary artery disease in Saudi subjects. Mol Cell Biochem. 2013 Aug,380(1-2):121-8.

PON1 - Paraoxonase 1 (rs854560) Paraoxonase (PON1) is an antioxidant enzyme involved in the radical elimination and in the lipometabolism. The polymorphisms rs854560 and rs662 lead to a reduced catalytic activity, and an increased risk of cardiovascular diseases. RES

Genotype

POP

Result options

T/T

18%

A/T

46% Increased risk of coronary heart disease/atherosclerosis/heart attack

A/A

36% Increased risk of coronary heart disease/atherosclerosis/heart attack

No increased risk of disease

Page 37 of 81

APOB R3500Q - Apolipoprotein B (rs5742904) Apolipoprotein B (ApoB) is the major protein component of the LDL proteins (low density lipoprotein), which are responsible for the transport of the cholesterol in the blood. As such, APOB regulates the LDL concentration in the organism. Rs5742904 polymorphism leads to an increased LDL cholesterol levels. RES

Genotype G/G

POP

Result options

98% No increased risk of disease

A/G

Significantly increased risk of coronary heart disease/atherosclerosis/heart attack Significantly increased risk of elevated LDL cholesterol levels (familial Hypercholesterolemia)

A/A

Significantly increased risk of coronary heart disease/atherosclerosis/heart attack Significantly increased risk of elevated LDL cholesterol levels (familial Hypercholesterolemia)

References Real et al. Influence of LDL receptor gene mutations and the R3500Q mutation of the apoB gene on lipoprotein phenotype of familial hypercholesterolemic patients from a South European population. Eur J Hum Genet. 2003 Dec,11(12):959-65. MeriĂąo-Ibarra et al. Screening of APOB gene mutations in subjects with clinical diagnosis of familial hypercholesterolemia. Hum Biol. 2005 Oct,77(5):663-73. Haiqing et al. Familial Defective Apolipoprotein B-100 and Increased Low-Density Lipoprotein Cholesterol and Coronary Artery Calcification in the Old Order Amish. Arch Intern Med. Nov 8, 2010, 170(20): 1850â&#x20AC;&#x201C;1855. Castillo et al. The apolipoprotein B R3500Q gene mutation in Spanish subjects with a clinical diagnosis of familial hypercholesterolemia. Atherosclerosis. 2002 Nov,165(1):127-35.

SREBF2 - Sterol regulatory element binding transcription factor 2 (rs2228314) SREBF2 or SREBP2 (sterol regulatory element-binding protein 2) is a transcription factor involved in the regulation of the cholesterol metabolism. The cholesterol concentration is kept in balance through the control of the transcriptional activity of various target genes. RES

Genotype

POP

Result options

G/G

52% No increased risk of coronary heart disease Predisposition to elevated LDL cholesterol levels

G/C

45% Increased risk of coronary heart disease/atherosclerosis/heart attack No predisposition to elevated LDL cholesterol levels

C/C

Increased risk of coronary heart disease/atherosclerosis/heart attack No predisposition to elevated LDL cholesterol levels

References Fan et al. Expression of sterol regulatory element-binding transcription factor (SREBF) 2 and SREBF cleavage-activating protein (SCAP) in human atheroma and the association of their allelic variants with sudden cardiac death. Published online Dec 30, 2008. Durst et al. The discrete and combined effect of SREBP-2 and SCAP isoforms in the control of plasma lipids among familial hypercholesterolaemia patients. Atherosclerosis. 2006 Dec,189(2):443-50.

Page 38 of 81

NOS3 - Nitric oxide synthase 3 (endothelial cell) (Ins/Del Int. 4) NO-synthases (NOS) are oxidases which catalyze the reaction of arginine to citrulline and nitric oxide. NOS3 is an endothelial nitric oxide synthase, predominantly expressed in endothelial cells on the inside of the blood vessels, where it indirectly adjusts the blood pressure and the afterload of the heart. Several polymorphisms in the NOS3 gene are associated with an increased risk of cardiovascular diseases. RES

Genotype

POP

Result options

Ins/Ins

76% No increased risk of disease

Ins/Del

22% No increased risk of disease

Del/Del

Increased risk of coronary heart disease/atherosclerosis/heart attack

References Casas et al. Endothelial nitric oxide synthase genotype and ischemic heart disease: meta-analysis of 26 studies involving 23028 subjects. Circulation. 2004 Mar 23,109(11):1359-65.

NOS3 - Nitric oxide synthase 3 (endothelial cell) (rs2070744) RES

Genotype T/T

POP

Result options

98% No increased risk of disease

C/T

No increased risk of disease

C/C

Increased risk of coronary heart disease/atherosclerosis/heart attack

References Rossi et al. The T(-786)C endothelial nitric oxide synthase genotype predicts cardiovascular mortality in high-risk patients. J Am Coll Cardiol. 2006 Sep 19,48(6):1166-74.

NOS3 - Nitric oxide synthase 3 (endothelial cell) (rs1799983) RES

Genotype

POP

Result options

G/G

40% No increased risk of disease

G/T

52% Increased risk of coronary heart disease/atherosclerosis/heart attack

T/T

Increased risk of coronary heart disease/atherosclerosis/heart attack

References Zhang et al. The G894T polymorphism on endothelial nitric oxide synthase gene is associated with increased coronary heart disease among Asia population: evidence from a Meta analysis. Thromb Res. 2012 Aug,130(2):192-7. Abdel-Aziz et al. Association of endothelial nitric oxide synthase gene polymorphisms with classical risk factors in development of premature coronary artery disease. Mol Biol Rep. 2013 Apr,40(4):3065-71.

Page 39 of 81

APOA1 - Apolipoprotein A-I (rs670) Apolipoprotein A1 (ApoA1) is the major protein component of HDL (high density lipoprotein) particles in the blood. These are responsible for the transport of the excess cholesterol to the liver, where it is further converted and eliminated. The polymorphism rs670 influences both the impact of polyunsaturated fatty acids on HDL cholesterol levels, as well as the risk of heart disease. RES

Genotype

POP

Result options

G/G

50% No increased risk of disease Polyunsaturated fatty acids (such as Omega 3) WORSEN the HDL cholesterol levels

A/G

38% Increased risk of coronary heart disease (OR: 1.47)/atherosclerosis/heart attack Polyunsaturated fatty acids (such as omega 3) improve the HDL cholesterol levels

A/A

12%

Increased risk of coronary heart disease (OR: 1.9)/atherosclerosis/heart attack Polyunsaturated fatty acids (such as omega 3) improve the HDL cholesterol levels

References Angotti E. et al. A polymorphism (G-->A transition) in the -78 position of the apolipoprotein A-I promoter increases transcription efficiency. J Biol Chem. 1994 Jul 1,269(26):17371-4. Juo S. H. et al. Mild association between the A/G polymorphism in the promoter of the apolipoprotein A-I gene and apolipoprotein A-I levels: a meta-analysis. Am J Med Genet. 1999 Jan 29,82(3):235-41. Ordovas J. M. et al. Polyunsaturated fatty acids modulate the effects of the APOA1 G-A polymorphism on HDL-cholesterol concentrations in a sex-specific manner: the Framingham Study. Am J Clin Nutr. 2002 Jan,75(1):38-46.

MTRR - 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (rs1801394) Methionine is a essential, sulfur containing proteinogenic amino acid. The synthesis of methionine is catalyzed by the methionine synthase enzyme, which in its turn requires homocysteine. The protein encoded by the MTRR gene (methionine synthase reductase) regenerates the inactive methionine synthase through methylation. RES

Genotype

POP

Result options

A/A

38% No increased risk of disease

A/G

34% Increased risk of coronary heart disease atherosclerosis/heart attack Predisposition to elevated homocysteine values

G/G

28% Increased risk of coronary heart disease atherosclerosis/heart attack Predisposition to elevated homocysteine values

References Cai et al. Genetic variant in MTRR, but not MTR, is associated with risk of congenital heart disease: an integrated meta-analysis. PLoS One. 2014 Mar 4,9(3):e89609. Olteanu et al. Differences in the efficiency of reductive activation of methionine synthase and exogenous electron acceptors between the common polymorphic variants of human methionine synthase reductase. Biochemistry. 2002 Nov 12,41(45):13378-85.

MMP3 - Matrix metallopeptidase 3 (stromelysin 1, progelatinase) (rs3025058) The matrix metalloproteinase-3 (MMP3), or Stromelysin1, is a zinc-dependent endopeptidase involved in the degradation of extracellular matrix components. As such, it plays an important role in the remodeling of tissues, wound healing, and inflammatory processes. The polymorphism (rs3025058) influences the risk of heart diseases. RES

Genotype

T/T T/Del Del/Del

POP

Result options

10% Increased risk of coronary heart disease (OR: 1.26)/atherosclerosis/heart attack 47% No increased risk of disease 43% Increased risk of coronary heart disease (OR: 1.26)/atherosclerosis/heart attack

References Abilleira et al. The role of genetic variants of matrix metalloproteinases in coronary and carotid atherosclerosis. J Med Genet. 2006 Dec,43(12):897-901. Epub 2006 Aug 11. Zee et al. Genetic risk factors in recurrent venous thromboembolism: A multilocus, population-based, prospective approach. Clin Chim Acta. 2009 Apr,402(1-2):189-92.

Page 40 of 81

GJA4 - Gap junction protein, alpha 4, 37kDa (rs1764391) The GJA4 gene (Gap junction alpha-4 protein) belongs to the connexin gene family. These transmembrane proteins are components of the intercellular channels (the so-called gap junctions), which link the adjacent cells with each other, and facilitate the exchange of ions and small molecules. Gap junctions are mainly found in the heart muscle, in epithelial cells and in the retina. RES

Genotype

POP

T/T

14%

Increased risk of coronary heart disease (OR: 1.5)

C/T

41%

No increased risk of disease

C/C

45% Increased risk of coronary heart disease (OR: 1.5)

Result options

References Zhao et al . Cx37 C1019T Polymorphism May Contribute to the Pathogenesis of Coronary Heart Disease. Genet Test Mol Biomarkers. 2014 Apr 28.

ITGB3 - Integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61) (rs5918) The integrin beta 3 (ITGB3), or CD61, is a transmembrane protein involved in the signal transmission between cells and the extracellular matrix. It has been proven that carriers of the C allele (rs5918) have an increased risk of cardiovascular diseases. In addition, the polymorphism influences the blood-thinning effect of the aspirin drug. RES

Genotype

POP

Result options

T/T

74% No increased risk of disease Aspirin protects against thrombosis

T/C

24% Increased risk of coronary heart disease (OR: 1.5)/atherosclerosis/heart attack Aspirin provides no protection against thrombosis

C/C

Increased risk of coronary heart disease (OR: 1.5)/atherosclerosis/heart attack Aspirin provides no protection against thrombosis

References Undas et al. Pl(A2) polymorphism of beta(3) integrins is associated with enhanced thrombin generation and impaired antithrombotic action of aspirin at the site of microvascular injury. Circulation. 2001 Nov 27,104(22):2666-72. Weiss et al. A polymorphism of a platelet glycoprotein receptor as an inherited risk factor for coronary thrombosis. N Engl J Med. 1996 Apr 25,334(17):1090-4.

