Genetic variants of coagulation factor XIII and the risk of myocardial infarction in young women

Several proteins are involved in thrombus formation. Coagulation factor XIII is, upon activation by thrombin, responsible for the crosslinking of fibrin monomers. The protein consists of four chains, which are encoded on different chromosomes: two B-chains (encoded on chromosome 1q31 – q32·1) that have no enzymatic activity and serve as carriers of the A-chains, and two A-chains (chromosome 6p25 – p24) that consist of the protransgluteminase that is involved in the crosslinking. This process determines clot structure and thus clot permeability and resistance to shear stress and fibrinolysis (Lorand, 2001; Kobbervig & Williams, 2004). Genetic variants in one of the two F13 genes (F13A1 and F13B) have been shown to be associated with an altered risk of both arterial and venous thrombosis. (Reiner et al, 2002; Komanasin et al, 2005; Shafey et al, 2007) Recently, we determined four single nucleotide polymorphisms (SNPs) in F13A1 and F13B in a sub-study of the RATIO (Risk of Arterial Thrombosis In relation to Oral contraceptives) study, a population based case–control study into the risk factors of arterial thrombosis in young women. We reported that the F13A1 204Phe variant was associated with a nine-fold increased risk for ischaemic stroke in young women. Oral contraceptives use further increased this risk (odds ratio 20; 95% confidence interval 9–46) (Pruissen et al, 2008). Given that Ischaemic Stroke (IS) and Myocardial Infarction (MI) are both subtypes of arterial thrombosis, we hypothesized that the risk of MI is also increased by these genetic variants of FXIII. We thus set out to assess the relationship between FXIII SNPs and the risk of MI in the RATIO study. The RATIO study is a multicentre, population-based case–control study. The study consists of three sub-studies on MI, IS and peripheral arterial disease (Tanis et al, 2001; Kemmeren et al, 2002). In short, for this study we included 218 women aged 18–50 years who were hospitalized for a confirmed first MI in one of 16 participating hospitals. Random digit dialling yielded 767 women aged 18–50 years who served as controls; the control group was frequency-matched to the patients for age (in 5-year categories), residence, and year of the MI. Furthermore, the women did not have a history of coronary heart disease, cerebrovascular event, or peripheral vascular disease. All participants filled in a questionnaire on possible risk factors for arterial thrombosis and provided DNA. Details on patient characteristics, recruitment and selection can be found elsewhere (Tanis et al, 2001). Informed consent was obtained from all participants in accordance with the Declaration of Helsinki. A total of four genetic variants were genotyped with the 5′ nuclease/TaqMan assay: Val34Leu (rs5985), Tyr204Phe (rs3024477), and Pro564Leu (rs5982) variants in the FXIII subunit A gene (F13A1) and the His95Arg variant (rs6003) in the FXIII subunit B gene (F13B). Primer sequences, probe sequences, and restriction enzymes used are available on request. Laboratory technicians were unaware of case–control status and other patient characteristics. The effect of the FXIII-variants on the risk of MI was assessed by the calculation of odds ratios as measures of rate ratios with the corresponding 95% confidence intervals with logistic regression. Odds ratios were calculated per genotype and according to dominant inheritance pattern and were adjusted for the stratification factors age (on a continuous scale), area of residence and calendar year. The baseline characteristics of patients and controls are displayed in Table I. As expected, patients reported more cardiovascular risk factors than controls. Oral contraceptive use increased the risk of MI two-fold (odds ratio 2·3; 95% confidence interval, 1·6–3·3). Genotype distributions and corresponding odds ratios are shown in Table II. The overall call rate was 97·8% (range, 96·1–98·7%). No deviation from Hardy–Weinberg Equilibrium was found in the control women for any of the genotypes. Only the 564Leu variant of F13A1 had a weakly increased risk of 40% (OR 1·40; 95% confidence interval 1·01–1·93) in the dominant inheritance pattern analysis. The increase in risk for the F13A1 Pro564Leu variant was confined to the heterozygous carriers (1·46; 1·05–2·03): the homozygous carriers of the minor allele had the same risk of disease as the homozygous carriers of the major allele (0·96; 0·40–2·28). The F13A1 Val34Leu, F13A1 Tyr204Phe and F13B His95Arg SNPs did not alter MI risk in both the dominant and the per genotype analyses. The 564Leu variant is known to lower FXIII plasma level and increase FXIII activity (Anwar et al, 1999; Gallivan et al, 1999). This, together with the lack of dose response, does not add to a plausible biological mechanism that explains the increase in risk of MI in heterozygous, nor does the absence of an effect in homozygotes. This suggests that the increase in risk we observed for the heterozygous genotype is a false positive finding. An earlier study on FXIII SNPs suggested an increased risk of IS for F13A1 34Leu and F13A1 204Phe, but not for MI. However, due to the limited number of cases (68 MI cases and 36 IS cases) no definite conclusions could be drawn (Reiner et al, 2002). The modest protective effect of F13A1 34Leu variant on MI could not be replicated, probably due to lack of power (Shafey et al, 2007). Earlier results from the RATIO study showed a nine-fold increased risk of IS for carriers of the F13A1 204Phe whereas carriers of the F13B 95Arg variant had a 1·7-fold increase in this risk. (Pruissen et al, 2008) So, although MI and IS are both subforms of arterial thrombosis, SNPs in the F13 genes have different effects. These differences in risk factors suggest that the different forms of arterial thrombosis have a different aetiology. Further study into the differences between the aetiology of MI and IS as subforms of arterial thrombosis is warranted. The authors thank the contributors to the earlier phases of the RATIO study. We are indebted to Mrs P. J. Noordijk, who performed the DNA analyses. This study was supported by a grant from the Leducq Foundation, Paris, France for the development of Transatlantic Networks of Excellence in Cardiovascular Research (grant 04 CVD 02) and by the Netherlands Heart Foundation, The Netherlands (grant NHS 97·063). BS; data analysis and drafting of manuscript, AA; study design, data analysis and supervision, FRR; study design and supervision. None.