Abstract 3188: Increased Risk of Acute Myocardial Infarction and Elevated Levels of C-reactive Protein in Carriers of the Thr-87 Variant of the ATP Receptor P2Y11
Extracellular ATP acting on the membrane receptor P2Y11 is a regulator of inflammatory cells and has inotropic effects on cardiac myocytes. We hypothesized that polymorphisms in the receptor could influence the risk of acute myocardial infarction (AMI). A P2Y11 receptor polymorphism in residue 87 (Ala-87-Thr) of the P2Y11 receptor was identified and genotyped in two subgroups of the MalmöDiet and Cancer study (MDC, n=28098): one AMI case-control study (n=3732) with two paired matched controls per AMI case and one randomized group of the MDC with cardiovascular risk factor data (MDC-CV, n= 6103). The Thr-87 polymorphism of the P2Y11 gene was more common in patients with AMI (22.9%) than in the controls (19.8%):odds ratio (O.R.) of 1.21 (1.02 − 1.44, P = 0.03, 95% C.I.). Even stronger associations between the Thr-87 allele and AMI were found when the AMI group was restricted to cases with family history of AMI: O.R. 1.32 (1.02 − 1.69, P = 0.03); early onset AMI, O.R. 1.43 (1.13 − 1.82, P = 0.003) and family history AMI combined with early onset AMI: O.R. 1.50 (1.11 − 2.18, P = 0.01), supporting a genetic mechanism. A greater risk of AMI was found in Thr-87/Thr-87 homozygotes compared to carriers of Ala-87/Ala-87: O.R. 1.94 (1.02 − 3.66, P = 0.04) in the group as a whole, and O.R. 2.48 (1.02 − 6.05, P = 0.046) in the early onset AMI subgroup, suggesting a genetic dosage effect of the Thr-87-allele. Associations of cardiovascular risk factors with the Thr-87 allele were probed using the MCD-CV group (n=6103). The inflammatory marker C-reactive protein was significantly elevated in carriers of the Thr-87 variant of the P2Y11 receptor (1.6 mg/L, 0.7–3.0, median, interquartile range) compared to Ala-87 homozygotes (1.3 mg/L, 0.7–2.8, P = 0.001). No differences between genotypes were found regarding blood pressure, lipids, body-mass index, smoking or diabetes mellitus. The common Ala-87-Thr polymorphism of the P2Y11 receptor is associated with AMI, probably via a pro-inflammatory mechanism, and could be used for risk evaluation. The P2Y11 receptor is a promising drug target in the prevention of myocardial infarction and cardiovascular inflammatory disease.