CETP - Cholesteryl ester transfer protein, plasma (rs708272) The cholesterol ester transfer protein (CETP) is a pore-forming protein involved in the lipoprotein metabolism. It is mainly expressed in the liver, and ensures the transfer of cholesterol esters from HDL to LDL or VLDL, in exchange for triglycerides. The polymorphism rs708272 influences the regulation of HDL cholesterol levels. RES

Genotype

POP

Result options

T/T

13%

C/T

70% Predisposition to bad HDL cholesterol values (the good cholesterol)

No predisposition to bad HDL cholesterol values (the good cholesterol)

C/C

17%

Predisposition to bad HDL cholesterol values (the good cholesterol)

References Radovica et al. The association of common SNPs and haplotypes in CETP gene with HDL cholesterol levels in Latvian population. PLoS One. 2013 May 13,8(5):e64191. Agirbasli et al. Multi-locus candidate gene analyses of lipid levels in a pediatric Turkish cohort: lessons learned on LPL, CETP, LIPC, ABCA1, and SHBG. OMICS. 2013 Dec,17(12):636-45. Wang et al. CETP gene polymorphisms and risk of coronary atherosclerosis in a Chinese population. Lipids Health Dis. 2013 Nov 27,12:176.

Page 41 of 81

MTHFR - Methylenetetrahydrofolate reductase (NAD(P)H) (rs1801133) The methylenetetrahydrofolate reductase (MTHFR) is involved in many metabolic pathways in the human body. In the homocysteine metabolism, it is responsible for the degradation of homocysteine to methionine. The rs1801133 polymorphism leads to a reduced enzymatic activity of methylenetetrahydrofolate reductase, and thus to an increased homocysteine level. RES

Genotype

POP

Result options

T/T

C/T

44% Predisposition to elevated homocysteine values Vitamin DOES NOT lower the homocysteine levels

C/C

47% No predisposition to elevated homocysteine values Vitamin lowers the homocysteine levels

Predisposition to elevated homocysteine values Vitamin DOES NOT lower the homocysteine levels

References Ashfield-Watt P.A. et al. Methylenetetrahydrofolate reductase 677C-->T genotype modulates homocysteine responses to a folate-rich diet or a low-dose folic acid supplement: a randomized controlled trial. Am J Clin Nutr. 2002 Jul,76(1):180-6. BĂ¸naa K.H. et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med. 2006 Apr 13,354(15):1578-88. Lewis S. J. et al. Meta-analysis of MTHFR 677C->T polymorphism and coronary heart disease: does totality of evidence support causal role for homocysteine and preventive potential of folate? BMJ. 2005 Nov 5,331(7524):1053.

APOE - apolipoprotein E (E2/E3/E4) APOE (apolipoprotein E) metabolizes triglyceride-rich lipoprotein constituents, and plays a central role in the lipid metabolism. The ApoE gene is present in three common types, which are called allele E2, E3 and E4. The E4 allele is associated with an increased risk of heart disease and Alzheimer. RES

Genotype

POP

E2/E2

No increased risk of coronary heart disease/atherosclerosis/heart attack No predisposition to elevated LDL cholesterol levels Predisposition to elevated triglyceride levels

E2/E3

Increased risk of coronary heart disease/atherosclerosis/heart attack No predisposition to elevated LDL cholesterol levels Predisposition to elevated triglyceride levels

E3/E3

66% No increased risk of coronary heart disease/atherosclerosis/heart attack No predisposition to elevated LDL cholesterol levels No predisposition to elevated triglyceride levels

E2/E4

E3/E4

24% Increased risk of coronary heart disease/atherosclerosis/heart attack Predisposition to elevated LDL cholesterol levels Predisposition to elevated triglyceride levels

E4/E4

Result options

Increased risk of coronary heart disease/atherosclerosis/heart attack Predisposition to elevated LDL cholesterol levels Predisposition to elevated triglyceride levels

References Muendlein A et al. Synergistic effects of the apolipoprotein E epsilon3/epsilon2/epsilon4, the cholesteryl ester transfer protein TaqIB, and the apolipoprotein C3 -482 C>T polymorphisms on their association with coronary artery disease. Atherosclerosis. 2008 Jul,199(1):179-86. Burman D et al. Relationship of the ApoE polymorphism to plasma lipid traits among South Asians, Chinese, and Europeans living in Canada. Atherosclerosis. 2009 Mar,203(1):192-200. Roberto Elosua et al. Association of APOE genotype with carotid atherosclerosis in men and women the Framingham Heart Study. October 2004 The Journal of Lipid Research, 45, 1868-1875. Dallongeville et al. Modulation of plasma triglyceride levels by apoE phenotype: a meta-analysis. J Lipid Res. 1992 Apr,33(4):447-54. Breslow et al. Genetic Basis of Lipoprotein Disorders. Circulation. 1995 Jan 15,91(2):505-12. Davignon et al. Apolipoprotein E polymorphism and atherosclerosis. Arteriosclerosis. 1988 Jan-Feb,8(1):1-21. Cubrilo-Turek et al. Apolipoprotein E genotypes and metabolic risk factors for coronary heart disease in middle-aged women. Coll Antropol. 1998 Jun,22(1):149-55.

Page 42 of 81

NOS1AP - Nitric oxide synthase 1 (neuronal) adaptor protein (rs16847548) The nitric oxide synthase 1 adaptor protein (NOS1AP) is an adapter protein which binds the signal molecule nNOS (neuronal nitric oxide synthase) with other molecules, facilitating their interaction. NOS1AP polymorphisms are associated with a prolonged QT interval, and an increased risk of sudden cardiac death. RES

Genotype

T/T

74% No increased risk of sudden cardiac death

T/C

25% Increased risk of sudden cardiac death (OR: 1.3)

C/C

POP

Result options

Increased risk of sudden cardiac death (OR: 2.6)

References Arking et al. Multiple independent genetic factors at NOS1AP modulate the QT interval in a multi-ethnic population. PLoS One. 2009,4(1):e4333. Crotti et al.NOS1AP is a genetic modifier of the long-QT syndrome. Circulation. 2009 Oct 27,120(17):1657-63. Kao et al. Genetic variations in nitric oxide synthase 1 adaptor protein are associated with sudden cardiac death in US white community-based populations. Circulation. 2009 Feb 24,119(7):940-51.

NOS1AP - Nitric oxide synthase 1 (neuronal) adaptor protein (rs12567209) The nitric oxide synthase 1 adaptor protein (NOS1AP) is an adapter protein which binds the signal molecule nNOS (neuronal nitric oxide synthase) with other molecules, facilitating their interaction. NOS1AP polymorphisms are associated with a prolonged QT interval, and an increased risk of sudden cardiac death. RES

Genotype

POP

Result options

G/G

85% No increased risk of sudden cardiac death

A/G

14%

Protection against sudden cardiac death (OR: 0.51)

A/A

Increased risk of sudden cardiac death (OR: 1.31)

References Kao et al. Genetic variations in nitric oxide synthase 1 adaptor protein are associated with sudden cardiac death in US white community-based populations. Circulation. 2009 Feb 24,119(7):940-51. Liu et al. A common NOS1AP genetic polymorphism, rs12567209 G>A, is associated with sudden cardiac death in patients with chronic heart failure in the Chinese Han population. J Card Fail. 2014 Apr,20(4):244-51. Eijgelsheim et al. Genetic variation in NOS1AP is associated with sudden cardiac death: evidence from the Rotterdam Study. Hum Mol Genet. Nov 1, 2009, 18(21): 4213â&#x20AC;&#x201C;4218.

NOS1AP - Nitric oxide synthase 1 (neuronal) adaptor protein (rs10494366) The nitric oxide synthase 1 adaptor protein (NOS1AP) is an adapter protein which binds the signal molecule nNOS (neuronal nitric oxide synthase) with other molecules, facilitating their interaction. NOS1AP polymorphisms are associated with a prolonged QT interval, and an increased risk of sudden cardiac death. RES

Genotype

POP

Result options

G/G

10% Predisposition to increased QT-interval duration (+ 4 to 7,9 ms)

G/T

48% Predisposition to increased QT-interval duration (+ 1,7 to 4,6 ms)

T/T

42% No Predisposition to increased QT-interval duration

References Aarnoudse et al. Common NOS1AP variants are associated with a prolonged QTc interval in the Rotterdam Study. Circulation. 2007 Jul 3 Arking et al. A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization. Nat Genet. 2006 Jun,38(6):644-51.

Page 43 of 81

Prevention Early diagnosis Treatment

THROMBO SENSOR Effectively prevent thrombosis • Possible diagnosis of an increased risk of thrombosis • Analysis of the 3 genes relevant for thrombosis • Analysis of 7 gene variations, for the effect of more than 4 relevant drugs • A thrombosis prevention program adapted to your genes • Increased protection against heart attack, stroke or pulmonary embolism • Warning of drugs that can trigger thrombosis • Better chances of recovery by optimal medical therapy • For women: Are the hormonal preparations dangerous for your health?

CARDIOVASCULAR SYSTEM

Thrombosis Thrombosis is a disease in which blood clots form in the bloodstream. These clots can clog certain blood vessels and reduce the flow of blood to the heart or to areas in the brain, leading to damage or even the death of the affected tissue. When the blood supply to part of the brain is cut off, a stroke occurs. If the blood supply to the heart is affected, it causes a heart attack. The most common form of thrombosis is a reduction of blood circulation in the legs by a blood clot. The danger here is that, if the clots dissolve, they can move and restrict the blood flow to the brain, the heart or the lungs. Genetic screening tests for the detection of a risk of thrombosis are unfortunately rarely performed, and since there are no noticeable symptoms until the occurrence of thrombosis, most people do not know that they are genetically predisposed.

if you know your genetic health risk, you can take preemptive measures, and, in most cases, even prevent the occurrence of thrombosis.

