OVERVIEW
How genetic variants can disrupt protective systems in our body
MICRONUTRIENTS Genes fulfill a number of protective roles in the body OXIDATIVE STRESS
GPX1 SOD2
TNFa
AGRESSIVE IMMUNE SYSTEM
IL1A
MTHFR
REGULATE HOMOCYSTEINE
MTRR
GSTM1
REMOVE TOXINS FROM BODY
GSTT1
MICRONUTRIENTS
Genetic variants disrupt protective effect OXIDATIVE STRESS
GPX1 SOD2
TNFa
AGRESSIVE IMMUNE SYSTEM
IL1A
MTHFR
REGULATE HOMOCYSTEINE
MTRR
GSTM1
REMOVE TOXINS FROM BODY
GSTT1
OVERVIEW
How micronutrients can recover some of the lost function
MICRONUTRIENTS
Certain micronutrients can recover lost function OXIDATIVE STRESS
GPX1 SOD2
Vit E Vit C
Vit A ALA
TNFa
AGRESSIVE IMMUNE SYSTEM
IL1A
MTHFR
REGULATE HOMOCYSTEINE
MTRR
GSTM1
REMOVE TOXINS FROM BODY
GSTT1
Folic acid Vit B12
Vit B6
Calcium Iron
Selenium
MICRONUTRIENTS The concept: Test 50+ genes and determine the requirement of 22 micronutrients Bone Health Osteoporosis (Calcium, Vit D, Magnesium)
Eye Health Macular Degeneration (Antioxidants)
Joint Health Rheumatoid Arthritis (Omega3)
Metabolic Health Iron overload disorder (Iron)
Heart health Cholesterol (Omega3) Homocysteine (Folic acid, B-Vitamins)
Food intolerances Lactose Intolerance (calcium) Coeliac disease (Multivitamin)
Cognitive Health Alzheimers disease (Antioxidants)
Detoxification Heavy metals (Calcium, Selenium, Iron)
OVERVIEW
One example of how genetics influence micronutrient requirement
OXIDATIVE STRESS Free radicals damage cells
5% of oxygen SOD2
Superoxide
Mitochondria
SOD3
SOD1
HydrogenPeroxide
5% of oxygen becomes Superoxide, a free radical. 3 genes protect the cell in various locations from these damaging chain reactions
CYTOPLASM OF A CELL
OXIDATIVE STRESS Free radicals damage cells
5% of oxygen
Superoxide
Mitochondria
SOD3
SOD1
HydrogenPeroxide
27% of the population has a genetic variant in this gene, abolishing its protective effect.
CYTOPLASM OF A CELL
OXIDATIVE STRESS Free radicals damage cells
5% of oxygen
Superoxide
Mitochondria
SOD3
SOD1
HydrogenPeroxide
Superoxide damages cells and speeds up ageing and disease development.
CYTOPLASM OF A CELL
OXIDATIVE STRESS Free radicals
OXIDATIVE STRESS Free radicals damage cells
5% of oxygen
ALA
ALA Vit A
Superoxide
Vit A
ALA
Vit E SOD3
SOD1
HydrogenPeroxide
Vit C Vit A
Vit C
Mitochondria
Antioxidants can help neutralize free radicals before they do any harm if available in the right quantities.
CYTOPLASM OF A CELL
OXIDATIVE STRESS Free radicals damage cells
5% of oxygen
ALA
ALA Vit A
Superoxide
Vit A
ALA
Vit E SOD3
SOD1
HydrogenPeroxide
Vit C Vit A
Vit C
Mitochondria
The lost protection from superoxide can be recovered
CYTOPLASM OF A CELL
OXIDATIVE STRESS Free radicals damage cells
SOD2 If SOD2 is active, it protects the cells. Only normal amounts of antioxidants are required.
SOD2
Vit A Vit E
ALA Vit C
e.g. 100mg
OXIDATIVE STRESS Free radicals damage cells
SOD2
SOD2 If SOD2 is deactivated, the protective function is lost. Higher antioxidant dosages are necessary.
SOD2
Vit A Vit E
ALA Vit C
e.g. 100mg
Vit A Vit E
e.g. ALA 300mg
Vit C
OVERVIEW
Another example of how genetics influence micronutrient requirement
OXIDATIVE STRESS
GPX1 – a Selenoprotein neutralizing free radicals The GPX1 gene produces an enzyme, that protects from oxidative stress as well.
GPX1
GPX1 Free Radical
OXIDATIVE STRESS
GPX1 – a Selenoprotein neutralizing free radicals Selenium
GPX1
GPX1 is a selenoprotein, meaning it needs dietary selenium to work.
