In Finnish individuals, Mikkola et al. (1994) identified a G-to-T transition in exon 2 of the F13A1 gene that results in a val34-to-leu (V34L) substitution. The variant was present in 23% of controls, suggesting that it represents a common polymorphism. The amino acid substitution was located close to a thrombin activation site (Kohler et al., 1998; Catto et al., 1998).
Among 398 Caucasian patients investigated for coronary artery disease, Kohler et al. (1998) found that the prevalence of the V34L polymorphism was decreased in patients with myocardial infarction (608446) compared to those without (32% vs 50%; p = 0.0009) and was also lower than in 196 controls (32% vs 48%; p = 0.005). The findings suggested a protective effect of the leu34 allele against myocardial infarction.
Franco et al. (1999) presented evidence that the homozygous state for the V34L mutation is a strong protective factor against venous thrombosis (see 188050) in a study of 189 patients with deep venous thrombosis and 187 controls. V34L was detected in 38.6% of the patients and in 41.2% of controls. Homozygosity for leu34 was found in 1.6% of the patients and in 9.6% of the controls, yielding an odds ratio (OR) for venous thrombosis of 0.16. The OR for heterozygotes was 1.1.
By in vitro studies Ariens et al. (2000) found that the val34-to-leu substitution increased the rate of factor XIIIA activation by thrombin and resulted in abnormal fibrin clot structure. Clots formed by leu34 had thinner fibrin fibers and reduced mass/length ratio of the fibers, as well as a finer meshwork and decreased permeation characteristics compared to clots formed by val34. Lateral aggregation of fibrin fibers was impaired by leu34.
In a study of the V34L polymorphism in 531 very low birth weight infants (birth weight less than 1,500 g) and 301 control infants born at term, Gopel et al. (2002) found no difference in allele frequencies between the 2 groups. Very low birth weight infants who were heterozygous or homozygous for the L34 allele had a significantly reduced risk for white matter disorders than infants without the polymorphism (3.6% vs 10.4%, p = 0.003) but had a moderately increased risk for subsequent isolated ventricular hemorrhage (14.3% vs 10.1%, p = 0.17).
Reiner et al. (2003) hypothesized that possession of the V34L polymorphism might modulate the prothrombotic effects of estrogen and help explain the variation in incidence of arterial thrombotic events among postmenopausal women using hormone replacement therapy. In a population-based case-control study of 955 postmenopausal women, they assessed the associations of factor XIII genotypes and their interactions with estrogen therapy on risk of nonfatal myocardial infarction (MI). The presence of the leu34 allele was associated with a reduced risk of MI (OR = 0.70, 95% CI = 0.51-0.95).
In a meta-analysis of 12 articles evaluating the affect of the V34L variant on the risk of myocardial infarction, including 3,663 patients and 5,080 controls, Shafey et al. (2007) found that the val34-to-leu variant conferred a protective effect. Compared to the val/val genotype, val/leu heterozygotes had an odds ratio of 0.79 (p = 0.008), and leu/leu homozygotes had an odds ratio of 0.83 (p = 0.03). Under a different statistical analysis, the leu/leu genotype was not significant, likely due to low frequency.
