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Stanner SA, Hughes J, Kelly CNM, Buttriss J. A review of the epidemiological evidence for the ‘antioxidant hypothesis’. Public Health Nutrition: 2003;7(3):407-422.
Katan. Lancet. 1986
Given that ‘the gradient in serum cholesterol levels in the population is associated with a gradient in APOE [genotype]’, under the causal hypothesis we would expect to see a corresponding association between APOE and cancer. The absence of such a genetic association ‘would suggest that the association between low cholesterol and cancer is spurious’.
Mendelian Laws, published 1866
The law of segregation: Hereditary traits are determined by pairs of factors, which segregate (separate) during gamete formation and reunite in the zygote.
B = yellow b = green BB/bb
P-generation B/B b/b homozygotes
Gametes B b
F1 generation B/b Random process
B/b B/b Heterozygotes
Gametes B b B b
F2 generation B/B, B/b, b/B b/b Random process
Yellow Green
3 1
Independent assortment: The alleles of one pair of genes segregate independently of other pairs of genes during gametogenesis
P generation B/B A/AYellow, roundB = yellow b = green
b/b a/aGreen, wrinkledA = round a = wrinkled
Gametes B A b a
F1 B/b A/aYellow/round
B/b A/aYellow/round
Gametes BA Ba bA ba BA Ba bA ba
F2 9/16 yellow/round (¾ x ¾)3/16 yellow/wrinkled (¾ x ¼)3/16 green/round (¼ x ¾)1/16 green/wrinkled (¼ x ¼)
Gametes BA Ba bA ba
BA B/B A/A B/B A/a B/b A/A B/b A/a
Ba B/B A/a B/B a/a B/b A/a B/b a/a
bA B/b A/A B/b A/a b/b A/A b/b A/a
ba B/b A/a B/b a/a b/b A/a b/b a/a
9 : 3 : 3 :1
Mendel’s Experiment - visit to home page
If the APOE gene is randomized then we will not expect an association between the genotype and cancer under Ho
If IP D is confounded or due to reverse causation D IP, then there should be no G D association.
Low cholesterol cancer
confounders
Cancer low cholesterol
MRC-trial + trial in Hungary
Folate Vitamins High risk women NTD
0 0 N00 D00
0 + N0+ D0+
+ 0 N+0 D+0
+ + N++ D++
PR
Could we have avoided the NTDs caused by low folate intake?
( ) / ( )( ) / ( )
.D D N ND D N N
0 +0
00 0 00 0
0 3
If TT, Tt, tt are associated with different levels of homocystein, one would expect these genotypes to carry different risks for NTD
Since these genotypes are randomized at birth, other correlates of homocystein are not expected to be associated with the genotypes
Important use of MR could be to eliminate confounding as a cause of associations between E and D in situations where randomization is not an option.
Mendelian deconfounding.
All populations have slow and fast metabolizers of alcohol guided by genetic factors
ALCOHOL ACETALDEHYDE ACETIC ACID
Slow metabolizers at step 1 = High level of alcoholSlow metabolizers at step 2 = High level of acetaldehyde
1 2
Genotype Slow metabolisers CVD
But Slow metabolisers AlcoholCVD ?
Genotype influence phenotype
Fixed alcohol intake: slow metabolisers CVD
Alcohol metabolism
ADH1 produces two different enzymes: 1 – fast, 2 – slow.
If alcohol protects against MI 2 should have low risk given the same intake.
Relative risks of myocardial infarction according to the genotypes
Variable ADH3 Genotype P value
11 1 2 2 2
No. Of subjects (%)
Patients 161 (51) 184 (46) 51 (13)
Controls 279 (36) 361 (47) 130 (17)
Relative risk (95% CI)
Matched 1.0 0.90 (0.69-1.17) 0.72 (0.50-1.05) 0.09
Multivariate 1.0 0.81 (0.61-1.09) 0.64 (0.43-0.98) 0.03
Multivariate, with adjustment for
1.0 0.83 (0.62-1.11) 0.65 (0.43-0.99) 0.04
alcohol consumption
Multivariate relative risk of myocardial infarction according to the genotypes and the level of daily alcohol consumption
0
0.2
0.4
0.6
0.8
1
1.2
Relative risk of myocardial infarction
< 1 Drink/day > 1 Drink/day
y1
y2
y3
P = 0.04
P = 0.04
P = 0.001
Alcohol esophageal cancer
Alcohol (not carcinogenic in animal models)Confounding, modification of carcinogens – tissue damageMetabolite – acetaldehyde?
Elimination of acetaldehyde – ALDH2 enzymeA point mutation in ALDH2 ALDH2 x 2 x 2Allele and inability to metabolize acetaldehyde
Alcohol ALDH2 x 2 x 2: 18 times higher peakALDH2 x 1 x 2: 5 times higher peak
thanALDH2 x 1 x 1
Lewis, Sarah J. and Smith, George Davey. Alcohol, ALDH2, and Esophageal Cancer: A Meta-analysis which Illustrates the Potentials and Limitations of a Mendelian Randomization Approach. Cancer Epidemiol Biomarkers Prev. 2005;14(8):1967-1971
Lewis, Sarah J. and Smith, George Davey. Alcohol, ALDH2, and Esophageal Cancer: A Meta-analysis which Illustrates the Potentials and Limitations of a Mendelian Randomization Approach. Cancer Epidemiol Biomarkers Prev. 2005;14(8):1967-1971
Lewis, Sarah J. and Smith, George Davey. Alcohol, ALDH2, and Esophageal Cancer: A Meta-analysis which Illustrates the Potentials and Limitations of a Mendelian Randomization Approach. Cancer Epidemiol Biomarkers Prev. 2005;14(8):1967-1971
Plasma fibrinogen correlates with MI
A common mutation in G A the -fibrinogen gene is associated with high fibrinogen levels.
