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


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 haptoglobin 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 to 28.3 and 34.6% for haptoglobin 1/1, 2/1, and 2/2, respectively (P = 0.02, P-trend = 0.007). Cumulative incidence (including 33 baseline prevalent cases) also increased from 24.1 to 32.3 and 39.1%, respectively (P = 0.07, P-trend = 0.02). In Cox proportional hazards models adjusting for traditional CAD risk factors, the haptoglobin 2/2 genotype was associated with increased CAD incidence compared with the haptoglobin 1/1 genotype (hazard ratio [HR] 2.21, 95% CI 1.05-4.65, P = 0.04). Although the risk associated with the haptoglobin 2/1 genotype did not reach significance (1.78, 0.84-3.79, P = 0.13), there remained a significant trend across the three groups (P = 0.03).


CONCLUSIONS
These data support the hypothesis that the haptoglobin genotype influences cardiovascular risk in type 1 diabetes.
Costacou
Tina
T
Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. costacout@edc.pitt.edu
Ferrell
Robert E
RE
Orchard
Trevor J
TJ
D000328:Adult; D017668:Age of Onset; D015992:Body Mass Index; D002318:Cardiovascular Diseases / Q000235:genetics*; D015331:Cohort Studies; D003327:Coronary Disease / Q000453:epidemiology / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000235:genetics*; D003925:Diabetic Angiopathies / Q000453:epidemiology / Q000473:pathology*; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006242:Haptoglobins / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010414:Pennsylvania; D012307:Risk Factors
D006242:Haptoglobins