GPX1 Free Radical
OXIDATIVE STRESS
GPX1 – a Selenoprotein neutralizing free radicals GPX1
GPX1
Selenium
Free Radical
OXIDATIVE STRESS
GPX1 – a Selenoprotein neutralizing free radicals GPX1
GPX1
Selenium
OXIDATIVE STRESS
GPX1 – a Selenoprotein neutralizing free radicals GPX1
GPX1
Selenium
Neutralized
OXIDATIVE STRESS Selenium deficiency and GPX1 activity
Selenium deficient 30% activity As selenium is required for GPX1 activity, selenium deficiency causes low activity and low protection.
OXIDATIVE STRESS Selenium deficiency and GPX1 activity more selenium has Selenium deficientAdding been shown to increase
30% activity
GPX1 activity and hence protection from oxidative stress.
More Selenium 70% activity
OXIDATIVE STRESS Polymorphism in the GPX1 gene 7% of the population carries a genetic variant that makes the enzyme lass effective.
GPX1
GPX1 Free Radical
OXIDATIVE STRESS Polymorphism in the GPX1 gene
GPX1
GPX1
Selenium
Free Radical
OXIDATIVE STRESS Polymorphism in the GPX1 gene
GPX1
GPX1
Selenium
Weaker binding (e.g. 50% weaker)
OXIDATIVE STRESS Selenium deficiency and GPX1 activity
Selenium normal 35% activity Even with normal selenium levels, the overall activity is low in carriers of this genetic variant.
OXIDATIVE STRESS Selenium deficiency and GPX1 activity
Selenium normal 35% activity
Increasing selenium levels to above normal levels recovers the lacking function of the enzyme.
MORE Selenium 60% Activity
OXIDATIVE STRESS Free radicals
OXIDATIVE STRESS
Dosage based on genetics
GPX1 If the person carries a functional GPX1-Gene, he receives the normal RDA as recommended by official agencies to be applicable to everyone.
55 Âľg / Day
OXIDATIVE STRESS
Dosage based on genetics
GPX1
GPX1 If the gene carries the variant, we increase selenium levels to recover the lost activity.
55 µg / Day
96 µg / Day
OVERVIEW
An example how some nutrients can have no effect
OXIDATIVE STRESS Coenzyme Q10 needs to be activated
Q10
Q10 – No effect Coenzyme Q10 has no antioxidant effect by itself and yet it is one of the most expensive Micronutrient available.
OXIDATIVE STRESS Coenzyme Q10 needs to be activated
Q10
Q10 – No effect NQO1
Q10
Ubiquinol Oxidative protection
UBI
The NQO1 Gene first must produce an enzyme converting inactive Coenzyme Q10 to active Ubiquinol.
OXIDATIVE STRESS Coenzyme Q10 needs to be activated
Q10
Q10 – No effect NQO1
Q10 Ubiquinol is a very potent free radical inhibitor.
Ubiquinol Oxidative protection
UBI
UBI
Free radical
OXIDATIVE STRESS Free radicals
OXIDATIVE STRESS Coenzyme Q10
Q10
Q10 – No effect
NQO1
Q10
Due to a genetic variant 30% of the population have less activity and 4% have no activity of the NQO1 gene.
OXIDATIVE STRESS Coenzyme Q10
Q10
Q10 – No effect
NQO1
Q10
Free Radicals
Free radicals accumulate and damage the cells
OXIDATIVE STRESS Coenzyme Q10
Q10 – No effect
Q10
NQO1
Q10 The only way to recover this function is through ingesting active Ubiquinol as supplement.
UBI
UBI
Free UBI Radicals UBI UBI
UBI UBI
OXIDATIVE STRESS Coenzyme Q10
Q10 – No Effect
Q10
NQO1
Q10 Alternatively, other antioxidants in higher dosages can protect from free radicals.
E ALA C
C
Free Radicals E
E E C
ALA
ALA
OXIDATIVE STRESS Free radicals damage cells
NQO1
Q10
People with active NQO1 genes can use Coenzyme Q10 as antioxidative support
OXIDATIVE STRESS Free radicals damage cells
NQO1
NQO1 People with inactive NQO1 genes require Ubiquinol and/or other antioxidants to recover lost function
E
Q10 Q10
C
UBI ALA
OVERVIEW
One example where micronutrient supply through food might be too low
LACTOSE INTOLERANCE Genetics of Lactose intolerance
GENETICS Normal process in a baby Lactose can not be absorbed in the intestine Glucose
GLU LactASE enzyme splits lactose into smaller absorbable sugars Galactose
GLU
Babies produce this enzyme throughout the first years of their life to be able to digest milk
Lactase-Gene
GENETICS Normal process in an adult
GLU Lactose is food source for bacteria
GLU Evolutionarily, Adult (cavemen) had no access to milk, needed no enzyme and so production was gradually swithed off with increasing age.
