There remains the possibility of unidentified linkage disequilibrium with genes modulating other conventional cardiac risk factors, with elevated plasma lipids being previously linked to carriage of the PlA2 allele. This hypothesis is however not supported by the data analysed within the Y-27632 present meta-analysis, with only one study finding higher triglycerides in carriers of the PlA2 allele and conflicting reports on the levels of lipoprotein. Interestingly, Grove et al found that the association between carriage of the PlA2 allele and MI decreased as cholesterol levels increased, suggesting once again that the true effect of the PlA2 allele may be diluted and hence concealed by the concomitant presence of conventional risk factors. The proximity of the PlA1/A2 epitope to the ligand binding site of GPIIIa has led investigators to consider how the single amino acid substitution of proline for leucine may affect the cycle of ligand association and dissociation with the fibrinogen receptor. Studies have been inconclusive, with no difference observed in static systems but an enhancement of binding and outside-in signalling seen in cell culture under conditions of shear stress, thus potentially resulting in circulating platelets having a higher basal level of activation. Similarly to plasma lipids, plasma fibrinogen concentration has been suggested as a potential modulator of the increased risk secondary to carriage of the PlA2 allele, but as with the lipid hypothesis, studies included in this meta-analysis do not support this association. Three studies reported a higher levels of fibrinogen in certain subgroups of individuals carrying the PlA2 allele and two studies reported higher fibrinogen levels in PlA1 homozygous subjects. Resistance to aspirin has been suggested as another potential mechanism by which carriage of the PlA2 allele may cause increased cardiovascular risk. However, a recent large metaanalysis has suggested that this is not the case. There is however significant inter-study heterogeneity, and the need for further studies in this regard remains. A final avenue of investigation has been whether the PlA1/A2 antigens affect the degree or morphology of atherosclerosis. Carotid plaque morphology was examined by magnetic resonance imaging in 1,202 participants in the atherosclerotic risk in communities study. Subjects who carried the PlA2 allele were found to have plaques with thinner fibrous caps, and these thinner caps represent the major precursor lesion for ACS. However, this study was limited by a low frequency of the minor allele and technical constraints resulting in plaque morphology being assessed only in individuals with thick arterial walls. A potential limitation of this meta-analysis is the presence of a mortality bias that may attenuate or entirely obscure any true association. Almost a third of individuals with a first major coronary event die out-of-hospital, and are not accounted for in the predominantly retrospective data presented in this metaanalysis. In fact, in most studies the subject must have survived a cardiac event for a number of months or even years to be available for inclusion.