Haptoglobin genotype: a determinant of cardiovascular complication risk in type 1 diabetes

Abstract

Objective: Haptoglobin (Hp) is a plasma protein that binds free hemoglobin, thereby inhibiting hemoglobin-induced oxidative damage. We investigated the association between the Hp genotype and the incidence of coronary artery disease (CAD) in a cohort of individuals with childhood-onset type 1 diabetes.

Research Design and Methods: Participants from the Epidemiology of Diabetes Complications Study who were free of CAD at study entry and had DNA available were selected (n=453; mean age, 27.1 years and diabetes duration, 18.8 years). CAD was defined as angina, ischemic electrocardiogram, myocardial infarction confirmed by Q-waves on electrocardiogram or hospital records, angiographic stenosis >50%, or revascularization.

Results: The proportions of the cohort with the Hp 1/1, 2/1 and 2/2 genotypes were 11.5%, 41.3% and 47.2%, respectively. During 18 years of follow-up, there were 135 (29.8%) incident CAD events. Univariately, the proportion of CAD events increased from 15.4% (Hp 1/1), to 28.3% (Hp 2/1) and 34.6% (Hp 2/2) (p=0.02, p-trend=0.007). Cumulative incidence (including 33 baseline prevalent cases) also increased from 24.1% (Hp 1/1), to 32.3% (Hp 2/1), and 39.1% (Hp 2/2) (p=0.07, p-trend=0.02). In Cox proportional hazards models adjusting for traditional CAD risk factors, the Hp 2/2 genotype was associated with increased CAD incidence compared to the Hp1/1 genotype (HR=2.21, 95% CI=1.05-4.65, p-value=0.04). Although the risk associated with the Hp 2/1 genotype did not reach significance (HR=1.78, 95% CI=0.84-3.79, p-value=0.13), there remained a significant trend across the three groups (p=0.03).

Conclusions: These data support the hypothesis that the Hp genotype influences cardiovascular risk in type 1 diabetes.