Gene is deactivated with increasing age
Age++
Lactase-Gene
GENETICS Lactose intolerance – a normal process in adults
Lactase-Enzyme
The normal process is a gradual decrease in enzyme production
1 in 6 caucasians: Lactase enzyme is deactivated
Light symptoms Intermediate Symptoms
Lactose intolerance
Severe symptoms 10
20
30
40 50 Age (Years)
60
70
GENETICS Genetic variant causing Lactose TOLERANCE in adulthood
GLU
GLU
SNP Genetic variant disrupts „Age-Deactivation“
Age++
Lactase-Gene
GENETIK Lactose intolerance 5 of 6 caucasians: Lactase enzyme is produced throughout life
Lactase-Enzyme
1 in 6 caucasians: Lactase enzyme is deactivated
Light symptoms Intermediate Symptoms
Lactose intolerance
Severe symptoms 10
20
30
40 50 Age (Years)
60
70
GENETICS How did lactose intolerance arise?
Genetic variation arose in one person in northern Europe 10 000 years ago
GENETICS How did lactose intolerance arise?
Famine caused many people to die
GENETICS How did lactose intolerance arise? Milk as additional source of food = Survival & procreation Advantage 80% of europeans today carry this one genetic variant that arose back then.
GENETICS How did lactose intolerance arise? Lactose tolerance
Lactose tolerance is hence only a european phenomenon
Lactose INtolerance
GENETICS How did lactose intolerance arise? Lactose tolerance
Lactose tolerance was spread through colonization and emigration from europe
Lactose INtolerance
GENETICS Consequence for micronutrient dosing
Age++
Lactase-Gene
LACTOSE TOLERANT
= 600mg calcium through food
Lactose tolerant individuals thend to have a higher calcium intake and cover much of their requirement through their diet.
GENETICS Consequence for micronutrient dosing
Age++
Lactase-Gene
LACTOSE TOLERANT
= 600mg calcium through food
Ca Ca
200mg/day
Calcium RDA 800mg/day Since the RDA applicable to everyone is 800mg, some people dont get quite enough from their nutrition and would benefit from supplementation.
= 800mg calcium/day
GENETICS Consequence for micronutrient dosing
Age++
Age++
Lactase-Gene
LACTOSE INTOLERANT
LACTOSE TOLERANT
= 600mg calcium through food
People with a genetic variant in the LCT gene eat no milk products and ingest significantly less calcium through their diet.
Calcium RDA 800mg/day
Ca Ca
Lactase-Gene
200mg/day
= 800mg calcium/day
= 30mg calcium through food
GENETICS Consequence for micronutrient dosing
Age++
Age++
Lactase-Gene
LACTOSE INTOLERANT
LACTOSE TOLERANT
= 600mg calcium through food
Calcium RDA 800mg/day
= 30mg calcium through food
Ca
Ca
Ca Ca
Lactase-Gene
200mg/day
A higher supplementation is required to reach the RDA.
770mg/day
Ca Ca
Ca
= 800mg calcium/day
Ca Ca
OVERVIEW
One example where requirement of micronutrient might be higher than normal
GENETICS
Next question: Is the RDA enough?
Osteoporosis – brittle bones The question is, is the RDA enough or might some people need even more calcium?
OSTEOPOROSIS
Bone mineral density
Bone density and age
Bone density tends to increase up to the age of 30 and then gradually decrease with age.
Normal process: Bone density decreases slightly with age
Osteopenia Osteoporosis 10
20
30
40 50 Age (Years)
60
70
OSTEOPOROSIS Bone density and age
Bone mineral density
Normal process: Bone density decreases slightly with age Genetic variants: Bone density is lost rapidly
Osteopenia Osteoporosis 10
20
30
Genetic variants increase bone mineral density loss with increasing age. Prevention is required.
40 50 Age (Years)
60
70
OSTEOPOROSIS Bone density and age
Bone mineral density
PREVENTION
Osteopenia Osteoporosis 10
20
30
As with saving money, prevention must be started as early as possible to be effective.
40 50 Age (Years)
60
70
OSTEOPOROSIS
Bone mineral density
Bone density and age
PREVENTION Osteopenia Osteoporosis 10
20
30
As with saving money, prevention must be started as early as possible to be effective.
40 50 Age (Years)
60
70
OSTEOPOROSIS
Bone mineral density
Bone density and age
Osteopenia Osteoporosis 10
20
30
PREVENTION As with saving money, prevention must be started as early as possible to be effective.
40 50 Age (Years)
60
70
OSTEOPOROSIS What dose of calcium is optimal?
1500 mg
The European food safety agency (EFSA) states the RDA of calcium to be 800mg. This applies to everyone.
800 mg
0 mg
RDA according to EFSA
OSTEOPOROSIS What dose of calcium is optimal?
1500 mg In scientific studies, 1200mg have been shown to be protective and reduce fracture risk.