Therefore, a genetic predisposition is usually not detected until after the occurrence of thrombosis; this, however, may have fatal consequences. Genetic screening tests are still far too rarely performed, although they will allow one to be aware of the increased risk, and take the necessary preemptive measures, in some cases even allowing him to avoid the disease altogether. Several genes prevent the formation of blood clots in the veins. If one of these genes is defective, it cannot perform its task, and the risk of forming a blood clot increases significantly. Everyone has two genes of each type, and about one in twenty people carries a defect in at least one gene, thus being a carrier with an approximately 8- fold higher risk of thrombosis than the general population. About one in 200 people carries an error in both genes of a genotype, and has a 80 -fold higher thrombosis risk. Having defective genes does not necessary mean the patient will suffer from thrombosis, because only a fraction of those affected also develop the disease. Other factors also strongly contribute, such as obesity, bed rest and inactivity, prolonged air travel, contraceptive pill, pregnancy, etc. . This is why this genetic testing is so important; Page 45 of 81

CARDIOVASCULAR SYSTEM

Relevant genes for thrombosis Three genetic variations have been identified that can significantly increase the risk of thrombosis. Through an analysis of these three polymorphisms, the risk of developing a thrombosis can be determined, and reduced with specific preventive measures. The following genes have an impact on your risk of thrombosis:

Genetic risks and traits SYMBOL

rs NCBI

POLYMORPH.

GENOTYPE

RESPOND

PROTECT.

RISK

Factor-V

rs6025

G>A

G/G

Factor-II

rs1799963

G>A

G/G

PAI1

rs1799889

G>del

G/G

Page 46 of 81

Summary of effects Certain genes are responsible for preventing blood clotting in the blood vessels. Variations in these genes may interfere with this process, and therefore increase the risk of the formation of a blood clot, and, subsequently, thrombosis. Here you can see a summary of the impact that genetic variations have on your health and your body: ➤ Your risk of developing venous thrombosis is not increased ➤ Your risk of developing arterial thrombosis is the same as for the general population. Your risk of developing thrombosis NORMAL

INCREASED

▲

Risk of venous thrombosis NORMAL

INCREASED

▲ Risk of arterial thrombosis NORMAL

INCREASED

▲

Page 47 of 81

CARDIOVASCULAR SYSTEM

Prevention Based on your genetic profile, you have no increased risk of thrombosis. Your risk is the same as for the general population, and no special precautions are necessary. Even people with no genetic predisposition to thrombosis can still be affected by it. Therefore, the following preventative measures should be taken by everyone. Staying still for a long periods of time can lead to the formation of a clot. This can happen when a person is in bed for a long period because of sickness or after surgery Long intervals without moving, and even during prolonged sitting in a car or plane during long-distance traveil. These may lead to impaired blood flow that fosters the formation of a blood clot. To prevent this, take regular breaks during long trips, or walk in the plane to stretch your legs. Other risk factors for thrombosis include obesity and pregnancy, which both increase pressure in the veins. Smoking and an unhealthy diet are also risk factors for thrombosis.

Page 48 of 81

CARDIOVASCULAR SYSTEM

Effect on relevant drugs Your genetic profile has an impact on the effect of drugs prescribed for thrombosis and associated diseases. This information can help your doctor choose the correct dosage of the right medications to minimize side effects.

Blood thinners (anticoagulant) Drugs for the treatment of thrombosis

effect

Breakdown

Adverse Reaction

recommended dose*

alternative?

clopidogrel

likely higher

~100%

Normal

~100%

Not neccessary

prasugrel

Normal

~100%

Normal

~100%

Not neccessary

rwarfarin (FDA!)

Normal

~100%

Normal

~100%

Not neccessary

swarfarin (FDA!)

Normal

~100%

Normal

5-7%

Not neccessary

ticagrelor

Normal

~100%

Normal

~100%

Not neccessary

REMEMBER: Only your doctor can prescribe the correct drugs and dosage. NEVER stop taking a drug or change the dose: consult your doctor instead!

Page 49 of 81

SCIENCE

Thrombo Sensor Factor-V - Coagulation factor V (proaccelerin, labile factor) (rs6025) The so-called factor V Leiden mutation is a genetically transmitted clotting defect, associated with an increased risk of thrombosis. This defect inhibits the degradation of factor V and the protein retains its coagulant effect. RES

Genotype

POP

A/A

Increased risk of thrombosis (venous) (OR: 80!)

A/G

Increased risk of thrombosis (venous) (OR: 7)

G/G

96% No increased risk of thrombosis (venous)

Result options

References Juul et al. Factor V Leiden and the risk for venous thromboembolism in the adult Danish population. Ann Intern Med. 2004 Mar 2,140(5):330-7. Brenner et al. Venous Thromboembolism Associated With Double Heterozygosity for R506Q Mutation of Factor V and for T298M Mutation of Protein C in a Large Family of a Previously Described Homozygous Protein C -Deficient Newborn With Massive Thrombosis: Blood. 1996 Aug 1,88(3):877-80. Zee et al. An Evaluation of Candidate Genes of Inflammation and Thrombosis in Relation to the Risk of Venous Thromboembolism. Circulation. Feb 2009, 2(1): 57–62. Rosendaal et al. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Br J Haematol. 2002 Mar,116(4):851-4. Kamphuisen et al. Thrombophilia screening: a matter of debate. Neth J Med. 2004,62:180-187. Ridker et al. Ethnic distribution of factor V Leiden in 4047 men and women. Implications for venous thromboembolism screening, Jama 277 (1997) 1305-1307.

Factor-II - Coagulation factor II (thrombin) (rs1799963) The prothrombin mutation (factor II mutation) is a blood coagulant disorder. The risk of venous thrombosis is significantly increased by the polymorphism rs1799963, which allows the creation of too much clotting factor, prothrombin, in the blood. RES

Genotype

POP

A/A

Increased risk of thrombosis (venous) (OR: 25)

A/G

Increased risk of thrombosis (venous) (OR: 5)

G/G

96% No increased risk of thrombosis (venous)

Result options

References Zee et al. An Evaluation of Candidate Genes of Inflammation and Thrombosis in Relation to the Risk of Venous Thromboembolism: The Women’s Genome Health Study. Circ Cardiovasc Genet. Feb 2009, 2(1): 57–62. Foka et al. Factor V Leiden and prothrombin G20210A mutations, but not methylenetetrahydrofolate reductase C677T, are associated with recurrent miscarriages. 2000 Feb,15(2):458-62. Andreassi et al. Prothrombin G20210A substitution and hormone therapy: indications for molecular screening, Clin Chem Lab Med 44 (2006) 514-521. Rosendaal et al. Hormonal replacement therapy, prothrombotic mutations and the risk of venous thrombosis. Br J Haematol. 2002 Mar,116(4):851-4. Ye et al. Seven haemostatic gene polymorphisms in coronary disease: meta-analysis of 66,155 cases and 91,307 controls. Lancet. 2006 Feb 25,367(9511):651-8.

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PAI1 - Phosphoribosylanthranilate isomerase (rs1799889) Plasminogen activator inhibitor-1 (PAI-1) is a glycoprotein belonging to the group of serine protease inhibitors. It inhibits the fibrinolytic activity, by inactivating tPA and urokinase. A defect in the PAI1 gene leads to an increased transcription, and a higher concentration PAI1. This condition is associated with an increased risk of thrombosis. RES

Genotype

POP

Result options

Del/Del

24% Increased risk of thrombosis (arterial) (OR: 1.84)

Del/G

48% Increased risk of thrombosis (arterial) (OR: 1.83)

G/G

28% No increased risk of thrombosis (arterial)

References Tsantes et al. Association between the plasminogen activator inhibitor-1 4G/5G polymorphism and venous thrombosis. A meta-analysis. Thromb Haemost. 2007 Jun,97(6):907-13. Fernandes et al. 4G/5G polymorphism modulates PAI-1 circulating levels in obese women. Mol Cell Biochem. 2012 May,364(1-2):299-301. Gardemann et al. The 4G4G genotype of the plasminogen activator inhibitor 4G/5G gene polymorphism is associated with coronary atherosclerosis in patients at high risk for this disease. Thromb Haemost. 1999 Sep,82(3):1121-6.

Page 51 of 81

Prevention Early diagnosis Treatment

TOXO SENSOR Optimal support for the detoxification of toxins • Genetic analysis of the ability to detoxify pollutants • Detoxification of heavy metals, pesticides, weed agents, chemicals, soot and smoke • Analysis of cells' oxidative stress • Action program to reduce pollution • Micronutrient recommendation for filtering the heavy metals from the body • Analysis of 10 genetic variations which influence on the detoxification process • Effects of alcohol, coffee and addictive substances on your health • Adjustment of lifestyle for optimal health

METABOLISM

Detoxification In our daily lives, we are increasingly exposed to toxic pollutants that enter our bodies. Our bodies produce enzymes that recognize and neutralize many toxins. Certain genes are responsible for the production of these enzymes. Some traits in those genes limit your body's ability to effectively neutralize toxic substances. This significantly increases your risk for a variety of conditions caused by toxins. Therefore, a complete analysis of health risks must include these detoxification genes. Genetic traits limiting detoxification are very common among the European population and the body's detoxification ability varies greatly from person to person. These genetic differences help to explain why a 90-year-old heavy smoker may be in great health while another individual develops cancer at the age of 35. Each person has an individual genetic profile and it follows that each person should employ individual preventative measures to maintain good health.

Since different genes are responsible for the detoxification of certain toxic substances, the toxic substances categories are listed individually and your gene analysis results are interpreted per category.

Page 53 of 81

METABOLISM

Phase 1 Detoxification from ashes and soot Polycyclic aromatic hydrocarbons (PAHs) are common atmospheric pollutants produced mainly by burning fossil fuels such as coal, natural gas and oil. These pollutants enter the body via a myriad of paths: in food and drinking water, through the lungs when fumes or smoke are inhaled, and even directly through the skin. Once in our bodies, they can cause many different types of cancer, including lung cancer, laryngeal cancer, stomach cancer, intestinal cancer and bladder cancer. There are a number of detoxification genes that regulate enzymes that bind and neutralize toxic substances in your body. Some genetic traits reduce your body's capacity to produce these enzymes, and exposure to toxic substances increases your individual risk of cancer many times over. It is therefore very important for persons with inefficient detoxification enzymes to learn about their elevated risk in order to minimize their exposure to toxic substances and remain healthy. Your gene analysis shows the following:

Genetic risks and traits SYMBOL

rs NCBI

POLYMORPH.

GENOTYPE

RESPOND

PROTECT.

