Abstract
BackgroundHaptoglobin (HP) is an acute phase protein that binds to freely circulating hemoglobin. HP exists as two distinct forms, HP1 and HP2. The longer HP2 form has been associated with cardiovascular (CVD) events and mortality in individuals with type 2 diabetes (T2DM).MethodsThis study examined the association of HP genotypes with subclinical CVD, T2DM risk, and associated risk factors in a T2DM-enriched sample. Haptoglobin genotypes were determined in 1208 European Americans (EA) from 473 Diabetes Heart Study (DHS) families via PCR. Three promoter SNPs (rs5467, rs5470, and rs5471) were also genotyped.ResultsAnalyses revealed association between HP2-2 duplication and increased carotid intima-media thickness (IMT; p = 0.001). No association between HP and measures of calcified arterial plaque were observed, but the HP polymorphism was associated with triglyceride concentrations (p = 0.005) and CVD mortality (p = 0.04). We found that the HP2-2 genotype was associated with increased T2DM risk with an odds ratio (OR) of 1.49 (95% CI 1.18-1.86, p = 6.59x10-4). Promoter SNPs were not associated with any traits.ConclusionsThis study suggests association between the HP duplication and IMT, triglycerides, CVD mortality, and T2DM in an EA population enriched for T2DM. Lack of association with atherosclerotic calcified plaque likely reflect differences in the pathogenesis of these CVD phenotypes. HP variation may contribute to the heritable risk for CVD complications in T2DM.
Highlights
Cardiovascular disease (CVD) is one of the major complications associated with type 2 diabetes mellitus (T2DM)
In its ancestral form, HP is a dimer, the HP 1–2 encoded protein exists as linear polymers containing 2–8 monomers, while the HP 2–2 encoded protein exists as circular polymers of 3–10 Hp monomers [6]
This study evaluated association of HP gene polymorphisms with subclinical CVD, mortality, and T2DM in 1208 European Americans (EA) individuals from the Diabetes Heart Study (DHS)
Summary
Cardiovascular disease (CVD) is one of the major complications associated with type 2 diabetes mellitus (T2DM). As of 2011, 25.8 million Americans had diagnosed T2DM [1]. T2DM is an independent risk factor for development of CVD with the relative risk of CVD mortality of 2.1 in men and 4.9 in women, relative to non-T2DM affected individuals [3,4]. Haptoglobin (HP) is a 54 kDa protein, found abundantly in the serum [5,6]. The HP gene has two major alleles: HP1, (containing five exons) and HP2, (containing seven exons) which likely arose from a duplication event involving exons 3 and 4, producing a 61 kDa protein [6]. The longer HP2 form has been associated with cardiovascular (CVD) events and mortality in individuals with type 2 diabetes (T2DM)
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