1200 mg
800 mg
0 mg
Known to be effective in scientific studies
RDA according to EFSA
OSTEOPOROSIS What dose of calcium is optimal?
1500 mg 1200 mg
A person with ni genetic risk for osteoporosis should follow the RDA
average (low) risk
800 mg
800mg
0 mg
Known to be effective in scientific studies
RDA according to EFSA
OSTEOPOROSIS What dose of calcium is optimal?
1500 mg maximum (high) risk
1200 mg
1200mg
Known to be effective in scientific studies
A person with high osteoporosis risk should follow the dosages we know to be protective from osteoporosis.
average (low) risk
800 mg
800mg
0 mg
RDA according to EFSA
OVERVIEW
Another example where requirement of micronutrient might be higher than normal
GENETICS
Next question: Is the RDA enough?
Heavy metal detoxification
PHASE 2 DETOXIFICATION Enzymes remove heavy metals from body
Heavy metal
GSTM1
GSTT1 GSTP1
In Phase 2 detoxification, toxins are modified and removed from the body by GST Genes/enzymes
Removed through kidneys
Enzymatic modification
Neutralized
PHASE 2 DETOXIFICATION Enzymes remove heavy metals from body
Heavy metal
GSTM1
GSTT1 GSTP1
60% of the population have at least one of these genes deactivated through genetic variants. Toxins such as lead are not neutralized.
Not neutralized
Toxicity, Cancer etc.
PHASE 2 DETOXIFICATION Enzymes remove heavy metals from body
Heavy metal Calcium supplementation binds Lead
GSTM1
GSTT1 GSTP1
Ca
Ca Ca
Calcium has been shown to bind and remove lead from the body. Hence, calcium supplementation can recover lost function.
Removed through kidneys
Calcium binds toxins
OVERVIEW
How different cenetic factors collectively determine the optimal dose of a micronutrient
CALCIUM What influences the optimal calcium amount? Recommended RDA
Lactose Intolerant
Osteoporosis Risk
Detoxification deficiency
NO +0 mg
NO +0 mg
NO +0 mg
YES +150 mg
YES NO +150 +0 mg mg
YES +100 mg
=1050mg
YES NO +150 +0 mg mg
YES +150 mg
YES NO +100 +0 mg mg
=950mg
YES +150 mg
YES +150 mg
YES +100 mg
=1200mg
=800mg
800 mg
Depending on genetic type, the calcium amount can be increased.
OVERVIEW
One example where one micronutrient has one effect in some and the opposite effect in other people
OMEGA 3 fatty acids An observation doctors frequently make
Person 1 with high cholesterol
Doctor recommends Omega3 supplements
Cholesterol improves
Most people assume fish oil capsules (omega 3) are beneficial for cholesterol und some are in fact right.
OMEGA 3 fatty acids An observation doctors frequently make
Person 1 with high cholesterol
Doctor recommends Omega3 supplements
Cholesterol improves
Person 2 with high cholesterol
Doctor recommends Omega3 supplements
Cholesterol becomes worse
What is the reason? APOA1 (A/A)
APOA1 (G/G)
In some cases the opposite happens. HDL Cholesterol becomes worse.
OMEGA 3 fatty acids An observation doctors frequently make
Person 1 with high cholesterol
Doctor recommends Omega3 supplements
Cholesterol improves
Person 2 with high cholesterol
Doctor recommends Omega3 supplements
Cholesterol becomes worse
What is the reason? APOA1 (A/A)
APOA1 (G/G)
This is caused by different genetic variations in the APOA1 gene.
OMEGA 3 fatty acids
What is the consequence?
Person 1 with high cholesterol APOA1 (A/A) Doctor recommends Omega3 supplements
Cholesterol improves
Person 2 with high cholesterol APOA1 (G/G) Doctor recommends Omega3 supplements
Doctor recommends Phytosterols!
Cholesterol improves Usind phytosterols instead of Omega-3 achieves the same cholesterol-improving effect.
Different micronutrients required to achieve same result
OMEGA 3 fatty acids
What daily dose is effective for improving HDL Cholesterol? RDA: 250 mg The RDA for Omega-3 is only 250mg. Far below the dosages shown to be effective in scientific studies.
Amounts shown to be effective: 1000-2900mg
OMEGA 3 fatty acids
What daily dose is effective for improving HDL Cholesterol? Daily dose 3000 mg
2900mg
Study 3
1500mg
Study 1
1000mg
Study 2
250mg
RDA according to EFSA
Ranges known to be effective among (also high risk) individuals
Range accepted to be sufficient for general population with average risk =RDA
0 mg
CHOLESTEROL Cholesterol is influenced by genes CETP
HDL
APOA5
Cholesterol OK
Genes that influence HDL cholesterol levels
In this case there is no genetic predisposition for bad HDL cholesterol levels
CHOLESTEROL Cholesterol is influenced by genes CETP
HDL
APOA5
Cholesterol OK
Genes that influence HDL cholesterol levels
APOA1
If APOA1 is of the beneficial variant, then Omega3 can be recommended at the low risk/RDA dose.
