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How to identify gene–environment interactions in a multifactorial disease: CHD as an example

Published online by Cambridge University Press:  07 March 2007

Philippa J. Talmud
Philippa J. Talmud*
Affiliation:
Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Rayne Building, Royal Free and University College London Medical School, London, WC1E 6JF, UK
*
Corresponding author: Dr Philippa J. Talmud, fax +44 20 7679 6212, email [email protected]
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Abstract

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CHD is a multifactorial disease, caused by both genetic and environmental factors. The inherited 'defective' genes will vary from individual to individual, and any single mutation is likely to be making only a small contribution to risk. The context dependency, i.e. the importance of environmental factors in influencing genetic risk, is now becoming evident. Thus, a mutation may have a modest effect on risk in individuals who maintain a low environmental risk, but a major effect in a high-risk environment. Methods of analysing gene–environment interactions on CHD risk will be discussed and illustrated with several examples. APOE has three common alleles, ɛ2, ɛ3 and ɛ4. The ɛ4 allele has consistently been associated with CHD risk, which has been confirmed by meta-analysis. However, when the effect of genotype on risk was considered in smokers and non-smokers separately, risk in non-smokers was similar in all APOE genotypes. By comparison, in the smokers, ɛ3 homozygotes, as expected, had an approximately 2-fold higher risk, while for ɛ4 carriers there was a significantly greater than additive effect of genotype and smoking on risk (P ≫0.007). Thus, the impact of the ɛ4 allele on CHD risk appears to be confined to current smokers, an effect that has been confirmed in several studies. Another example is the interaction between the alcohol dehydrogenase 3 gene variant and alcohol consumption on CHD risk (P ≫0.001), showing the context dependency of the effect. Thus, the importance of considering environmental factors as potential genotype-risk modifiers has major public health implications.

Keywords

Gene–environment interactionAPOEADH3DietAlcohol consumptionSmoking
Type
Meeting Report
Information
Proceedings of the Nutrition Society , Volume 63 , Issue 1 , February 2004 , pp. 5 - 10
Copyright
Copyright © The Nutrition Society 2004

