The major finding from this population-based case/control study of AMI survivors was that polymorphisms in GP6 were associated with AMI, whereas genetic variants in other candidate genes were not. Specifically, significant associations of rs1613662 and rs11084382 with AMI were observed, as well as an interaction between HRT with rs1613662 in postmenopausal women. The effect size (OR) of the minor alleles of these SNPs was approximately 0.70, representing a 30% reduction in risk for AMI.
Several published studies have implicated polymorphisms of the GP6 gene in coronary disease (15
). Contrary to our results indicating that the minor allele of the Ser219Pro missense polymorphism (rs1613662) was protective against AIM, Ollikainen et al. (16
) found that sudden death due to AMI was more common among men from Finland (mean age 55 years) who carried the minor allele, although this study comprised 34 cases and 92 controls. A report from Croft et al. on 525 MI patients and 474 controls (mean age = 61 years) in the United Kingdom (15
) indicated that after incorporating recognized CHD risk factors, the rs1613662 minor allele was not associated with AMI in men and women overall, however, it was associated with increased AMI in women who were also carriers of a beta-fibrinogen variant. Consistent with our results, Bray et al. (14
) observed that women (mean age = 66 years) homozygous for the rs1613662 minor allele may have been at reduced risk of AMI (though this trend was not statistically significant). However, they also reported that the rs1613662 minor allele was associated with increased risk of AMI among women on HRT. We, too, observed an interaction between HRT and GP6 on risk for AMI, however our results indicate that the rs1613662 minor allele was associated with decreased risk of AMI in women who have used HRT. Lastly, consistent with our results, a Japanese study of 376 cases of AMI (including both men and women) and 1080 control participants found that the minor (alanine) allele at the Thr249Ala polymorphism (rs2304167) in GP6, which is in 100% LD with our risk allele at rs11084382 in the HapMap Asian samples (Han Chinese in Beijing, China; Japanese in Tokyo, Japan)(18
), conferred a 2.3 fold excess risk of AMI after covariate adjustment (17
). These studies, however, have been limited in part by the modest number of participants, the varied definition of the phenotype, the use of clinic patients, the adjustment for various confounders, the lack of community-based study subjects, and/or the use of one or few SNPs within the GP6 locus to test for associations. We speculate that some of the inconsistencies among these studies may be due to survivorship bias. Our study, for example, included as cases only survivors of AMI, whereas Ollikainen et al. looked only at cases of mortality due to AMI. The opposite effects observed in these two studies may be explained by the role of GP6 in survivorship of AMI (i.e. minor allele predictive of AMI death and major allele predictive of AMI survivorship), rather than a direct role in disease pathogenesis. Taken together, these studies consistently show that genetic variation in GP6 is associated with risk of AMI, although it is unclear which variants contribute to this risk and what biological mechanism is responsible.
The present study benefits from several strengths including the large sample of incident cases and community-based controls, the incorporation of several non-genetic risk factors in our models, and the analysis of multiple GP6 SNPs and haplotypes. Haplotype analysis improves power to deterct association of a nearby untyped polymorphism compared to single-SNP analysis. Results of our haplotype analyses, which did not point to any specific haplotype(s) as driving the association, suggest that the missense polymorphism (not an untyped variant) may be the major causal variant (although other variants may also contribute to risk).
The results of this investigation are consistent with other studies suggesting that one or more polymorphisms in the GP6 gene influence the risk of AMI and are dependent on the use of HRT in women. There is a sound biological basis for this conclusion as thrombosis/fibrinolysis is involved in the evolution of coronary thrombosis and development of an AMI. Unfortunately, we did not have a measure of an intermediate phenotype to examine whether specific SNPs were functional. However, it has been recently reported (19
) that the degree of platelet aggregation was lower in some patients due to variation of the GP6 gene. It is unclear whether this finding is related to the protective effect of the missense polymorphism in our study. A future area of research would be to investigate whether any of these SNPs alter the ability of GP6 to bind to collagen. If polymorphisms in the GP6 locus could be linked with blood concentrations of proteins that are associated with risk of MI, pharmacologic interventions that alter these concentrations could be examined for their role in risk prediction viz-a viz alterations in the intermediate phenotype. The clinical indications for medications that alter platelet function are an active area of interest in this field. Unfortunately, we did not have data to address this question.
Other limitations of this data set include the fact that we examined survivors of AMI and therefore survivorship bias may have been introduced, as described above. Due to the study design, we do not know if the genetic associations present were related to incidence of AMI or case-fatality. This is an outstanding point of uncertainty and will need to be more carefully explored in future studies in order fully elucidate the role of GP6 on AMI.
In summary, we have shown that polymorphic variation at the GP6 locus is associated with risk of AMI in men and women and that this risk is modified by HRT. Our findings suggest that pharmacological approaches to platelet activity and thrombosis should be targeted towards GP6 to aid in the secondary prevention of AMI.