250mg OMEGA3
CHOLESTEROL Cholesterol is influenced by genes CETP
HDL
APOA5
Cholesterol OK
Genes that influence HDL cholesterol levels
APOA1
250mg OMEGA3
APOA1
250mg Phytoster.
If APOA1 reverses the effect of Omega3 fatty acids, the alternative, Phytosterols should be used instead.
CHOLESTEROL Cholesterol is influenced by genes CETP
HDL
APOA5
Cholesterol OK
Genes that influence HDL cholesterol levels CETP
HDL
APOA5
Cholesterol Too low
APOA1
250mg OMEGA3
APOA1
250mg Phytoster.
Certain genes cause bad HDL cholesterol levels. Stronger intervention neessary
CHOLESTEROL Cholesterol is influenced by genes CETP
HDL
APOA5
Cholesterol OK
Genes that influence HDL cholesterol levels CETP
HDL
APOA5
Cholesterol Too low
APOA1
250mg OMEGA3
APOA1
250mg Phytoster.
APOA1
1500mg OMEGA3
If APOA1 is beneficial, high doses of OMEGA 3 are recommended.
CHOLESTEROL Cholesterol is influenced by genes CETP
HDL
APOA5
Cholesterol OK
Genes that influence HDL cholesterol levels CETP
HDL
APOA5
Cholesterol Too low
If APOA1 is of the negative type, high doses of the alternative are given.
APOA1
250mg OMEGA3
APOA1
250mg Phytoster.
APOA1
1500mg OMEGA3
APOA1
1500mg Phytoster.
OVERVIEW
To summarize these few examples
SUMMARY Genes influence the requirement of Micronutrients Genes influence micronutrient effect Genes influence micronutrient dosage requirement By testing 50+ genes we can dose 22 micronutrients based on genes With 52 genes, there are 717 000 000 000 000 000 000 000 possible results Each micronutrient recipe is UNIQUE
OVERVIEW
How can one follow a specific micronutrient recipe?
CONCEPT OF NUTRIENTS How can you follow such variable recommendations? Use standard supplements? Dose always too high or too low
Individual gelatin capsules? Very expensive to produce
Microtransporter method!
Easy to mix Easy to automate Every mix possible Cheap to produce
CONCEPT OF NUTRIENTS How can you follow such variable recommendations?
Vitamin C mix
Vitamin A mix
Zink mix
50% w/w
4% w/w
11% w/w
Molecule of filler Molecule of Vitamin C Molecule of Vitamin A Molecule of Zink
We simply add different amounts of different pellet types to a mixture, mix and then instruct to take one spoon per day
6g
38g
22g
Zink mix Mixture for one genetic profile
Vitamin A mix Vitamin C mix
Instructions: ingest 8g/day
Amounts differ depending on genetic profile
NUTRIME Pellets taken with spoon
OVERVIEW
What is the status of the product?
STATUS The status of the project
Patent pending (worldwide) Genetic test ready (50+genes) Microtransporters developed (23 different types) Label and instructions completed Product ready for launch
NUTRIME Materials so far
NUTRIME Materials so far
OVERVIEW
What can we offer?
OFFER What we can offer AMWAY
Genetic test to be performed for each individual (Ready to launch) Report booklet (digital or high quality print and post) describing results Highest level of certification (ISO15189, Austria for medical genetics) Personalized recipe for every person Pellet production using your high quality natural vitamins and minerals
Shipment logistics for every order
OVERVIEW
Important aspects to consider
TO CONSIDER
Are these tests not medical genetic tests? One important aspect of nutrigenetic tests: The same test can be medical (if disease information is communicated), or a lifestyle test (if it only communicates nutrition advice).
LIFESTYLE
Makes you fat sensitive for obesity
PPARG
MEDICAL
Increases your risk of Diabetes by 38%
TO CONSIDER
Are these tests not medical genetic tests? Lifestyle Genetic tests can be offered without limitations. Medical genetic tests are limited to qualified physicians.
LIFESTYLE
Lactose intolerance
MEDICAL
LCT
You need more calcium because of your genes
You are 95% likely to develop lactose intolerance during your lifetime
TO CONSIDER
Are these tests not medical genetic tests? Another example:
LIFESTYLE
Osteoporosis
MEDICAL
LCT
You need more calcium because of your genes
Your risk of osteoporosis is 215% higher
TO CONSIDER
Are these tests not medical genetic tests? Another example:
LIFESTYLE
Detoxification
MEDICAL
GSTM1
You need more antioxidants because of your genes
Your risk of cancer is 130% higher due to bad detoxification
TO CONSIDER
Are these tests not medical genetic tests? Another example:
LIFESTYLE
OMEGA 3
MEDICAL
APOA1
You need Omega 3 for heart health
Omega 3 improves your HDL cholesterol (might be ok to communicate)
OVERVIEW
What about the science?
