New Interactive Effects Involving Factor XIII Gene Polymorphisms in Venous Thrombotic Disease.
Authors: Pintao Maria C. , Lourenço Dayse M. , Maffei Francisco H.A. , Morelli Vania M. , Araujo Amelia G. , Tavella Marli H. , Silva Wilson A. , Zago Marco A. , Franco Rendrik F. 
Published: October 2019

Abstract
Venous thrombosis (VT) is considered to be a multifactorial disorder in which several genetic and acquired risk factors interact dynamically. Coagulation factor XIII (FXIII) is an enzyme that participates in the final steps of the coagulation cascade. A number of gene variations have been described in both FXIII A and B subunits. FXIIIA Val34Leu, Tyr204Phe and Pro564Leu polymorphisms have been associated to increased specific activity of FXIII, and FXIIIA Val34Leu has been claimed to be protective against VT in several studies. In the FXIII B subunit, two common polymorphisms (His95Arg and G30899A) have been also reported, but its association with VT is uncertain. In addition, possible interactive effects between these polymorphisms and between these polymorphisms and the two most prevalent mutations associated with VT, factor V Leiden (FVL) and factor II (FII) G20210A mutations, have not been explored. In the present study, we determined the prevalence of the five above-mentioned FXIII polymorphisms in 418 consecutive patients with an objective diagnosis of VT and in 418 age-, gender- and race-matched controls in the BRATROS (Brazilian Thrombosis Study) case-control investigation. Genotyping for Val34Leu, Pro564Leu, His95Arg and G30899A was performed by PCR amplification followed by MseI, BstUI, NsiI and BspHI restriction digestion analysis, respectively. Genotyping for Tyr204Phe was performed by single-strand conformation polymorphism (SSCP) analysis followed by DNA sequencing of samples showing mobility shifts. Odds ratios (OR) as a measure of relative risks of VT, and 95% confidence intervals (CI95), were calculated. Stratified analyses were performed to search for interactions between the FXIII polymorphisms and between the FXIII polymorphisms, FVL and FII G20210A. Overall OR for VT linked to Val34Leu was 0,78 (CI95: 0,59–1,03); OR for heterozygotes (HT) was 0,85 (CI95: 0,64–1,13) and for homozygotes (HM) the OR was 0,33 (CI95: 0,15–0,71). Overall OR linked to G30899A was 1,06 (CI95: 0,81–1,39); OR for HT was 0,96 (CI95: 0,72–1,28) and for HM the OR was 1,58 (IC95: 1,00–2,49). No impacts over the risk of VT were observed, related to the other three polymorphisms investigated. When stratified analyses were performed to search for interactions, a trend towards increased risk of VT was detected when the Val34 allele was co-inherited with the Arg95 allele (OR 1,45; CI95: 0,97–2,18), and a trend towards decreased thrombotic risk was verified when the Leu34 and Leu564 alleles were co-inherited (OR 0,63; CI95: 0,40–1,00). Furthermore, increased risk for VT was observed when the mutant A30899 allele was co-inherited with FII G20210A, pointing to a notable interaction effect (OR 18,29; CI95: 2,41–138,87). The data confirm that homozygosity for FXIII Val34Leu is protective against the occurrence of VT in our population. In addition, the findings point to a previously unknown increased risk of VT related to homozygosity for FXIIIB G30899A of the order of 58%. Lastly, an impressive interactive effect (18-fold increased risk of VT) between FXIIIB G30899A and FII G20210A is reported for the first time. Taken together, the findings from the present investigation strengthen the clinical significance of FXIII in vascular thrombosis and reinforce the concept of VT as a multigenic disease.