There are two major classes of alleles for the haptoglobin (Hp) gene, denoted 1 and 2 (1). We have recently reported evidence that Hp is a major susceptibility gene for cardiovascular disease in the diabetic state (2,3). Moreover, we have provided a mechanism for this differential susceptibility conferred by the Hp type by demonstrating striking differences in the antioxidant protection afforded by the protein products of the different Hp alleles (4).

Mortality after myocardial infarction in the diabetic patient remains alarmingly high. Increased oxidative stress leading to increased ischemia-reperfusion injury may play a major role in explaining this poor outcome (5). Accordingly, we proposed that the Hp type would be predictive of mortality and major adverse cardiac events after acute myocardial infarction (AMI) in individuals with diabetes. We sought to prospectively test this hypothesis by determining the association between the Hp type and major adverse cardiac events occurring within 30 days of AMI in a consecutive series of 601 patients (224 diabetic subjects). We found a significantly increased mortality rate in the diabetic cohort in individuals with the Hp 2 allele (30-day mortality rate of 0% for Hp 1-1, 23% for Hp 2-1, and 25% for Hp 2-2, P = 0.014). The composite major adverse cardiac events rate (death, reinfarction, and revascularization) at 30 days was 11% in Hp 1-1, 51% in Hp 2-1, and 55% in Hp 2-2 (P < 0.0001). After multivariate analysis, using the Cox model, Hp type was significantly associated with the risk of adverse cardiac events in diabetic patients in the first 30 days after AMI (odds ratio 4.9, 95% CI 1.5–15.7, P = 0.007). There was no significant difference in the mortality rate or composite primary end point rate among nondiabetic patients segregated by Hp type.

The elevated mortality risk after AMI associated with diabetes appears to be restricted to those individuals with the Hp 2 allele. Determination of the Hp type may be of use in the evaluation of therapies to reduce cardiovascular mortality after AMI in diabetic individuals.

This study was supported by the Kennedy-Leigh Charitable Trust.

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