SCIENCE
Scientific background on the genes mentioned GENE: APOLIPOPROTEIN A1 (APOA1) Genetic Variant: rs670, G/A pos. -75 Promoter Disease risk: Effect of poly unsaturated fatty acid consumption on HDL (good) cholesterol Low risk genotypes: A/A or A/G show high HDL cholesterol levels High risk genotypes: G/G shows low HDL cholesterol levels The human Apolipoprotein A1 (APOA1) constitutes the major protein component of HDL (high-density lipoprotein; the socalled “good cholesterol”) in plasma. It promotes cholesterol efflux from tissues to the liver for excretion and is a cofactor for LCAT (lecithin cholesterol-acyltransferase) which is responsible for the formation of most plasma cholesteryl esters.
A relatively frequent promoter polymorphism (G/A pos. -75) in the human APOA1 gene modulates the transcription of the gene as shown in a series of in vitro experiments. Because low APOA1/HDL plasma levels constitute a well-known risk factor for coronary artery disease (CAD), scientists started to analyze and associate this polymorphism with plasma APOA1/HDL concentrations. Studies that examined this association reported contradictory results. As a consequence, it was suggested that the inconsistencies between studies could be the result of interactions with environmental factors that modulate the effect of this polymorphism. Ordovas et al. (2002) studied this proposed interaction in a population-based sample (755 men and 822 women) from the Framingham Offspring Study and found out that polyunsaturated fatty acids (PUFA) intake significantly modulates the effect of the APOA1 G/A pos. -75 polymorphism. In summary, in female carriers of the A-allele, higher PUFA intakes were associated with higher HDL-cholesterol concentrations, whereas the opposite effect was observed in G/G women. Their results illustrate the complexity of polymorphism-phenotype associations and underscore the importance of accounting for interactions between genes and environmental factors in population genetic studies. Subbiah MT (2007) wrote in a recent review on Nutrigenetics “From a dietary recommendation point of view, women with this mutation (A-allele carriers) should be counseled to consume higher levels of polyunsaturated fat.” According to the current embodiment, a person carrying the genotype G/G for the rs670 genetic variant does not benefit from a high PUFA diet in terms of HDL cholesterol levels. PUFAS should not be a part of nutritional supplements in this case. REFERENCES 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
SCIENCE
Scientific background on the genes mentioned
GENE: CADHERIN 13 (CDH13)
Genetic Variant: rs8055236 Disease risk: Cardiovascular disease Low risk genotypes: A/A (OR 1) High risk genotypes: A/G (OR1.91) and G/G (OR 2.23) The present variant describes a substitution from the genetic base A to the base G at the genetic location of the CDH 13 gene. The CDH13 gene encodes a member of the cadherin superfamily. The encoded protein is localized to the surface of the cell membrane and is anchored by a GPI moiety, rather than by a transmembrane domain. The protein lacks the cytoplasmic domain characteristic of other cadherins, and so is not thought to be a cell-cell adhesion glycoprotein. This protein acts as a negative regulator of axon growth during neural differentiation. It also protects vascular endothelial cells from apoptosis due to oxidative stress, and is associated with resistance to atherosclerosis. The Wellcome trust Case control Consortium demonstrated in 2007 on a study of 14,000 cases of seven common diseases and 3000 shared controls, that the risk of cardiovascular disease of a person is increased to an odds ratio of 1.91 in A/G heterozygotes and an odds ratio of 2.23 for homozygous mutants of this genetic variant when compared to the A/A wildtype (The welcome Trust Case Consortium, 2007). This genetic link between this genetic variant and cardiovascular disease was further demonstrated by Yan Y. in 2009 in the Framingham Heart Study Offspring Cohort. Genetic evaluation: According to the current embodiment, a person carrying the genotypes A/G or G/G for the rs8055236 genetic variant are considered to be at an increased risk of cardiovascular disease REFERENCES The Wellcome Trust Case Control Consortium (2007): Nature. 2007 June 7; 447(7145): 661–678. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Yan Y (2009): BMC Proc. 2009 Dec 15;3 Suppl 7:S118. Evaluation of population impact of candidate polymorphisms for coronary heart disease in the Framingham Heart Study Offspring Cohort. Yan Y, Hu Y, North KE, Franceschini N, Lin D.
