The chromosome 9p21 region and myocardial infarction in a European population
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OBJECTIVE: Sequence variation at Ch9p21 is a predisposing genetic factor for a number of diseases, including myocardial infarction (MI) and diabetes. We determined the risk of MI associated with various alleles and haplotypes, established and compared the predictive values of risk alleles, tested for the independence of associations between different risk alleles and MI, and sought to provide evidence for dual association of alleles with MI and diabetes. METHODS: With the use of 35 single nucleotide polymorphisms, together capturing common variation seen in the associated interval, we genotyped 3657 MI cases and 1211 controls prospectively sampled in a European population. RESULTS: Polymorphisms rs10757278 and rs1333049 both exhibited the strongest individual risk signal (OR, 1.45; 95% CI, 1.32-1.59). Two haplotype blocks were established, each of which was mainly represented by a pair of a risk-conferring and a protective haplotype, but none of the risk-associated haplotypes exhibited stronger effects than rs10757278 or rs1333049 alone. Specific polymorphisms (rs7865618, rs1537378, rs7857345, rs1333049) were identified as independent predictors of MI in multivariable models adjusted for conventional cardiovascular risk factors. In specific instances, the presence of two or three polymorphisms in a model, instead of only one, improved the discriminating power. Finally, evidence was provided to suggest dual association of rs7865618 with MI and diabetes. CONCLUSION: In keeping with published results, this work was consistent with the association of alleles and haplotypes at Ch9p21 with MI and extended prior knowledge by also showing independence of associations among different risk alleles and an association of a specific polymorphism with both MI and diabetes.