Background and Purpose--Recent findings of an association between polymorphisms of advanced glycosylation end product-specific receptor (AGER) and risk of diabetic vasculopathy have generated great interest. However, to date, no genetic-epidemiological data are available on risk of atherothrombotic events among nondiabetic populations.

Methods--Using DNA samples collected at baseline in a prospective cohort of 14 916 initially healthy American men, we evaluated 3 AGER genetic variants: -429T>C, -374T>A, and Gly82Ser, among 600 white individuals who subsequently developed atherothrombotic event (incident myocardial infarction or ischemic stroke) and among 600 age- and smoking-matched white individuals who remained free of reported vascular disease during follow-up (controls).

Results--Genotype distributions for the polymorphisms tested were in Hardy-Weinberg equilibrium. Haplotype-based conditional logistic regression, adjusting for other potential confounders, showed that haplotype C-T-Gly (myocardial infarction: odds ratio [OR], 0.60; 95% CI, 0.41 to 0.90; P=0.01) and haplotype T-A-Gly (ischemic stroke: OR, 0.63; 95% CI, 0.40 to 0.99; P=0.05), compared with the reference haplotype T-T-Gly, were associated with reduced risk of atherothrombosis. Prespecified analysis limited to those without baseline history of diabetes showed similar significant findings.

Conclusions--We found an association of specific AGER promoter gene haplotypes with reduced risk of incident myocardial infarction and ischemic stroke that was independent of the presence of diabetes.