The mystery of FXIII-A Val34Leu polymorphism

This polymorphism of the FXIII-A subunit gene started to stir considerable interest after a protective effect against myocardial infarction (MI) had been demonstrated for the Leu34 allele (Kohler et al, Thromb Haemost. 1998;79:8-13). Several follow-up studies were confirmatory, but contradictory results demonstrating the lack of protective effect also started to accumulate. As former studies showing no protective effect came from Mediterranean countries, it was presumed that in Mediterranean populations, well protected from arterial thrombotic events by environmental and other mechanisms, no further protection is provided by the Leu34 allele. But 2 most recent reports seem to oppose such a hypothesis. The first prospective study in this respect (ARIC study, Aleksic et al, Arterioscler Thromb Vasc Biol. 2002;22:348-352) was carried out in 4 US communities and did not provide evidence of a reduced coronary heart disease risk for the FXIII-A Leu34 allele.

In this issue, Butt and colleagues (page 3037) demonstrate in the Newfoundland population, a population of relatively homogenous genetic background, that in males the FXIII-A Leu34 allele exerts a predisposing (OR 3.3; 2.3-4.8) rather than protective effect for MI, and that it is neutral in females. The study also demonstrated that the prevalence of combined carriers for prothrombin 20210A and FXIII-A Leu34 is 12-fold higher in MI patients than in the control group, suggesting that gene-gene interactions may strongly influence the actual effect of Val34Leu polymorphism. The biochemical background of the polymorphism has been, at least in part, elucidated. Val34Leu is just 3 amino acids upstream of the thrombin cleavage site and the thrombin-induced release of activation peptide from the Leu34 variant occurs significantly faster than from wild-type FXIII-A. The structure of cross-linked fibrin seems also to be influenced by the polymorphism. But it still remains a mystery if gene-gene and gene-environment interactions may explain such divergent results and if the above biochemical changes directly relate to the risk of MI.