T64A polymorphism in beta(3)-adrenergic receptor gene (ADRB3) and coronary heart disease: a case-cohort study and meta-analysis

Objectives. A missense mutation of the human ADRB3 gene replacing tryptophan with arginine at codon 64 (Trp64Arg) has been related to obesity, insulin resistance, earlier onset of noninsulin-dependent diabetes mellitus and hypertension. These findings may also suggest an increased risk of coronary heart disease (CHD). We therefore investigated the role of this polymorphism on the occurrence of acute myocardial infarction (AMI) and CHD in a population of healthy Dutch women. Design. We performed a case-cohort study in a prospective cohort of 15 236 initially healthy Dutch women. We applied a Cox proportional hazards model with an estimation procedure adapted for case-cohort designs to study the relationship between the polymorphism and AMI (n = 71) and CHD (n = 211). In addition, a meta-analysis of published studies was performed using a random effect model. Results. Using the dominant model, carriers of the arginine allele (n = 222) compared to those with the more common genotype (n = 1508) were not at increased risk of AMI (hazard ratio = 1.60; 95% CI, 0.86-2.96) and for CHD (HR = 1.36; 95% CI, 0.92-2.02). We did not find any relationship using recessive and additive models, either. Our meta-analysis corroborated these findings by showing no significant association between the polymorphism and risk of CHD using different genetic models. Conclusions. Our study in combination with a meta-analysis of previous reports do not provide support for a role of missense mutation replacing tryptophan with arginine at codon 64 (Trp64Arg) at the human ADRB3 gene in CHD risk.