Blood, 15 April 2003, Vol. 101, No. 8, pp. 2904-2904
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.
Laszlo Muszbek
University of Debrecen
