Gender Dependent Association of Thrombospondin-4 A387P Polymorphism With Myocardial Infarction

Abstract

To the Editor: A recently identified novel missense variant of TSP-4, A389P (29926 G>C) was correlated with premature myocardial infarction (MI) by an exploratory genetic association study on 184 MI patients from the American population.1 In this study, the TSP-4 387P allele showed the strongest association, with an adjusted odds ratio for MI of 1.89 ( P =0.002 adjusted for covariates) for individuals carrying the 387P allele. This was replicated by the same group using a larger number of patients.2 An in vitro functional study of the TSP-4 A387P substitution provided further evidence in support of a proatherogenic effect. The TSP-4 A387P substitution was shown to have a gain of function effect leading to suppression of endothelial cell adhesion and proliferation.3 The TSP-4 A387P variant also shows ethnic distribution differences. The TSP-4 387P allele showed a dramatically lower prevalence in Asian Chinese populations compared with whites (3.8% versus 19.6 to 23.2%) and failed to associate with coronary artery disease (CAD) or MI in the studied populations.4–5 Interestingly, in a more recent investigation, the TSP-4 variant 387P allele was significantly associated with reduced risk, rather than increased risk, for premature MI (OR=0.43, 0.22 to 0.85) in Netherlands whites.6 Therefore, the true effect of TSP-4 A387P in MI remains unknown. We believe that the contradictory results may be caused by either population genetic mixture or the effects of different modifiers for the TSP-4387P allele among the different ethnic populations. We examined the TSP-4 A387P variant as part of our study to explore potential gene variants as risk factors for MI and the effect of interaction between different variants on MI. …