The G/A genotype correlated with plasma fibrinogen in men and in pre-menopausal women or post-menopausal women treated with HRT
ANOVA ANOVAp < 0.001 p < 0.001
2,4
2,6
2,8
3
3,2
3,4
3,6
3,8
G/G
G/A
A/A
****
****
*
Pla
sma
fi brin
og
en
(g
/ L)
Women Menn = 4,889 n = 3,972
GENOTYPE
If fibrinogen is a cause of MI, the G/A or A/A genotype should have high risk of MI.
Without ischemic heart disease
With ischemic heart disease
No. of women 3937 174
Genotype
G/G 0.63 (2467) 0.58 (101)
G/A 0.34 (1323) 0.40 (70)
A/A 0.04 (147) 0.02 (3)
A-allele 0.21 0.22
No. of men 2915 315
Genotype
G/G 0.64 (1877) 0.65 (204)
G/A 0.31 (913) 0.31 (98)
A/A 0.04 (124) 0.04 (13)
A-allele 0.20
C-reactive protein (CRP) is a maker of systemic inflammation.
CRP High Blood Pressure (HBP) - many studies show association
but could be
HBP CRP – reverse causation
Most studies haveMeasurement errors of confounders (obesity, smoking, social factors)Most studies rely on cross-sectional data; inversecausation
Smith GC, et al. Association of C-Reactive Protein with Blood Pressure and Hypertension: Life Course Confounding and Mendelain Randomization Tests of Causality. Arterioscler Thromb Vasc Biol. 2005;25:1051-1056.
Smith GC, et al. Association of C-Reactive Protein with Blood Pressure and Hypertension: Life Course Confounding and Mendelain Randomization Tests of Causality. Arterioscler Thromb Vasc Biol. 2005;25:1051-1056.
Some studies show that coffee correlates with stillbirth. If caffeine is the culprit we can examine this by studying slow and fast metabolism of caffeine. Slow metabolism should have the highest risk at fixed levels of coffee intake.
No studies are large enough to demonstrate this.
ALDH 2x2x2 Homozygotes 18 times higher peak acealdehyde levels ALDH 2x1x2 Heterozygoter 5 timesADH 2x1x1 Homozygotes
Chen et al. PLOS Medicine 2008 5 (3): e52Meteanalysis: search word in PubMed and ISI ALDH2, hypertension, blood pressure, cardiovascular disease, heart disease-studies published before 2007Reference listMeta-analysis guidelines
JAMA 2000;283:2008-12
Alcohol intake in matter for males:
ALDH 2x1x1 20-30g /dayALDH 2x1x2 10-15g /day ALDH 2x2x2 0-2g /day
Hypothesis
A high level of intrauterine exposure totestosterone increases the risk of autism / ADHD(Simon –Cohen)
Twin girls with a twin brother have a higher prenatal exposure than twin girls with a twin sister.We expect autism/ADHD to have genetic as well as environmental causesHow can we study it the intrauterine level of androgens play a role
Take Dz twins, compare females in FM sets with females in FF sets. FM females should have higher risksHow do we use mendelian randomization in this study?
Nitsch D., et al. Limits to Causal Inference based on Mendelian Randomization: A Comparison with Randomized Controlled Trails. Am J Epidemiol. 2006;163:397-403.
Comparison of RCT (intention to treat)
And MR
Nitsch D., et al. Limits to Causal Inference based on Mendelian Randomization: A Comparison with Randomized Controlled Trails. Am J Epidemiol. 2006;163:397-403.
Problems
Population stratification/genetic confounding: Different ethnic groups may have different genotypes and different disease risks.
Linkage disequilibrium – association between genes because they are located close together on the chromosome.
Gene 1 and Gene 2 associated-are in linkage disequilibrium:
Gen 2 Conf
Gene1 Exp Disease
Is Gene 1 a useful instrumental variable for Exp?
ConfMaternal Maternal obesity offspring obesityFTO
Offspring FTO
Can maternal FTO be used as an instrumental variable for Maternal obesity to study offspring obesity?
Limitations
Requires well defined and rather strong genetic risk factors with high penetrance.
Should not interfere with behaviour of relevance to the exposure under study – unless this exposure could be controlled in the design or analysis.
Slow metabolisers of alcohol tend to drink less.
Genes involved in detoxification only play a role when the toxic exposure is present (gene-environment interaction). Without the exposure the gene has no function.
Mendelian Randomization
First described as such by Katan (Lancet 1986; i: 507-81).
Is now being explored in situations where we have a genotype that is causally linked to a phenotype.
Smith GD, Ebrahim S. Mendelian randomization: prospects, potentials, and limitations. Int J Epidemiol 2004; 33: 30-42.
Katan MB. Commentary: Mendelian randomization, 18 years on. Int J Epidemiol 2004; 33: 10-11.
Chen et al. PLOS medicine 2008; 5: 461-470
OffspringGenotypea´a´
OffspringGenotype
aa
OffspringGenotypeaa´
OffspringGenotypea´a
MotherGenotypeaa´
FatherGenotypeaa´
Allele that is inheritedfrom each parent israndomly determined
Mendelian randomization in case-parent design
The case-parent triad design
aa’ aa Parents
aa’ Cases
a’ more frequent in cases than expected from Mendel laws (probability in this case 0.50)
If 4 parents look like this
GX/G GX/G : ¾ of offspring expected to have the SNP
GX/G G/G : ½ of offspring expected to have the SNP
GX/ GX G/G : All will have the SNP
G/G G/G : None will have the SNP
2.25 of their 4 affected children are expected to have the GX if the SNP correlate with the disease.
This expectation be tested, but a larger sample is needed.