RISK

CYP1A1

rs4646903

T>C

T/T

CYP1B1

rs1056836

C>G

C/C

Summary of effects ➤ Phase 1 Detoxification is not limited ➤ Detoxification from ashes, smoke and soot (grilled foods) is not limited Effectiveness of Phase 1 Detoxification

Detoxification from ashes, soot (food), smoke

EFFECTIVE

▲

INEFFECTIVE

▲

Page 54 of 81

INEFFECTIVE

METABOLISM

Phase 2 Detoxification from pesticides & heavy metals Detoxification genes 3 (GSTM1), 4 (GSTP1) and 5 (GSTT1) produce enzymes that bind and neutralize toxic substances often found in industrial solvents, herbicides, fungicides or insect repellent sprays, and also neutralize toxic heavy metals such as mercury, lead and cadmium. As long as they function efficiently, these genes ensure that these toxic substances effectively filtered out of your body. However, these genes can carry traits that prevent your body from adequately detoxifying. These traits significantly increase the risk of many different types of cancer and chronic fatigue syndrome.

Genetic risks and traits SYMBOL

rs NCBI

POLYMORPH.

GENOTYPE

RESPOND

PROTECT.

RISK

GSTM1

Zero allele

T=Zero allele

C/C

GSTT1

Zero allele

del=Zero allele

A/A

GSTP1

rs1695

A>G

A/A

Summary of effects ➤ Phase 2 Detoxification from pesticides, chemicals and heavy metals is not limited ➤ Your need for calcium, selenium, and zinc is average Effectiveness of Phase 2 Detoxification

Detoxification from heavy metals

EFFECTIVE

INEFFECTIVE

▲

Detoxification from pesticides, chemicals, fungicides, herbicides and insect repellent sprays EFFECTIVE

INEFFECTIVE

▲

Page 55 of 81

INEFFECTIVE

METABOLISM

Oxidative stress and free radicals Free radicals are created in cells during energy conversion. Free radicals are small, aggressive substances that damage the molecules around them through a chain reaction. They must be neutralized swiftly by the body. An imbalance between the creation and neutralization of free radicals is known as oxidative stress, which is one of the factors that affects the aging of your body and skin. Certain genes are responsible for the neutralization of free radicals. Unfortunately, many people have genetic traits that reduce their protection from free radicals. If your body does not have an innate ability to neutralize free radicals, you can consume higher levels of antioxidants â&#x20AC;&#x201C; such as beta-carotene, vitamin C, vitamin E and acetylcysteine â&#x20AC;&#x201C; that will increase your body's ability to resist oxidative stress. Coenzyme Q10 is a strong antioxidant that is capable of neutralizing free radicals, but only after being transformed into its active form, ubiquinol, by a certain gene. If this gene does not function, coenzyme Q10 cannot be transformed into ubiquinol and does nothing to protect against free radicals. It is therefore important to know if your body is capable of activating coenzyme Q10 to determine your need to take antioxidants.

Genetic risks and traits SYMBOL

rs NCBI

POLYMORPH.

GENOTYPE

RESPOND

PROTECT.

RISK

GSTM1

Zero allele

T=Zero allele

C/C

GSTT1

Zero allele

del=Zero allele

A/A

GSTP1

rs1695

A>G

A/A

SOD2

rs4880

Val16Ala

C/C

RESPOND

PROTECT.

GPX1

rs1050450

C>T

C/C

PROTECT.

NQO1

rs1800566

C>T

C/C

RESPOND

Page 56 of 81

Summary of effects ➤ ➤ ➤ ➤ ➤

You do not have an elevated level of oxidative stress in your cells You should consume the normally recommended amount of antioxidants Your body is able to activate inactive coenzyme Q10 Your diet or a dietary supplement can be a source of coenzyme Q10 Your need for selenium is average

Your oxidative stress in cells NORMAL

Recommended dose of antioxidants INCREASED

NORMAL

INCREASED

▲

Activation of coenzyme Q10 to ubiquinol

Recommended antioxidant substance

POSSIBLE

COENZY. Q10

NOT POSSIBLE

▲

Your daily requirement of selenium NORMAL INCREASED ▲

Page 57 of 81

VIT. C,E,A etc.

METABOLISM

Substances and risks We are all exposed to substances in our environment that affect us differently depending on our genes. Moderate consumption of alcohol poses no problem for most people, while others have a significantly elevated risk of alcohol dependence due to individual genetic variations. Illegal drugs also have different effects on our bodies. For instance, adolescents who smoke cannabis before the age of 16 have â&#x20AC;&#x201C; in combination with a specific genetic variation â&#x20AC;&#x201C; a 10-times higher risk of later developing schizophrenia. Your gene analysis shows the following:

Genetic risks and traits SYMBOL

rs NCBI

POLYMORPH.

GENOTYPE

RESPOND

PROTECT.

RISK

COMT

rs4680

G>A

G/G

RISK

CYP1A2

rs762551

C/A Pos. -163

A/A

PROTECT.

Page 58 of 81

Summary of effects ➤ You have a normal risk of alcoholism ➤ Consumption of cannabis before the age of 16 increases your risk of schizophrenia by 10.9 times higher ➤ Your body breaks down caffeine at a normale rate

Your risk of alcohol dependence NORMAL

INCREASED

▲ Your risk of schizophrenia (use of cannabis during adolescence) NORMAL INCREASED

How quickly is caffeine broken down? NORMAL ▲

▲

Page 59 of 81

SLOW

METABOLISM

Prevention Substances: You genes influence the effect that many substances, such as alcohol and caffeine, have on your body. Based on your genetic profile, you should be aware of the following traits: ALCOHOL Your genetic variations make you more likely to consume a large amount of alcohol, more likely to become alcoholic, and more likely to develop high blood pressure after drinking alcohol. Therefore, it would be advisable to consume little or no alcohol. SOY You have a genetic trait that reduces the activity of the COMT enzyme in your body. Soy contains substances that reduce this enzymeâ&#x20AC;&#x2122;s activity even further, and so you should avoid it. CAFFEINE Your body breaks down caffeine at a normale rate

Page 60 of 81

SCIENCE

Toxo Sensor CYP1A1 - Cytochrome P450, family 1, subfamily A, polypeptide 1 (rs4646903) The heme protein cytochrome P450-1A1 (CYP1A1) belongs to the group of phase I enzymes, and mediates the metabolism of environmental toxins and various xenobiotic substances. Defects in this gene can alter the enzymatic activity. RES

Genotype

T/T

62% Effective phase 1 detoxification of polycyclic aromatic hydrocarbons (PAHs) Effective detoxification of ash, soot and smoke

T/C

37% Limited phase 1 detoxification of polycyclic aromatic hydrocarbons (PAHs) (OR: 2.4) Limited detoxification of ash, soot and smoke

C/C

POP

Result options

Limited phase 1 detoxification of polycyclic aromatic hydrocarbons (PAHs) (OR: 2.4) Limited detoxification of ash, soot and smoke

References Sun et al. Polymorphisms in Phase I and Phase II Metabolism Genes and Risk of Chronic Benzene Poisoning in a Chinese Occupational Population. Carcinogenesis. 2008 Dec,29(12):2325-9. Marinković et al. Polymorphisms of genes involved in polycyclic aromatic hydrocarbons’ biotransformation and atherosclerosis. Biochem Med (Zagreb). Oct 2013, 23(3): 255–265. Wright et al. Genetic association study of CYP1A1 polymorphisms identifies risk haplotypes in nonsmall cell lung cancer. Eur Respir J 2010, 35: 152–159. Jarvis et al. CYP1A1 MSPI (T6235C) gene polymorphism is associated with mortality in acute coronary syndrome patients. Clin Exp Pharmacol Physiol. 2010 Feb,37(2):193-8.

CYP1B1 - Cytochrome P450, family 1, subfamily B, polypeptide 1 (rs1056836) CYP1B1 belongs to the cytochrome P450 superfamily. This protein catalyzes reactions for detoxification of endogenous metabolites and exogenous toxic substances. This catalytic activity can be affected by polymorphisms. RES

Genotype

POP

Result options

C/C

32% Effective phase 1 detoxification of polycyclic aromatic hydrocarbons (PAHs) Effective detoxification of ash, soot and smoke

C/G

45% Limited phase 1 detoxification of polycyclic aromatic hydrocarbons (PAHs) (OR: 3.4) Limited detoxification of ash, soot and smoke

G/G

23% Limited phase 1 detoxification of polycyclic aromatic hydrocarbons (PAHs) (OR: 3.4) Limited detoxification of ash, soot and smoke

References Nock et al. Associations between Smoking, Polymorphisms in Polycyclic Aromatic Hydrocarbon (PAH) Metabolism and Conjugation Genes and PAH-DNA Adducts in Prostate Tumors Differ by Race. Cancer Epidemiol Biomarkers Prev. Jun 2007, 16(6): 1236–1245. Hanna et al. Cytochrome P450 1B1 (CYP1B1) pharmacogenetics: association of polymorphisms with functional differences in estrogen hydroxylation activity. Cancer Res. 2000 Jul 1,60(13):3440-4. Tang et al. Human CYP1B1 Leu432Val gene polymorphism: ethnic distribution in African-Americans, Caucasians and Chinese, oestradiol hydroxylase activity, and distribution in prostate cancer cases and controls. Pharmacogenetics. 2000 Dec,10(9):761-6.

Page 61 of 81

GSTM1 - glutathione S-transferase mu1 (null allele) The glutathione S-transferases are found in the liver and in the lymphocytes, and are involved in the detoxification of endogenous and exogenous substances. A defective GSTM1 gene reduces the enzymatic activity of the protein, which leads to a limited cellular detoxification. RES

Genotype

POP

Result options

C/C

10% Effective phase 2 detoxification Effective detoxification of pesticides, chemicals, fungicides, weed agents, insect sprays and heavy metals Good protection against oxidative stress / free radicals

C/T

38% Limited phase 2 detoxification Limited detoxification of pesticides, chemicals, fungicides, weed agents, insect sprays and heavy metals Limited protection against oxidative stress / free radicals

T/T

52% Limited phase 2 detoxification Limited detoxification of pesticides, chemicals, fungicides, weed agents, insect sprays and heavy metals Limited protection against oxidative stress / free radicals

References McWilliams et al. Glutathione S-transferase M1 (GSTM1) deficiency and lung cancer risk. Cancer Epidemiol Biomarkers Prev 1995,4:589-594. Sreeja et al. Glutathione S-transferase M1, T1 and P1 polymorphisms: susceptibility and outcome in lung cancer patients. J Exp Ther Oncol. 2008,7(1):73-85. Funke et al. Genetic Polymorphisms in Genes Related to Oxidative Stress (GSTP1, GSTM1, GSTT1, CAT, MnSOD, MPO, eNOS) and Survival of Rectal Cancer Patients after Radiotherapy. J Cancer Epidemiol. 2009, 2009: 302047.

