Genes, lifestyle and coronary heart disease risk-epidemiological interaction studies

Abstract

Coronary heart disease (CHD) has multifactorial background involving both genetic and lifestyle factors, but much is still unknown about their interactions. The aim of this thesis was to study interactions focusing on apolipoprotein E (APOE), fat mass and obesity-related (FTO) and ghrelin/obestatin prepropeptide (GHRL) genes, as well as smoking, physical activity and diet. The study sample included 1831 cases with CHD (myocardial infarction or unstable angina) and 5175 population controls from two population-based studies: SHEEP, Stockholm and INTERGENE, Gothenburg. Interaction was assessed on the relative risk (RR) and risk difference (RD) scales. APOE-smoking interaction was found both on the RR and RD scales, so that subjects carrying the Ɛ2 allele had lower smoking-related CHD risk, adjusted OR 1.35 (95% CI 0.92-1.97) than non-carriers, with OR 2.17 (95% CI 1.82-2.59) in subjects with common genotype Ɛ3Ɛ3 and OR 2.43 (95% CI 1.88-3.14) in Ɛ4 carriers. Women carrying the Ɛ4 allele had particularly high smoking-related CHD risk with OR 3.69 (95% CI 2.33-5.83). A potential APOE-physical activity interaction was also observed, where the Ɛ2 allele counteracted while the Ɛ4 allele (vs Ɛ3Ɛ3) potentiated CHD risk from physical inactivity. Carriers of the FTO single nucleotide polymorphism (SNP) rs9939609 A allele (TA/AA vs TT) had increased CHD risk with OR 1.20 (95% CI 1.06-1.37), independent of body mass index (BMI). No evidence of interaction between FTO and physical activity was found, indicating that FTO-related CHD risk is not counteracted by increased physical activity. No clear interactions between FTO and macronutrients were found with a dichotomous variable of below/above median energy% intake. With a continuous energy% variable, excluding subjects reporting diet change, however, interaction was observed on the RR scale for FTO-fat and FTO-saturated fatty acids, suggesting slightly increased FTO-related CHD risk with lower energy% of fat or saturated fatty acids. Finally, a gene-gene interaction was found for SNPs FTO and GHRL rs35680 in a subsample of 420 INTERGENE controls, where the minor alleles had synergistic effects on BMI, supporting a mechanistic FTO-GHRL link behind obesity. To conclude, identification of gene-lifestyle interactions may contribute to enhanced understanding of mechanisms causing CHD.