The major finding of this study is that the Hp 2-2 polymorphism, and to a lesser extent the 2-1 polymorphism, predicts development of coronary artery calcification in people with type 1 diabetes over a period of 6 years. The findings were internally consistent, using two definitions of CAC progression in linear and logistic regression analyses. Our finding that Hp polymorphisms predict new CAC only in patients with diabetes is consistent with previous reports from studies using clinical CAD endpoints [9
Consistent with our findings, the Pittsburgh Epidemiology of Diabetes Complications Study of patients with type 1 diabetes, has shown an allele-dose effect of the Hp 2 allele on the risk of incident CAD [9
]. Thus, among individuals with type 1 diabetes, the Hp 2 allele plays an important role in subclinical coronary atherosclerosis and progression to clinical events.
The apparent lack of effect of Hp genotype on progression of CAC in patients already CAC positive is puzzling and requires further evaluation. While we adjusted for baseline extent of CAC in the models among patients already CAC positive, it is possible that residual confounding by the level of baseline CAC remains. In addition, incident CAC and CAC progression may reflect different biological processes and prognoses. The development of CAC is a process which increases risk for future acute coronary events, [5
] and CAC progression is a powerful predictor of mortality even among persons who already have CAC present; [6
] However, calcification of a plaque itself does not promote plaque rupture [19
No other cohorts with data about incident CAC in individuals with type 1 diabetes exist in which to validate our findings. However, the results of this study validate those from studies of clinical endpoints by using the subclinical outcome of CAC, thereby demonstrating that the Hp genotype is a robust biomarker for atherosclerosis in individuals with type 1 diabetes.
The different effect of Hp 1 and Hp 2 proteins on cardiovascular risk in patients with diabetes potentially derives from several mechanisms. First, Hp regulates the fate and toxicity of extracorpuscular hemoglobin [7
]. Upon binding to hemoglobin, the Hp 1 protein is superior to the Hp 2 protein in protecting against oxidation mediated by Hb derived iron [20
] and HDL dysfunction, [21
] particularly in the setting of diabetes. In addition, recent evidence suggests a more diverse physiologic role for Hp. Delanghe et al.
summarized the evidence that Hp polymorphisms play a role in the regulation of both T- and B- cells, particularly with respect to the immune response to atherosclerosis and Hb driven lipid oxidation [22
]. Other recent publications presented data suggesting that Hp (both genotype and circulating concentrations) has a role in remodeling the myocardium and, therefore, prognosis after myocardial infarction (MI) [23
]. To help elucidate these mechanisms, future observational research may want to study the association between Hp concentration and CAC development as well as the interaction between the immunologic profile of people with type 1 diabetes and Hp.