Novel platelet membrane glycoprotein VI dimorphism is a risk factor for myocardial infarction

Back-ground-Glycoprotein (GP) VI plays a crucial role in platelet activatio n and aggregation. We investigated whether polymorphic variation at the Gl? VI locus confers an increased risk of myocardial infarction (MI). Methods and Results-Coding and 5' and 3' non-coding regions of the Gl? VI g ene were analyzed by polymerase chain reaction and conformation sensitive g el electrophoresis in 21 healthy subjects. Ten dimorphisms, 5 of which pred icted amino acid substitutions (T13254C, A19871G, A21908G, A22630T, C22644A ), were identified. Two core haplotypes involving 7 dimorphisms (C10781A an d G10873A and all those predicting amino acid substitutions) were apparent. The contribution of the T13254C dimorphism, which predicted the substituti on of serine 219 by proline, to risk of MI was assessed in 525 patients wit h acute MI and 474 controls, all aged < 75 years. The allelic odds ratio (O R) for MI associated with the 13254C allele was 1.16 (95% CI, 0.91 to 1.46; P=0.23). Compared with corresponding control subgroups, the 13254CC genoty pe was more common among cases who were female (OR, 4.52; 95% CI, 1.23 to 1 6.64; P=0.029), nonsmokers (OR, 2.50; 95% CI, 0.98 to 6.38; P=0.048), aged greater than or equal to 60 years (OR, 6.48; 95% CI, 1.47 to 28.45; P=0.009 ) or carried the beta -fibrinogen -148T allele associated with increased fi brinogen levels (OR, 10.49; 95% CI, 1.32 to 83.42; P=0.02). In logistic reg ression analysis that took other cardiovascular risk factors into account, the interactions of GP VI genotype with age (P=0.005) and beta -fibrinogen genotype (P=0.035) remained significant. Conclusions-The Gl? VI 13254CC genotype increases the risk of MI, particula rly in older individuals, and the interaction of the GP VI 13254C allele wi th other candidate risk alleles may accentuate this risk.