Background:
The Hp 2-2 genotype has been associated with increased cardiovascular risk in type 2 diabetes, potentially relating to dysfunctional HDL mediated cholesterol efflux. We have shown that the Hp 2 allele predicts the development of both coronary artery disease (CAD) and kidney dysfunction also in childhood onset type 1 diabetes over 18 years of follow-up in the Epidemiology of Diabetes Complications (EDC) study. We now present results on the Hp-CAD association after an additional 7 year follow-up and Hp’s relation to impaired sterol efflux capacity, a proposed cardioprotective effect of HDL.
Methods:
Participants free of CAD at baseline and with Hp determined were studied (n=565; mean age, 27 and duration, 19 years; 11.5% Hp 1-1, 42.5% Hp 2-2). CAD was defined as EDC physician diagnosed angina, ischemic ECG changes (MC 1.3, 4.1-4.3, 5.1-5.3, 7.1), confirmed MI (MC 1.1, 1.2 or validated medical records), stenosis >50%, revascularization or CAD death. In a pilot study, serum HDL sterol efflux was assessed in Mifepristone stimulated ABCA1-BHK cells among 20 individuals (6 Hp 1-1; 7 Hp 2-1; 7 Hp 2-2) attending the 25 year exam.
Results:
During follow-up, 186 (32.9%) developed CAD. Incidence increased with the number of Hp 2 alleles (24.6% in Hp 1-1, 31.1% in Hp 2-1 and 37.1% in Hp 2-2, p-trend=0.04; Fig. 1). Multivariably, Hp 2-2 significantly increased risk by almost 80% (HR=1.79, 1.03-3.09). The risk associated with Hp 2-1 did not reach significance (HR=1.46, 0.85-2.53). In the pilot study, serum HDL sterol efflux was lower in Hp 2 allele carriers: 14.0% in Hp 1-1, 12.5% in Hp 2-1, 12.4% in Hp 2-2, p-trend=0.06, p-value Hp 1-1 vs Hp 2-1/2-2 =0.04.
Conclusion:
These results extend our previous findings of increased CAD risk associated with the Hp 2 allele in type 1 diabetes and further suggest that this allele associates with impaired sterol efflux capacity. These results support the hypothesis that sterol efflux explains the increased Hp 2 risk for CAD and should be confirmed prospectively.
Figure 1. CAD-free survival curves by Hp genotype
Insulin Resistance-Related Factors, but not Glycemia, Predict Coronary Artery Disease in Type 1 Diabetes: 10-year follow-up data from the Pittsburgh Epidemiology of Diabetes Complications study
