Genetic variants of the hemostatic system and development of transplant coronary artery disease

Background: The occurrence of coronary artery disease (CAD) after heart transplantation may represent an accelerated inflammatory and thrombotic response to coronary vascular endothelial cell injury. Several common mutations involving hemostasis and cellular adhesion proteins have been associated with genetic susceptibility to native coronary heart disease. The clinical setting of heart transplantation provides a unique opportunity to examine the relative contribution of circulating (i.e., recipient) vs local vascular (i.e., donor) hemostatic components to the occurrence of CAD. Methods: We performed genotyping for several common hemostatic polymorphisms among 53 cardiac transplant patients and their heart donors. Patients were observed for an average of 43 months, and the presence of transplant CAD was determined by coronary angiography. Results: The development of transplant CAD did not relate to recipient hemostatic genotype, but 2 donor polymorphisms (PAI-1 4G/5G and alpha(2) integrin C807T) were important predictors of transplant CAD. The risk ratio (RR) of transplant CAD associated with donor PAI-1 4G/4G genotype was 2.6 (95% confidence interval [Cl] 1.1-6.2) and was modified by recipient cytomegalovirus status, hyperlipidemia, diabetes, and recipient factor XIII Val34Leu genotype. The RR of transplant CAD associated with donor alpha(2) integrin 807 T/T genotype was 7.4 (95% CI, 2.5-22.0). Conclusions: Genetic and metabolic factors contributed by both donor and recipient may interact at the level of the coronary vessel wall in the development of transplant-associated CAD, and this finding may provide additional support for the importance of local thrombotic response to endothelial injury in the pathogenesis of this disorder.