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Mendelian Randomization: A Deconfounding Method for Understanding Health Associations

Explore Mendelian Randomization as a method to clarify causal relationships and avoid confounding in health research. Learn how genetic randomization can shed light on connections between factors such as cholesterol, cancer, alcohol, and cardiovascular disease.

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Mendelian Randomization: A Deconfounding Method for Understanding Health Associations

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  1. Mendelian Randomization A deconfounding method Dr. Jørn Olsen Epi 200B February 23 & 25, 2010

  2. 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.

  3. Violent death/cancer Se-cholesterol Cause Confounding Reverse causation?

  4. 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’.

  5. This argument assumes that the APOE gene is randomly allocated according to the laws of Mendel

  6. 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.

  7. Independent assortment: The alleles of one pair of genes segregate independently of other pairs of genes during gametogenesis

  8. 9 : 3 : 3 :1 Mendel’s Experiment - visit to home page

  9. APOE + High Se-chol APOE - Low Se-chol

  10. If the APOE gene is randomized then we will not expect an association between the genotype and cancer under Ho

  11. G IP D Genotype Low cholesterol Cancer G = gene IP = intermediate phenotype D = disease

  12. 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

  13. IP G D G --- D not present in population at risk

  14. Observations Folate NTD Confounding? Folate NTD C C Randomized trial

  15. + + ( D D ) / ( N N ) + + + + + = = 0 +0 0 . 3 + + ( D D ) / ( N N ) + + 00 0 00 0 MRC-trial + trial in Hungary PR Could we have avoided the NTDs caused by low folate intake?

  16. Mechanism Folate Homocystein NTD Genotype MTHFR (TT) Homocystein NTD ?

  17. If TT, Tt, tt are associated with different levels of homocystein, one would expect these genotypes to carry different risks for NTD

  18. MTHFR (TT) NTD Homocystein

  19. Since these genotypes are randomized at birth, other correlates of homocystein are not expected to be associated with the genotypes

  20. 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.

  21. Alcohol and CVD Most studies show the following: CVD alcohol drinks/day 0 6

  22. Observation Alcohol CVD Confounding Alcohol CVD Diet Smoking Exercise Etc.

  23. 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 alcohol Slow metabolizers at step 2 = High level of acetaldehyde 2 1

  24. Genotype Slow metabolisers CVD But Slow metabolisers Alcohol CVD ? Genotype influence phenotype Fixed alcohol intake: slow metabolisers CVD

  25. 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.

  26. Relative risks of myocardial infarction according to the genotypes

  27. Multivariate relative risk of myocardial infarction according to the genotypes and the level of daily alcohol consumption P = 0.04 P = 0.04 P = 0.001

  28. ALDH2 Alcohol Acetaldehyde Acetic acid ALDH2•1•1 fast ALDH2•2•2 slow

  29. Alcohol esophageal cancer Alcohol (not carcinogenic in animal models) Confounding, modification of carcinogens – tissue damage Metabolite – acetaldehyde?

  30. Elimination of acetaldehyde – ALDH2 enzyme A point mutation in ALDH2 ALDH2 x 2 x 2 Allele and inability to metabolize acetaldehyde Alcohol ALDH2 x 2 x 2: 18 times higher peak ALDH2 x 1 x 2: 5 times higher peak than ALDH2 x 1 x 1

  31. 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

  32. 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

  33. 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

  34. Plasmafibrinogen (g/L) 3,8 **** 3,6 * 3,4 **** G/G 3,2 Plasmafibrinogen (g/L) G/A 3 A/A 2,8 2,6 2,4 Women Men n = 4,889 n = 3,972 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 ANOVA p < 0.001 p < 0.001 GENOTYPE

  35. If fibrinogen is a cause of MI, the G/A or A/A genotype should have high risk of MI.

  36. 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

  37. Or CRP HBP C1 C2

  38. Most studies have Measurement errors of confounders (obesity, smoking, social factors) Most studies rely on cross-sectional data; inverse causation

  39. GG, GC, CC; G associated with high levels of CRP

  40. 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.

  41. 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.

  42. 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.

  43. Alcohol Acetaldehyde Eliminated Alcohol Dehydrogenates ALDH2

  44. ALDH 2x2x2 Homozygotes 18 times higher peak acealdehyde levels • ALDH 2x1x2 Heterozygoter 5 times • ADH 2x1x1 Homozygotes

  45. Acetaldehyde cause nausea, headache etc. that makes drinking alcohol unpleasant-lowers the exposure

  46. Is alcohol in high levels causing hypertension? Alcohol BP Diet Obesity Stress Physical activity

  47. ALDH2 Alcohol BP CI..CN

  48. Chen et al. PLOS Medicine 2008 5 (3): e52 • Meteanalysis: search word in PubMed and ISI ALDH2, hypertension, blood pressure, cardiovascular disease, heart disease-studies published before 2007 • Reference list • Meta-analysis guidelines JAMA 2000;283:2008-12

  49. Alcohol intake in matter for males: • ALDH 2x1x1 20-30g /day • ALDH 2x1x2 10-15g /day • ALDH 2x2x2 0-2g /day

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