SCIENCE
Scientific background on the genes mentioned GENE: CORONARY HEART DISEASE, SUSCEPTIBILITY TO, 8 (CHDS8) Genetic Variant: rs1333049 Disease risk: coronary heart disease Low risk genotypes: G/G (OR 1) High risk genotypes: G/C and C/C Two of the most frequently and thoroughly studied genetic variants for coronary heart disease susceptibility are SNPs rs10757278 and rs1333049. These two SNPs are in strong linkage disequilibrium (LD, meaning that testing one completely predicts the states of the other genetic variant) and are practically “equivalent”. In view of this strong LD specific risk evaluation can be done by only genotyping rs1333049. First identified in a study of the Wellcome Trust Case Control Consortium (2007; approx. 2.000 cases and 3.000 controls) the rs1333049 SNP was associated with CAD having an OR of 1,47 and 1,90 for hetero- and homozygotes respectively. Additional large studies could replicate this finding. A meta-analysis confirmed again the association of rs1333049 with CAD in 12.004 cases and 28.949 controls with an OR of 1,24 per allele. In the analysis ofSchunkert et al. (2008) there was no interaction concerning the risk of CAD between rs1333049 and numerous traditional risk factors, including history of MI; the population attributable risk (PAR) was 22 %. Furthermore Samani NJ. et al. (2007) demonstrated, that in their model the prediction of MI on the basis of the Framingham/PROCAM score was improved by using the rs1333049 genotyping information. The association of this locus with CAD was also confirmed with the equivalent rs10757278 by Helgadottir A. et al. (2007) in a total of 4.587 cases and 12.767 controls all of European origin. The association of the G-allele of rs10757278 with CAD was highly significant resulting in an OR of 1,26-1,28 for heterozygotes and 1,64 for homozygotes according to an autosomaladditive model. This effect was even more pronounced in case of early-onset (men≤50 years, women≤60 years) myocardial infarction (MI) with an OR of 1,49 and 2,02 respectively. According to the current embodiment, a person carrying the genotypes G/C or C/C for the rs1333049 genetic variant are considered to be at an increased risk of cardiovascular disease. REFERENCES The Wellcome Trust Case Control Consortium (2007): Nature. 2007 June 7; 447(7145): 661–678. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Helgadottir A. et al., 2008; PMID 18176561 Helgadottir A. et al., 2007; PMID 17478679
SCIENCE
Scientific background on the genes mentioned GENE: APOLIPOPROTEIN A5 (APOA5) Genetic Variant: rs662799 Disease risk: Cardiovascular disease and hypertriglyceridemia Low risk genotypes: T/T (OR 1) High risk genotypes: T/C (OR 1.98) or C/C (OR1.98) Apoliporotein A-V (A5) is an important regulator of several lipoprotein fractions including plasma triglyceride (TG) and HDLcholesterol. The mature APOA5 protein is expressed in the liver only and secreted into the plasma. One of the most frequently studied polymorphism of the APOA5 gene is -1131 T/C (located in the promoter region). The genotype frequency of – 1131 T/C differs between populations: The MAF (Minor Allele Frequency) of the C-allele is ≈ 30 % in Japanese while only ≈ 12-15 % in Caucasians. The variant - 1131 C-allele is associated with significantly higher plasma triglyceride in multiple populations (Japan, USA, Germany, Hungary, UK etc.) and in several cases with significantly decreased HDL-cholesterol concentrations. Both are basic characteristics of the Metabolic Syndrome (MS) and are established risk factors for Cardiovascular Disease (CVD).
Yamada et al. (2007) reported in 1788 subjects that the -1131 C- allele was significantly associated (OR=1,57) with Metabolic Syndrome according to a dominant model, plasma triglyceride were significantly higher and HDL lower than in T/T carriers. In a study performed by Maász et al. (2007) the 1131 C- allele – was again significantly associated with the Metabolic Syndrome, with higher plasma triglyceride and lower HDL- concentrations. Most of the studies however yielded only significant associations of –1131 T/C variant with higher triglyceride levels and in several fewer cases with lower HDL. Szalai et al. (2004) investigated the possible association of –1131 T/C polymorphism with Coronary Artery Disease (CAD) in 308 patients referred to coronary bypass surgery and in 310 controls. The prevalence of –1131 C-allele was significantly higher in CAD patients, 10,9 % against 5,7 % (p < 0,001). After multiple adjustment: OR=1,98 for developing CAD in risk-allele carriers. Vaessen et al. (2006) investigated the relationship between APOA5/Triglyceride and CAD in a nested case-control, the Epic-Norfolk Population Study (n= 1034 cases / 2031 controls). The minor –1131 C-allele was significantly associated with higher triglyceride concentrations and its frequency was higher in CAD cases. According to the current embodiment, a person carrying the genotypes T/C or C/C for the rs662799 genetic variant are considered to be at an increased risk of cardiovascular disease. REFERENCES Yamada Y. et al., 2007; PMID 16806226 Maász A. et al., 2007; PMID 17922054 Szalai C. et al., 2004; PMID 15177130 Vaessen S.F. et al., 2006; PMID 16769999