References

Abifadel, M, Varret, M, Rabes, JP, Allard, D, Ouguerram, K, Devillers, M et al. (2003) Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nature Genetics 34, 154–156.CrossRefGoogle ScholarPubMed
Bosron, WF, Lumeng, L & Li, TK (1988) Genetic polymorphism of enzymes of alcohol metabolism and susceptibility to alcoholic liver disease. Molecular Aspects of Medicine 10, 147–158.CrossRefGoogle ScholarPubMed
Corder, EH, Saunders, AM, Strittmatter, WJ, Schmechel, DE, Gaskell, PC, Small, GW, Roses, AD, Haines, JL & Pericak-Vance, MA (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261, 921–923.CrossRefGoogle ScholarPubMed
Doll, R & Hill, AB (1966) Mortality of British doctors in relation to smoking; observation on coronary thrombosis. National Cancer Institute Monographs 19, 205–268.Google ScholarPubMed
Doll, R, Peto, R, Hall, E, Wheatley, K & Gray, R (1997) Alcohol and coronary heart disease reduction among British doctors: confounding or causality?. European Heart Journal 18, 23–25.CrossRefGoogle ScholarPubMed
Fickl, H, Van Antwerpen, VL, Richards, GA, Van der Westhuyzen, DR, Davies, N, Van der Walt, R, Van der Merwe, CA & Anderson, R (1996) Increased levels of autoantibodies to cardiolipin and oxidised low density lipoprotein are inversely associated with plasma vitamin C status in cigarette smokers. Atherosclerosis 124, 75–81.CrossRefGoogle ScholarPubMed
Ginsberg, HN, Kris-Etherton, P, Dennis, B, Elmer, PJ, Ershow, A & Lefevre, M, et al. (1998) Effects of reducing dietary saturated fatty acids on plasma lipids and lipoproteins in healthy subjects: the DELTA Study, protocol 1. Arteriosclerosis, Thrombosis and Vascular Biology 18, 441–449.CrossRefGoogle ScholarPubMed
Goldstein, JL & Brown, MS (1989) Familial hypercholesterolemia. In The Metabolic Basis of Inherited Disease, 6th ed. pp. 1215–1250 [Scriver, CH, Beaudet, AI, Sly, WS, Valle, D, editors]. New York: McGraw-Hill Book Co.Google Scholar
Haskell, WL (1986) The influence of exercise training on plasma lipids and lipoproteins in health and disease. Acta Medica Scandinavica 711, Suppl., 25–37.CrossRefGoogle ScholarPubMed
Hines, LM, Stampfer, MJ, Ma, J, Gaziano, JM, Ridker, PM, Hankinson, SE, Sacks, F, Rimm, EB & Hunter, DJ (2001) Genetic variation in alcohol dehydrogenase and the beneficial effect of moderate alcohol consumption on myocardial infarction. New England Journal of Medicine 344, 549–555.CrossRefGoogle ScholarPubMed
Humphries, SE, Hawe, E, Dhamrait, S, Miller, GJ & Talmud, PJ (2003) In search of genetic precision. Lancet 361, 1908–1909.CrossRefGoogle ScholarPubMed
Humphries, SE, Talmud, PJ, Hawe, E, Bolla, M, Day, IN & Miller, GJ (2001) Apolipoprotein E4 and coronary heart disease in middle-aged men who smoke: a prospective study. Lancet 358, 115–119.CrossRefGoogle ScholarPubMed
Innerarity, TL, Mahley, RW, Weisgraber, KH, Bersot, TP, Krauss, RM, Vega, GL, Grundy, SM, Friedl, W, Davignon, J & McCarthy, BJ (1990) Familial defective apolipoprotein B-100: a mutation of apolipoprotein B that causes hypercholesterolemia. Journal of Lipid Research 31, 1337–1349.CrossRefGoogle ScholarPubMed
Ioannidis, JP, Ntzani, EE, Trikalinos, TA & Contopoulos-Ioannidis, DG (2001) Replication validity of genetic association studies. Nature Genetics 29, 306–309.CrossRefGoogle ScholarPubMed
Jolivalt, C, Leininger-Muller, B, Bertrand, P, Herber, R, Christen, Y & Siest, G (2000) Differential oxidation of apolipoprotein E isoforms and interaction with phospholipids. Free Radical Biology in Medicine 28, 129–140.CrossRefGoogle ScholarPubMed
Keavney, B, Parish, S, Palmer, A, Clark, S, Youngman, L, Danesh, J, McKenzie, C, Delepine, M, Lathrop, M, Peto, R & Collins, R (2003) Large-scale evidence that the cardiotoxicity of smoking is not significantly modified by the apolipoprotein E epsilon 2/epsilon 3/epsilon 4 genotype. Lancet 361, 396–398.CrossRefGoogle ScholarPubMed
Poirier, J, Davignon, J, Bouthillier, D, Kogan, S, Bertrand, P & Gauthier, S (1993) Apolipoprotein E polymorphism and Alzheimer's disease. Lancet 342, 697–699.CrossRefGoogle ScholarPubMed
Rice, KM & Holmans, P (2003) Allowing for genotyping error in analysis of unmatched case-control studies. Annals of Human Genetics 67, 165–174.CrossRefGoogle ScholarPubMed
Savolainen, MJ & Kesaniemi, YA (1995) Effects of alcohol on lipoproteins in relation to coronary heart disease. Current Opinion in Lipidology 6, 243–250.CrossRefGoogle ScholarPubMed
Shields, PG (2000) Epidemiology of tobacco carcinogenesis. Current Oncology Reports 2, 257–262.CrossRefGoogle ScholarPubMed
Smith, JD, Miyata, M, Poulin, SE, Neveux, LM & Craig, WY (1998) The relationship between apolipoprotein E and serum oxidation-related variables is apolipoprotein E phenotype dependent. International Journal of Clinical Laboratory Research 28, 116–121.CrossRefGoogle ScholarPubMed
Wallace, AJ, Mann, JI, Sutherland, WH, Williams, S, Chisholm, A, Skeaff, CM, Gudnason, V, Talmud, PJ & Humphries, SE (2000) Variants in the cholesterol ester transfer protein and lipoprotein lipase genes are predictors of plasma cholesterol response to dietary change. Atherosclerosis 152, 327–336.CrossRefGoogle ScholarPubMed
Wilson, PW, Schaefer, EJ, Larson, MG & Ordovas, JM (1996) Apolipoprotein E alleles and risk of coronary disease. A meta-analysis. Arteriosclerosis, Thrombosis and Vascular Biology 16, 1250–1255.CrossRefGoogle ScholarPubMed