GSTP1 - Glutathione S-transferase pi 1 (rs1695) The glutathione S-transferases are found in the liver and in the lymphocytes, and are involved in the detoxification of endogenous and exogenous substances. The GSTP1 enzymes are involved in the metabolism of endogenous metabolites, and protect the cells against oxidative stress, similar with GSTM1 and GSTT1. RES

Genotype

POP

Result options

A/A

48% Effective phase 2 detoxification Effective detoxification of pesticides, chemicals, fungicides, weed agents, insect sprays and heavy metals Good protection against oxidative stress / free radicals

A/G

42% Limited phase 2 detoxification Limited detoxification of pesticides, chemicals, fungicides, weed agents, insect sprays and heavy metals Limited protection against oxidative stress / free radicals

G/G

10% Limited phase 2 detoxification Limited detoxification of pesticides, chemicals, fungicides, weed agents, insect sprays and heavy metals Limited protection against oxidative stress / free radicals

References Sreeja et al. Glutathione S-transferase M1, T1 and P1 polymorphisms: susceptibility and outcome in lung cancer patients. J Exp Ther Oncol. 2008,7(1):73-85. Miller et al. An association between glutathione S-transferase P1 gene polymorphism and younger age at onset of lung carcinoma. Cancer. 2006 Oct 1,107(7):1570-7. Funke et al. Genetic Polymorphisms in Genes Related to Oxidative Stress (GSTP1, GSTM1, GSTT1, CAT, MnSOD, MPO, eNOS) and Survival of Rectal Cancer Patients after Radiotherapy. J Cancer Epidemiol. 2009, 2009: 302047. St端cker et al. Genetic polymorphisms of glutathione S-transferases as modulators of lung cancer susceptibility. Carcinogenesis. 2002 Sep, 23(9):1475-81.

Page 62 of 81

GSTT1 - glutathione S-transferase theta 1 (null allele) The glutathione S-transferases are found in the liver and in the lymphocytes, and are involved in the detoxification of endogenous and exogenous substances. A defective GSTM1 gene reduces the enzymatic activity of the protein, which leads to a limited cellular detoxification. RES

Genotype

A/A

POP

Result options

36% Effective phase 2 detoxification Effective detoxification of pesticides, chemicals, fungicides, weed agents, insect sprays and heavy metals Good protection against oxidative stress / free radicals

A/DEL

42% Limited phase 2 detoxification Limited detoxification of pesticides, chemicals, fungicides, weed agents, insect sprays and heavy metals Limited protection against oxidative stress / free radicals

DEL/DEL

22% Limited phase 2 detoxification Limited detoxification of pesticides, chemicals, fungicides, weed agents, insect sprays and heavy metals Limited protection against oxidative stress / free radicals

References Sreeja et al. Glutathione S-transferase M1, T1 and P1 polymorphisms: susceptibility and outcome in lung cancer patients. J Exp Ther Oncol. 2008,7(1):73-85. Funke et al. Genetic Polymorphisms in Genes Related to Oxidative Stress (GSTP1, GSTM1, GSTT1, CAT, MnSOD, MPO, eNOS) and Survival of Rectal Cancer Patients after Radiotherapy. J Cancer Epidemiol. 2009, 2009: 302047.

SOD2 - Superoxide dismutase 2, mitochondrial (rs4880) SOD2 encodes the superoxide dismutase enzyme 2 and it is involved in the degradation of reactive oxygen molecules (ROS), thus protecting the body against oxidative stress. Defects may affect the enzymatic activity of the SOD2 enzyme, resulting in a limited protection against the free radicals. RES

Genotype

POP

Result options

C/C

20% Good protection against oxidative stress / free radicals

C/T

53% Limited protection against oxidative stress / free radicals

T/T

27% Limited protection against oxidative stress / free radicals

References Sutton et al. The manganese superoxide dismutase Ala16Val dimorphism modulates both mitochondrial import and mRNA stability. Pharmacogenet Genomics. 2005 May,15(5):311-9. Funke et al. Genetic Polymorphisms in Genes Related to Oxidative Stress (GSTP1, GSTM1, GSTT1, CAT, MnSOD, MPO, eNOS) and Survival of Rectal Cancer Patients after Radiotherapy. J Cancer Epidemiol. 2009, 2009: 302047.

Page 63 of 81

GPX1 - Glutathione Peroxidase (rs1050450) The GPX gene encodes the enzyme glutathione peroxidase, which catalyzes the reduction of peroxides and hydrogen peroxide. Thus, GPX plays a role in protecting the body against oxidative stress. RES

Genotype

C/C

67% Good protection against oxidative stress / free radicals

C/T

26% Limited protection against oxidative stress / free radicals

T/T

POP

Result options

Limited protection against oxidative stress / free radicals

References Tang et al. Association between the rs1050450 glutathione peroxidase-1 (C > T) gene variant and peripheral neuropathy in two independent samples of subjects with diabetes mellitus. Nutr Metab Cardiovasc Dis. 2012 May,22(5):417-25. Bhatti et al. Lead exposure, polymorphisms in genes related to oxidative stress and risk of adult brain tumors. Cancer Epidemiol Biomarkers Prev. Jun 2009, 18(6): 1841â&#x20AC;&#x201C;1848. Xiong et al. Association study between polymorphisms in selenoprotein genes and susceptibility to Kashin-Beck disease. Osteoarthritis Cartilage. 2010 Jun,18(6):817-24. Soerensen et al. The Mn-superoxide dismutase single nucleotide polymorphism rs4880 and the glutathione peroxidase 1 single nucleotide polymorphism rs1050450 are associated with aging and longevity in the oldest old. Mech Ageing Dev. 2009 May,130(5):308-14. Steinbrecher et al. Effects of selenium status and polymorphisms in selenoprotein genes on prostate cancer risk in a prospective study of European men. Cancer Epidemiol Biomarkers Prev. 2010 Nov,19(11):2958-68. Chen et al. GPx-1 polymorphism (rs1050450) contributes to tumor susceptibility: evidence from meta-analysis. J Cancer Res Clin Oncol. 2011 Oct,137(10):1553-61. Karunasinghe et al. Serum selenium and single-nucleotide polymorphisms in genes for selenoproteins: relationship to markers of oxidative stress in men from Auckland, New Zealand. Genes Nutr. 2012 Apr,7(2):179-90. Hong et al. GPX1 gene Pro200Leu polymorphism, erythrocyte GPX activity, and cancer risk. Mol Biol Rep. 2013 Feb,40(2):1801-12. Jablonska E et al. Association between GPx1 Pro198Leu polymorphism, GPx1 activity and plasma selenium concentration in humans. Eur J Nutr. 2009 Sep,48(6):383-6.

NQO1 - NAD(P)H dehydrogenase, quinone 1 (rs1800566) The enzyme NAD(P)H dehydrogenase, encoded by the NQO1, is a so-called oxidoreductase, and catalyzes the oxidation of nicotinamide adenine dinucleotide (NAD). The polymorphism rs1800566 inhibits the enzymatic activity, and coenzyme Q10 cannot be converted into ubiquinol, or the conversion is slower than normal. RES

Genotype

C/C

66% The enzyme NQO1 effectively converts the coenzyme Q10 into the antioxidant ubiquinol.

C/T

30% The enzyme NQO1 converts the coenzyme Q10 into the antioxidant ubiquinol at a slower rate

T/T

POP

Result options

The enzyme NQO1 cannot convert the coenzyme Q10 into the antioxidant ubiquinol

References Fischer et al. Association between genetic variants in the Coenzyme Q10 metabolism and Coenzyme Q10 status in humans. Published online Jul 21, 2011. Freriksen et al. Genetic polymorphism 609C>T in NAD(P)H:quinone oxidoreductase 1 enhances the risk of proximal colon cancer. J Hum Genet. 2014 May 15.

Page 64 of 81

COMT - Catechol-O-methyltransferase (rs4680) The enzyme catechol-O-methyltransferase (COMT) can inactivate various substances (epinephrine, norepinephrine, and dopamine) and perform the reduction. In addition, COMT may inhibit the effect of various drugs. The COMT rs4680 polymorphism is associated with psychological disorders, such as schizophrenia, eating disorders and alcoholism. RES

Genotype

POP

Result options

A/A

20% No effect Increased risk of alcoholism

A/G

55% Increased risk of schizophrenia when cannabis is consumed under the age of 16 years (OR: 2.5) Normal risk of alcoholism

G/G

25% Increased risk of schizophrenia when cannabis is consumed under the age of 16 years (OR: 10.9) Normal risk of alcoholism

References Caspi et al. Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction. Biol Psychiatry. 2005 May 15,57(10):1117-27. Kauhanen J et al. Association between the functional polymorphism of catechol-O-methyltransferase gene and alcohol consumption among social drinkers. Alcohol Clin Exp Res. 2000 Feb,24(2):135-9.

CYP1A2 - cytochrome P450, family 1, subfamily A, polypeptide 2 (rs762551) The heme protein cytochrome P450-1A2 (CYP1A2) belongs to the group of cytochrome P450 enzymes, and metabolizes various xenobiotic substances (including caffeine), medications, and estrogens. The polymorphism rs762551 is associated with the risk of breast cancer. RES

Genotype

POP

A/A

51%

A/C

42% Caffeine is broken down slowly Coffee consumption does not influence the appearance of breast cancer

C/C

Result options Caffeine is broken down normally The consumption of 2 or more cups of coffee per day delays the appearance of breast cancer with approximately 7 years (59.8 years instead of 52.6 years).

Caffeine is broken down slowly Coffee consumption does not influence the appearance of breast cancer

References B책geman et al. Coffee consumption and CYP1A2*1F genotype modify age at breast cancer diagnosis and estrogen receptor status. Cancer Epidemiol Biomarkers Prev. 2008 Apr,17(4):895-901.

Page 65 of 81

Prevention Early diagnosis Treatment

BONE HEALTH SENSOR Osteoporosis: Stopping bone density loss and improving treatment • Genetic assessment of innate osteoporosis risk • Analysis of more than 3 relevant genetic variations • Assessment of calcium absorption capacity • Adapted diet and prevention program for osteoporosis • Effectiveness assessment of various therapies (bisphosphate, raloxifene, alendronate, hormones) • Analysis of more than 12 genetic variations, for the effect of more than 18 relevant drugs • Increased treatment success through customization • Medically supervised prevention program

MOBILITY

Osteoporosis Osteoporosis is a disease that affects the bones. It causes bones to lose mass and strength, and makes them more fragile and easier to fracture. Even in normal development, bones become more likely fracture with age. Bones reach maximum strength at about the age of 30, and bone mass decreases moderately after that time. However, some genetic traits lead to reduced bone strength, which increases the risk of osteoporosis and bone fractures, especially of the hips, forearms and vertebra. This risk grows with age. women, mainly because the body no longer produces the bone-protective hormone estrogen. The disease is very common: one in three women over the age of 50 is diagnosed with osteoporosis. As estrogen, the female sex hormone, plays a significant role for women in the formation of bone, women who have had lower estrogen levels throughout their life (e.g. due to a late start of menstruation or premature menopause) are particularly at risk.