SCIENCE
Scientific background on the genes mentioned GENE: QUINONE ACCEPTOR OXIDOREDUCTASE 1 (NQO1)
Genetic variant: rs1800566, Pro187Ser Disease risk: Reduced conversion of Coenzyme Q10 to ubiquinol and increased oxidative stress High enzyme activity genotypes: C/C Low enzyme activity genotypes: C/T or T/T NAD(P)H dehydrogenase [quinone] 1 is an enzyme that in humans is encoded by the NQO1 gene. This gene is a member of the NAD(P)H dehydrogenase (quinone) family and encodes a cytoplasmic 2-electron reductase. This FAD-binding protein forms homodimers and reduces quinones to hydroquinones. Coenzyme Q10 is an oil-soluble, vitamin-like substance and present in most eukaryotic cells, primarily in the mitochondria. It is a component of the electron transport chain and participates in aerobic cellular respiration, generating energy in the form of ATP. Ninety-five percent of the human body’s energy is generated this way. Therefore, those organs with the highest energy requirements—such as the heart, liver and kidney—have the highest CoQ10 concentrations. There are three redox states of coenzyme Q10: fully oxidized (ubiquinone), semiquinone (ubisemiquinone), and fully reduced (ubiquinol). The capacity of this molecule to exist in a completely oxidized form and a completely reduced form enables it to perform its functions in the electron transport chain and as an antioxidant respectively. In order for Coenzyme Q10 to act as an antioxidant, the molecule needs to be converted to Ubiquinol and this transition is performed by the NQO1 enzyme. The genetic variant rs1800566 produces a completely inactive enzyme and the conversion of Coenzyme Q10 is significantly slowed. Therefore supplementation of Coenzyme Q10 has no beneficial health effect in carriers of the homozygous polymorphism. According to the current embodiment, a person carrying the genotype C/T is considered to be an intermediate metabolizer of Coenzyme Q10 and a person carrying the T/T genotype is considered to be a poor metabolizer of Coenzyme Q10.
REFERENCES PMID: 9271353 PMID: 16551570 PMID: 10208650 Aberg F, EL Appelkvist, G Dallner, and L Ernster. Distribution and redox state of ubiquinones in rat and human tissues. Arch Biochem Biophys 295 (2): 230–4, 1992. Alleva R, M Tomasetti, M Battino, et al. The roles of coenzyme Q10 and vitamin E on the peroxidation of human low density lipoprotein subfractions. Proc Natl Acad Sci 92(20):9388-91, 1995. Bentinger M, M Tekle, G Dallner. Coenzyme Q – biosynthesis and functions. Biochem Biophys Res Commun 396(1):74-79, 2010. Bhagavan HN and RK Chopra. Coenzyme Q10: Absorption, tissue uptake, metabolism and pharmacokinetics. Free Radical Research 40 (5): 445–53, 2006.
OVERVIEW
And many more…
TOUR OF THE LAB
A short tour of our facilities
Novogenia reception area
DNA extraction laboratory
DNA extraction laboratory
storage rack for swabs currently being processed
DNA analysis laboratory
meeting room and video conferencing station
meeting room and video conferencing station
head office
Dr. Daniel Wallerstorfer Founder and CEO
Sandra at the recetion desk
Maria at the reception desk
Saskia bringing new samples for analysis
paper forms are photographed and digitalized
we write our own software
presentations and trainings held via Skype
Florian at the sample processing queue
Saskia and Michael planning processes at the board
Thomas sterilizing his hands
Daniel picking up swabs to be processed
Jenny at our DNA extraction robot #1
Saskia checking the validity of barcoded swabs
Florian preparing DNA extraction
swabs are scanned and registered in the system
one swab goes into one slot in a 96 well plate
the swabs are trimmed
a full plate of swabs is moved to the DNA extraction robot
192 swabs are extracted in 1,5h
DNA is the transferred into a DNA plate
DNA extraction is fully automated
we have 3 large DNA extraction robots
and 2 small DNA extractors
total extraction capacity: 100 000 swabs per month
we use high capacity 384 well plates
these can analyze 72 samples at once
mixing DNA with reagents is also automated
plates are cooled during preparation for analysis
Daniel preparing a liquid handling robot
Robots use filter tips to avoid contamination
Reagents are prepared in UV sterilized cabinets
Maria preparing the analysis process
the Viia7 is the most advanced DNA analyzer
the machine can analyze 384 genes in 1h
adding up to 720 samples per 10h day
we operate a loading robot for 24/7 operation
the robot removes completed plates and loads new ones
plates are barcode labeled and automatically recorded
total analysis capacity is 51 000 samples per month
every bay holds 45 plates or 3200 customers
our alternative DNA analyzer in ring-format
office area â&#x20AC;&#x201C; we are largely paper less
opened swabs are sprayed with DNA degrading chemicals