Abstract 1898: Risk Variants Identified in Genome-wide Association Studies and Their Role in Myocardial Infarction
Background: Following findings from genome-wide association studies that sequence variations at 9p21.3 and some other chromosomal loci are genetic factors for coronary heart disease, we investigated whether these variants influenced the risk of myocardial infarction (MI).
Methods and results: The study population consisted of 3657 patients with MI and 1211 control individuals. TaqMan assays were designed and used for genotyping. rs7865618 and rs1333049, the lead polymorphisms of different haplotype blocks (located at some distance from the genes encoding the cyclin-dependent kinase inhibitors 2A and 2B, CDKN2A and CDKN2B) in the 9p21.3 region, were strongly associated with MI (Table⇓). rs2943634 (no gene in associated interval), rs12510359 (in gene for cytoskeletal protein palladin, PALLD), rs6922269 (in gene for methylenetetrahydrofolate dehydrogenase 1-like, MTHFD1L), rs1799889 (also known as 4G/5G polymorphism in gene for plasminogen activator inhibitor type 1 or serpin peptidase inhibitor clade E member 1, SERPINE1), rs3025058 (also known as 5A/6A polymorphism in gene for matrix metalloproteinase 3, MMP3), and rs4804611 (in gene for a zinc finger protein, ZNF627), all implicated in disease risk in the original genome-wide discovery studies, were not associated with MI in this investigation (Table⇓). In meta-analyses, rs1799889 (4G/5G polymorphism in SERPINE1; 13282 cases/16514 controls) and rs3025058 (5A/6A polymorphism in MMP3; 10061 cases/8084 controls) were not related to coronary atherosclerosis [OR 1.08 (95%CI 0.98 –1.17) and OR 1.00 (95%CI 0.85–1.19), respectively]. Haplotypes of tagging polymorphisms in SERPINE1 and MMP3 were not associated with MI (P≥0.11).
Conclusions: Associations of lead polymorphisms at 9p21.3 with MI were replicated in this study, in good agreement with reported effect sizes. No corroboration was obtained for relationships of polymorphisms located at some other chromosomal loci, including SERPINE1 and MMP3.