Most fractures involve the hips, forearms and vertebrae. In normal development these bones grow throughout childhood and reach maximum strength at about age 30. After that time, bone mass gradually decreases, leading to somewhat more brittle bones. However, some traits in the genes that are responsible for bone formation can cause your bones to become unusually fragile over time. As you age, this leads to increased bone loss and fractures. About 80% of osteoporosis cases occur in post-menopausal

The osteoporosis is a common disease for men over the age of 70. Although women are more often affected by osteoporosis, this disease affects both sexes, and its development is accelerated by certain risk factors such as poor diet and unhealthy lifestyle. Not only calcium, but also numerous other micronutrients (such as minerals, amino acids, and vitamins) are important in maintaining healthy bones. Bones have the capability to store calcium, but these reserves are depleted in the case of nutritional deficiencies, for providing the calcium needed for other important processes in the body. Vitamin D also plays an important role in the absorption of calcium from food. In the case of the elderly, the conversion to the active form of vitamin D is poor; in addition, the vitamin D intake from food is too low. As such the vitamin D deficiency is a largely spread problem, but one that can be easily solved. The incipient phases of the disease are sometimes not associated with any recognizable symptoms, and the diagnosis is made only when Page 67 of 81

the first bone fractures occur. Previous to this point, the bone density is, however, compromised, and the bones may be fractured even in the case of low injuries or low effort, and can occur, for example, when bending or lifting a heavy bag. If the disease is diagnosed at a late stage, treatment is based on preventing falls and increasing bone density as much as possible. This is achieved through a diet rich in calcium and vitamin D, adequate exercise and by use of medication that promotes bone metabolism. The best defense against osteoporosis is, and will remain, prevention. The earlier the disease is diagnosed, the more quickly you can take action to stop bone deterioration. Preventing bone loss is always easier than recovering lost bone. That is exactly what makes this gene test so valuable for preventative health care: you learn what your personal risk of disease is and can often completely prevent the disease from developing and following a prevention program tailored to your individual needs.

Page 68 of 81

MOBILITY

Genes associated with osteoporosis So far, scientists have identified 4 genes with traits linked to an increased risk of osteoporosis. An analysis of all 4 traits allows us to determine your genetic risk for osteoporosis as well as some other genetic traits linked to this disease. The following genes affect the preservation of bone mass:

Genetic risks and traits SYMBOL

rs NCBI

POLYMORPH.

GENOTYPE

RESPOND

PROTECT.

RISK

Col1A1

rs1800012

G/T Pos. 1546 (S/s)

G/G

RESPOND

VDR

rs1544410

G/A IVS7 Pos.+283

G/G

0.61

RESPOND

PROTECT.

ESR1

rs2234693

-397T>C

C/C

RESPOND

PROTECT.

LCT

rs4988235

T>C

T/T

Page 69 of 81

Summary of effects Some genetic traits reduce your risk of osteoporosis, while others increase risk. Genetic traits that impair calcium uptake also affect bone mass. Here is a summary of the effects that the genetic variations have on your health and body: ➤ Your risk of osteoporosis is not elevated (OR = 1) ➤ Bisphosphate is especially effective for osteoporosis prevention ➤ You have a normal capacity for absorbing calcium Your risk for osteoporosis PROTECTION

AVERAGE RISK

INCREASED

▲

Effectiveness of bisphosphate therapy HIGH

REDUCED

▲ Your capacity to absorb calcium NORMAL

REDUCED

▲

Page 70 of 81

MOBILITY

Prevention Genetic analysis shows that you do not have an increased risk of osteoporosis and do not need to place a strong emphasis on taking preventive measures necessary other than the general rules of a healthy life style. However, you should avoid medications that are associated with an increased risk of osteoporosis. Everyone loses some bone mass over time. So even though you do not have a genetic predisposition for osteoporosis, you should still take steps to minimize your bone loss. Eat a balanced diet, and make sure that you consume enough dairy products (if you are not lactose intolerant), which are a good source of calcium. Calcium is the raw material necessary for bone regeneration, and it is vital to make sure you are getting enough. â&#x17E;¤ Ensure an adequate uptake of vitamin D. The body produces this vitamin in the presence of sunlight, so you should spend as much time as possible outdoors. Vitamin D is also contained in food products such as fish, and in lower quantities in milk, as well as in some nutritional supplements (fish oils). Depending on your own requirements, you can also take vitamin D as medical treatment. â&#x17E;¤ Sport is, of course, recommended to everybody. Endurance and mild power oriented exercise is recommended to strengthen the bones and muscles.

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MOBILITY

Effect on relevant drugs The effect that various medications will have on you depends on your genetic profile. Genetic variations indicate that the dosage of some drugs should be adjusted. The following recommendations are based on your genetic analysis:

Painkillers (analgesics) Painkillers

effect

Breakdown

Adverse Reaction

recommended dose*

alternative?

alfentanil

Normal

~100%

Normal

~100%

Not neccessary

buprenorphine

Normal

~100%

Normal

~100%

Not neccessary

codeine (FDA!)

likely higher

~20%

common

~20%

Advisable

enflurane

Normal

~100%

Normal

~100%

Not neccessary

fentanyl

Normal

~100%

Normal

~100%

Not neccessary

halothane

Normal

~100%

Normal

~100%

Not neccessary

hydrocodone

Normal

~0%

common

Advisable

isoflurane

Normal

~100%

Normal

~100%

Not neccessary

levacetylmethadol

likely higher

~100%

Normal

~100%

Not neccessary

lidocaine

Normal

~100%

Normal

~100%

Not neccessary

methadone

Normal

~90%

Normal

~100%

Not neccessary

methoxyflurane

Normal

~100%

Normal

~100%

Not neccessary

oxycodone

Normal

~0%

common

Advisable

paracetamol

Normal

~100%

Normal

~100%

Not neccessary

phenacetin

Normal

~100%

Normal

~100%

Not neccessary

ropivacaine

Normal

~100%

Normal

~100%

Not neccessary

sevoflurane

Normal

~100%

Normal

~100%

Not neccessary

tramadol (FDA!)

likely higher

~40%

common

~50%

Advisable

zolmitriptan

Normal

~100%

Normal

~100%

Not neccessary

REMEMBER: Only your doctor can prescribe the correct drugs and dosage. NEVER stop taking a drug or change the dose: consult your doctor instead!

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SCIENCE

Bone Health Sensor Col1A1 - Collagen, type I, alpha 1 (rs1800012) The protein encoded by COL1A1 (collagen type I, alpha 1) is the main protein component of the bone matrix. Defects in the COL1A1 structure cause changes in the bone matrix. RES

Genotype

POP

Result options

G/G

81%

No increased risk for osteoporosis BIS-phosphonate therapy is effective

G/T

17%

Increased risk of osteoporosis (OR: 1.26) BIS-phosphonate therapy is less effective

T/T

Increased risk of osteoporosis (OR: 1.78) BIS-phosphonate therapy is less effective

References Jin et al. Polymorphisms in the 5' flank of COL1A1 gene and osteoporosis: meta-analysis of published studies. Osteoporos Int. 2011 Mar,22(3):911-21. Qureshi et al. COLIA1 Sp1 polymorphism predicts response of femoral neck bone density to cyclical etidronate therapy. Calcif Tissue Int. 2002 Mar,70(3):158-63. Epub 2002 Feb 19.

VDR - Vitamin D (1,25- dihydroxyvitamin D3) receptor (rs1544410) The vitamin D receptor protein (VDR) is the primary regulator of calcium and bone metabolism. Vitamin D also controls a variety of important functions, such as: calcium absorption, bone growth and the production of hormones. A defect in this gene leads, inter alia, to changes of the bones density. RES

Genotype

POP

Result options

G/G

35% Protection against osteoporosis (OR: 0.61) Hormone replacement therapy is effective in the prevention of osteoporosis Raloxifene is less effective in the treatment of osteoporosis Bisphosphonate therapy is effective

A/G

43% Increased risk of osteoporosis (OR: 1.26) BIS-phosphonate therapy is less effective

A/A

22% Increased risk of osteoporosis (OR: 1.78) BIS-phosphonate therapy is less effective

References Jia et al. Vitamin D receptor BsmI polymorphism and osteoporosis risk: a meta-analysis from 26 studies. Genet Test Mol Biomarkers. 2013 Jan,17(1):30-4. Palomba et al. BsmI vitamin D receptor genotypes influence the efficacy of antiresorptive treatments in postmenopausal osteoporotic women. A 1-year multicenter, randomized and controlled trial. Osteoporos Int. 2005 Aug,16(8):943-52. Palomba et al. Raloxifene administration in post-menopausal women with osteoporosis: effect of different BsmI vitamin D receptor genotypes. Hum Reprod. 2003 Jan,18(1):192-8.

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ESR1 - Estrogen receptor 1 (rs2234693) Estrogens have a positive effect on the human skeleton, through the regulation of bone metabolism, the control of the optimal bone mass and the limitation of bone loss. Defects in this gene can negatively influence these effects. RES

Genotype

POP

Result options

C/C

15%

No increased risk for osteoporosis Hormone replacement therapy is effective in the prevention of osteoporosis

C/T

51%

Increased risk of osteoporosis (OR: 2) Hormone replacement therapy is less effective in the prevention of osteoporosis

T/T

34% Increased risk of osteoporosis (OR: 4) Hormone replacement therapy is less effective in the prevention of osteoporosis

References Sonoda et al. Interaction between ESRÎą polymorphisms and environmental factors in osteoporosis. J Orthop Res. 2012 Oct,30(10):1529-34. Wang et al. Susceptibility genes for osteoporotic fracture in postmenopausal Chinese women. J Bone Miner Res. 2012 Dec,27(12):2582-91 van Meurs JB et al. Association of 5' estrogen receptor alpha gene polymorphisms with bone mineral density, vertebral bone area and fracture risk. Hum Mol Genet. 2003 Jul 15,12(14):1745-54.

LCT - lactase (rs4988235) The LCT gene provides instructions for making the lactase protein, an enzyme which helps to digest lactose in the small intestine, so that it can be absorbed. If the LCT gene is defective, the lactose cannot be properly digested. In this case the lactose intolerance occurs. Avoiding the dairy products leads to a reduced absorption of calcium. RES

Genotype

POP

Result options

T/T

55% Normal calcium intake from food

T/C

36% Normal calcium intake from food

C/C

Reduced calcium intake from food

References Koek et al. The T-13910C polymorphism in the lactase phlorizin hydrolase gene is associated with differences in serum calcium levels and calcium intake.

Page 74 of 81

CUSTOMER SERVICE

Customer Service Questions or comments about our service? Our customer service team is happy to help with any enquiries, questions or problems. You can contact us in the following ways:

➤ Office: 0046 (0) 31-30 99 111 ➤ info@dna-medic.com Our team is looking forward to your call. Customer satisfaction is our first priority. If you are not fully satisfied with our service, please let us know. We will do our best to help find a satisfactory solution to your problem.

Contact | Impressum DNA MEDIC SCANDINAVIA AB OLOF ASKLUNDS GATA 1 S-421 30 VÄSTRA FRÖLUNDA SWEDEN

Page 75 of 81

CERTIFICATIONS

Certifications The Novogenia laboratory is one of the most modern and automated laboratories in Europe, and has numerous certifications and quality assurance systems that meet international standards or even exceed them. The various fields of business are certified separately to the highest standards.

Analysis for Lifestlye-purposes

Analysis of medical genetic samples

Certified through analysis in our ISO 15189 certified laboratory

Certified through analysis in an ISO 17025 certified laboratory

Medical interpretation of genetic analyses

Scientific release of analysis results

Certified through analysis in our ISO 15189 certified laboratory

Licensed for medical genetic analyses by the Austrian government

Company and office Certified through ISO 9001

Page 76 of 81

TECHNICAL DETAILS

Technical details Address

Method of analysis

Olof Asklundsgata 1 42130 Västra Frölunda SWEDEN

Automated DNA extraction, HRM analysis (as needed), mass spectrometry and TaqMAN real time PCR

Order number

Detection rate

DEMO_DNAMEDIC

~99%

Date of birth

Sample type

01/01/1985

Cheek swab / saliva sample

Responsible company

Analysis times

DNA MEDIC SCANDINAVIA AB OLOF ASKLUNDS GATA 1 S-421 30 VÄSTRA FRÖLUNDA SWEDEN

Sample received: 01/06/2014 Analysis started: 02/06/2014 Analysis completed: 04/06/2014 Report generated: 04/06/2014

Analyzing laboratory

Version

Novogenia GmbH Saalachstrasse 92 5020 Salzburg AUSTRIA

v223 MEDIC

Laboratory director Dr. Daniel Wallerstorfer, B.Sc.

Page 77 of 81

REFERENCES All our results and processes are based on current scientific information and comply completely with all legal requirements. Prostate Health Sensor (Prostate Cancer) ➤ S. Lilly Zheng et al. Cumulative Association of Five Genetic Variants with Prostate Cancer, N Engl J Med 2008;358:910-9 ➤ Holick CN, Stanford JL, Kwon EM, Ostrander EA, Nejentsev S, Peters U. Comprehensive association analysis of the vitamin D pathway genes, VDR, CYP27B1, and CYP24A1, in prostate cancer. Cancer Epidemiol Biomarkers Prev. 2007 Oct;16(10):1990-9. ➤ S. Lilly Zheng et al. Association Between Two Unlinked Loci at 8q24 and Prostate Cancer Risk Among European Americans. JNCI Journal of the National Cancer Institute 2007 99(20):1525-1533 ➤ Zhiyong Ma et al, Polymorphisms of fibroblast growth factor receptor 4 have association with the development of prostate cancer and benign prostatic hyperplasia and the progression of prostate cancer in a Japanese population. Int. J. Cancer: 123, 2574–2579 (2008) ➤ H. Nguyen et al.:Normal Human Ejaculatory Duct Anatomy: A Study of Cadaveric and Surgical Specimens In: The Journal of Urology, Volume 155, Issue 5, Pages 1639-1642 ➤ www.krebshilfe.net ➤ Barry MJ, Fowler FJ, O'Leary MP, et al. (November 1992). "The American Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association". ➤ eMedicine - Transurethral Microwave Thermotherapy of the Prostate (TUMT) : Article by Jonathan Rubenstein ➤ www.urologielehrbuch.de ➤ PreventProstateCancer.info: A Brief Overview of Benign Prostatic Hyperplasia (BPH) ➤ MacDonald R; Wilt TJ; Howe RW (December 2004). "Doxazosin for treating lower urinary tract symptoms compatible with benign prostatic obstruction: a systematic review of efficacy and adverse effects". BJU International 94 (9): 1263–70. ➤ MacDonald R; Wilt TJ (October 2005). "Alfuzosin for treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia: a systematic review of efficacy and adverse effects". Urology 66 (4): 780–8. ➤ Roehrborn CG (December 2001). "Efficacy and safety of oncedaily alfuzosin in the treatment of lower urinary tract symptoms and clinical benign prostatic hyperplasia: a randomized, placebocontrolled trial". Urology 58 (6): 953–9. ➤ Holmium Laser Enucleation of the Prostate; Results at 6 Years, Gilling PJ, Aho, TF, Frampton CM, et al. Eur Urol 2008 Apr:53(4):744-9 ➤ Bundesministerium für Gesundheit ➤ http://www.bccancer.bc.ca ➤ Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, Feuer EJ, Thun MJ (2005). "Cancer statistics, 2005". CA Cancer J Clin 55 (1): 10–30. ➤ Miller DC, Hafez KS, Stewart A, Montie JE, Wei JT (September 2003). "Prostate carcinoma presentation, diagnosis, and staging: an update form the National Cancer Data Base". Cancer 98 (6): 1169–78 ➤ Mongiat-Artus P, Peyromaure M, Richaud P, Droz JP, Rainfray M, Jeandel C, Rebillard X, Moreau JL, Davin JL, Salomon L, Soulié M (December 2009). "[Recommendations for the treatment of prostate cancer in the elderly man: A study by the oncology committee of the French association of urology]" (in French). Prog. Urol. 19 (11): 810–7 ➤ Picard JC, Golshayan AR, Marshall DT, Opfermann KJ, Keane TE (November 2009). "The multi-disciplinary management of high-risk prostate cancer". Urol. Oncol ➤ Prostatakrebs-Kodierhilfe. Tumorzentrum Freiburg 2007 ➤ UICC: What are the changes between the 6th and 7th editions? ➤ Christian Wittekind, Hans-Joachim Meyer (Hrsg.): TNM: Klassifikation maligner Tumoren. Wiley-VCH Verlag, 7. Auflage 2010 ➤ Ronald J. Zagoria, Glenn A. Tung: Genitourinary Radiology.

Mosby, St. Louis 1997 ➤ Poon KS, McVary KT. Curr Urol Rep. 2009 Jul;10(4):279-86. Dietary patterns, supplement use, and the risk of benign prostatic hyperplasia. ➤ C.M. Yablon, M.P. Banner, P. Ramchandani, E.S. Rovner: Complications of prostate cancer treatment: spectrum of imaging findings. Radiographics (2004) 24(Suppl 1):S181-S194 ➤ G. L. Lu-Yao u. a.: Survival following primary androgen deprivation therapy among men with localized prostate cancer. In: JAMA 300, 2008, S. 173–181 ➤ I. F. Tannock u. a.: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. In: NEJM 351, 2004, S. 1502–1512. ➤ C.R. Porter et al.: 25-year prostate cancer control and survival outcomes: a 40-year radical prostatectomy single institution series. J Urol. (2006) 176(2):569-74 ➤ American Cancer Society ➤ Deutsche Gesellschaft für Urologie ➤ Berkow SE et al.: Diet and survival after prostate cancer diagnosis. Nutr Rev. (2007) 65(9):391-403 ➤ Kolonel LN: Fat, meat, and prostate cancer. Epidemiol Rev (2001) 23(1):72-81 ➤ Michaud et al.: A prospective study on intake of animal products and risk of prostate cancer. Cancer Causes Control. (2001) 12(6):557-67. ➤ Skinner HG, Schwartz GG: Serum calcium and incident and fatal prostate cancer in the National Health and Nutrition Examination Survey. Cancer Epidemiol Biomarkers Prev. (2008) 17: 2302-5 ➤ Sonnenmangel fördert Krebs!, Medical Tribune, 42. Jg., Nr. 23, 8. Juni 2007, S. 21 ➤ Wigle DT, Turner MC, Gomes J, Parent ME (March 2008). "Role of hormonal and other factors in human prostate cancer". Journal of Toxicology and Environmental Health. Part B, Critical Reviews 11 (3-4): 242–59 ➤ Kirsh VA, Peters U, Mayne ST, Subar AF, Chatterjee N, Johnson CC, Hayes RB (August 2007). "Prospective study of fruit and vegetable intake and risk of prostate cancer". J. Natl. Cancer Inst. 99 (15): 1200–9 ➤ Shannon J, Phoutrides E, Palma A, Farris P, Peters L, Forester A, Tillotson CJ, Garzotto M (2009). "Folate intake and prostate cancer risk: a case-control study". Nutr Cancer 61 (5): 617–28 ➤ Herschman JD, Smith DS, Catalona WJ (August 1997). "Effect of ejaculation on serum total and free prostate-specific antigen concentrations". Urology 50 (2): 239–43

Cardiovascular sensor (cardiovascular disease) ➤ Herold, Innere Medizin 2008 ➤ MSD Manual, Handbuch Gesundheit, Goldmann, 2.Auflage ➤ Deutsche Gesellschaft zur Bekämpfung von Fettstoffwechselstörungen und ihren Folgeerkrankungen DGFF e.V ➤ Cholesterin, Wozu wir es brauchen und warum es uns krank macht, C.H.Beck, 1999 Dr. Ursel Wahrburg, Dr. Gerd Assmann ➤ Cholesterin, Risiko für Herz und Gefäße, Edita Pospisil, 2008 ➤ NCEP, Nationales Cholesterin-Erziehungsprogramm ➤ Daniel Steinberg (2007). The Cholesterol Wars: The Cholesterol Skeptics vs the Preponderance of Evidence. Boston: Academic Press. ➤ Philips et al. Gene-nutrient interaction and gender may modulate the association between ApoA1 And ApoB gene polymorphisms and metabolic syndrom risk. Atherosclerosis 2011.214(2):408-14 American Heart Association ➤ Olson RE (February 1998). ""Discovery of the lipoproteins, their role in fat transport and their significance as risk factors"". J. Nutr. 128 (2 Suppl): 439S–443S. PMID 9478044 ➤ Lewington S, Whitlock G, Clarke R, Sherliker P, Emberson J,

Page 78 of 81

Halsey J, Qizilbash N, Peto R, Collins R (December 2007). ""Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths"". Lancet 370 (9602): 1829–39. ➤ National Cholesterol Education Program (NCEP) ➤ Atherosclerosis. 2011 Feb:214(2):397-403. Epub 2010 Nov 16. Strong association of the APOA5-1131T>C gene variant and earlyonset acute myocardial infarction. De Caterina R, Talmud PJ, Merlini PA, Foco L, Pastorino R, Altshuler D, Mauri F, Peyvandi F, Lina D, Kathiresan S, Bernardinelli L, Ardissino D: Gruppo Italiano Aterosclerosi ➤ Defesche, J. C.. Kastelein, J. J. P. : Molecular epidemiology of familial hypercholesterolaemia. (Letter) Lancet 352: 1643-1644, 1998 ➤ Hobbs et al. 1992 Hum Mut 1:445 ➤ Defesche et al. 1998 FH workshop 1997 ➤ Lombardi et al. 1998 MEDPED 1998 ➤ Redeker et al. 1998 EAS 98 ➤ Schmidt et al. 2000 Atheroscler 148: 431 ➤ Association of APOE genotype with carotid atherosclerosis in men and women, the framingham Heart Study: Roberto Elosua et al. The journal of lipid research 45, 1868-1875, 2004" ➤ Bilguvar K. et al., 2008; PMID 18997786 ➤ Helgadottir A. et al., 2008; PMID 18176561 ➤ Helgadottir A. et al., 2007; PMID 17478679 ➤ Karvanen J. et al., 2009; PMID 18979498 ➤ Samani N.J. et al., 2007; PMID 17634449 ➤ Schunkert H. et al., 2008; PMID 18362232 ➤ Wellcome Trust Case Control Consortium 2007; PMID 17554300 ➤ Aarnoudse A.J. et al., 2007; PMID 17576865 ➤ Arking D.E. et al., 2006; PMID 16648850 ➤ Eijgelsheim M. et al., 2009; PMID 18927126 ➤ Kao W.H. et al., 2009; PMID 19204306 ➤ Lehtinen A.B. et al, 2008; PMID 18235038 ➤ Newton-Cheh C. et al., 2007; PMID 17903306 ➤ Raitakari O.T. et al., 2009; PMID 18785031 ➤ Ashfield-Watt P.A. et al., 2002; PMID 12081832 ➤ Bonaa K.H. et al.; 2006; PMID 16531614 ➤ Khandanpour N. et al., 2009; PMID 19157768 ➤ Lewis S.J. et al., 2005; PMID 16216822 ➤ Lichtenstein A.H., 2009; PMID 18997166 ➤ Lonn E. et al., 2006; PMID 16531613 ➤ McNulty H. et al., 2008; PMID 18412997 ➤ Ruiz J.R. et al., 2007; PMID 17298693 ➤ Wald D.S. et al., 2006; PMID 17124224 ➤ Wang X. et al., 2007; PMID 17544768 ➤ Angotti E. et al., 1994; PMID 8021234 ➤ Juo S.H. et al., 1999; PMID 10215547 ➤ Ordovas J.M. et al., 2002; PMID 11756058 ➤ Ordovas J.M., 2004; PMID 15070444 ➤ Subbiah M.T., 2007; PMID 17240315 ➤ Tuteja R. et al., 1992; PMID 1618307 ➤ Angelopoulos T.J. et al., 2008; PMID 18806463 ➤ Bennet A.M. et al., 2007; PMID 17878422 ➤ Caslake M.J. et al., 2008; PMID 18779276 ➤ Jofre-Monseny L. et al., 2008; PMID 18203129 ➤ Lovegrove J.A. et al., 2008; PMID 18412994 and PMID 18721398 ➤ Masson L.F. et al., 2003; 12716659 ➤ Minihane A.M. et al., 2007; PMID 17466101 ➤ Minihane A.M. et al., 2000; PMID 10938022 ➤ Aberle J. et al., 2005; PMID 15996212 ➤ Aouizerat B.E. et al., 2003; PMID 12671030 ➤ Dorfmeister B. et al., 2007; PMID 17197160 ➤ Evans D. et al., 2003; PMID 12937897 ➤ Grallert H. et al., 2007; PMID 17768309 ➤ Klos K.L. et al., 2005; PMID 15604515 ➤ Lai C.Q. et al., 2007; PMID 17431185 ➤ Lai C.Q. et al., 2006; PMID 16636175 ➤ Maász A. et al., 2007; PMID 17922054 ➤ Szalai C. et al., 2004; PMID 15177130 ➤ Vaessen S.F. et al., 2006; PMID 16769999 ➤ Wang J. et al., 2008; PMID 18779834 ➤ Yamada Y. et al., 2007; PMID 16806226

Thrombo Sensor (Thrombosis) ➤ Bertina, R. M.; Koeleman, B. P. C.; Koster, T.; Rosendaal, F. R.; Dirven, R. J.; de Ronde, H.; van der Velden, P. A.; Reitsma, P. H. : Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 369: 64-67, 1994. PubMed ID : 8164741 ➤ J.-M.Hahn, Innere Medizin, 5.Auflage, S.321-323 ➤ Ridker, P. M.; Miletich, J. P.; Stampfer, M. J.; Goldhaber, S. Z.; Lindpaintner, K.; Hennekens, C. H. : Factor V Leiden and risks of recurrent idiopathic venous thromboembolism. Circulation 92: 2800-2802, 1995. PubMed ID : 7586244

➤ A.Encke, H.K. Bredding, Die venöse Thrombose- Prophylaxe und Therapie, 2000, S.45-49, S.150-158 ➤ Rosendaal FR, Koster T, Vanderroucke, JP, and others. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood 1995; 85: 1504-8. ➤ Internist MR Dr.Karl F.Maier, Thrombosen und Venenerkrankungen, 2003, S.37-82 ➤ Bettina Kemkes-Matthes/Oehler, Blutgerinnung und Thrombose, 3.Auflage, 2001, S.69-132 ➤ Lüllmann, Pharmakologie und Toxologie, 16. Auflage, S.178-199, 362-404 ➤ MSD Manual, Handbuch Gesundheit, 2.Auflage ➤ Lancet. 1995 Dec 16;346(8990):1593-6. Enhancement by factor V Leiden mutation of risk of deep-vein thrombosis associated with oral contraceptives containing a third-generation progestagen. Bloemenkamp KW, Rosendaal FR, Helmerhorst FM, Büller HR, Vandenbroucke JP. ➤ Majerus, P. W. : Bad blood by mutation. Nature 369: 14-15, 1994. PubMed ID : 8164730 ➤ Juul, K.; Tybjaerg-Hansen, A.; Schnohr, P.; Nordestgaard, B. G. : Factor V Leiden and the risk for venous thromboembolism in the adult Danish population. Ann. Intern. Med. 140: 330-337, 2004. PubMed ID : 14996674 ➤ Braun, A.; Muller, B.; Rosche, A. A. : Population study of the G1691A mutation (R506Q, FV Leiden) in the human factor V gene that is associated with resistance to activated protein C. Hum. Genet. 97: 263-264, 1996. PubMed ID : 8566967 ➤ Corsetti J.P. et al., 2008; PMID 18096824 ➤ Gardemann A. et al., 1999; PMID 10494775 ➤ Martinelli N. et al., 2008; PMID 18253477 ➤ Roest M. et al., 2000; PMID 10618306 ➤ Saely C.H. et al., 2008; PMID 18619429 ➤ Tsantes A.E. et al., 2007; PMID 17581326 ➤ Tsantes A.E. et al., 2007; PMID 17549286 ➤ Ye Z. et al., 2006; PMID 16503463 ➤ Burzotta F. et al., 2004; PMID 14676252 ➤ Casas J. P. et al., 2004; PMID 15534175 ➤ Cushman M. et al., 2004; PMID 15467059 ➤ Dentali F. et al., 2006; PMID 16397131 ➤ Marchiori A. et al., 2007; PMID 17650440 ➤ Psaty B.M. et al., 2001; PMID 11180734 ➤ Dentali F. et al., 2006; PMID 16397131 ➤ Juul K. et al., 2004; PMID 14996674 ➤ Marchiori A. et al., 2007; PMID 17650440 ➤ Mohllajee A.P. et al., 2006; PMID 16413847 ➤ Rosendaal F.R. et al., 2002; PMID 11886391 ➤ Rossouw J.E. et al., 2002; PMID 12117397 ➤ Scarabin P.Y. et al. 2003; PMID 12927428 ➤ Seed M.; 2004; PMID 15243220 ➤ Smith N.L. et al. 2004; PMID 15467060 ➤ Weischer M. et al., 2009; PMID 19524925

Toxo Sensor (Detoxification of toxins) ➤ García-Closas M et al. NAT2 slow acetylation, GSTM1 null genotype, and risk of bladder cancer: results from the Spanish Bladder Cancer Study and meta-analyses. Lancet. 2005 Aug 20-26;366(9486):649-59. ➤ Dufour C et al. Genetic polymorphisms of CYP3A4, GSTT1, GSTM1, GSTP1 and NQO1 and the risk of acquired idiopathic aplastic anemia in Caucasian patients. Haematologica. 2005 Aug;90(8):1027-31. ➤ Kyoung-Mu Lee et al. CYP1A1, GSTM1, and GSTT1 Polymorphisms, Smoking, and Lung Cancer Risk in a Pooled Analysis among Asian Populations. Cancer Epidemiology, Biomarkers & Prevention May 2008 17; 1120 ➤ Luch, A. (2005). The Carcinogenic Effects of Polycyclic Aromatic Hydrocarbons. London: Imperial College Press. ISBN 1-86094-417-5. ➤ Bundesinstitut für Risikobewertung: Polyzyklische aromatische Kohlenwasserstoffe (PAK) in Spielzeug. Aktualisierte Stellungnahme Nr. 051/2009 des BfR vom 14. Oktober 2009, Abschnitt 3.1.3 „Exposition“. ➤ Carcinogenesis. 2005 Dec;26(12):2207-12. Epub 2005 Jul 28. CYP1A1 and CYP1B1 polymorphisms and risk of lung cancer among never smokers: a population-based study. Wenzlaff AS, ➤ Gao Y, Cao Y, Tan A, Liao C, Mo Z, Gao F.Glutathione S-transferase M1 polymorphism and sporadic colorectal cancer risk: An updating meta-analysis and HuGE review of 36 case-control studies. Ann Epidemiol. 2010 Feb;20(2):108-21. ➤ S.W. Baxter, E.J. Thomas and I.G. Campbell. GSTM1 null polymorphism and susceptibility to endometriosis and ovarian cancer. Carcinogenesis, Vol. 22, No. 1, 63-66, January 2001 ➤ Tamer L, Calikoğlu M, Ates NA, Yildirim H, Ercan B, Saritas E, Unlü A, Atik U. Glutathione-S-transferase gene polymorphisms (GSTT1, GSTM1, GSTP1) as increased risk factors for asthma. Respirology.

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