Sex-specific effect of CPB2 Ala147Thr but not Thr325Ile variants on the risk of venous thrombosis: A comprehensive meta-analysis

Abstract

BackgroundThrombin activatable fibrinolysis inhibitor (TAFI), encoded by the Carboxypeptidase B2 gene (CPB2), is an inhibitor of fibrinolysis and plays a role in the pathogenesis of venous thrombosis. Experimental findings support a functional role of genetic variants in CPB2, while epidemiological studies have been unable to confirm associations with risk of venous thrombosis. Sex-specific effects could underlie the observed inconsistent associations between CPB2 genetic variants and venous thrombosis.MethodsA comprehensive literature search was conducted for associations between Ala147Thr and Thr325Ile variants with venous thrombosis. Authors were contacted to provide sex-specific genotype counts from their studies. Combined and sex-specific random effects meta-analyses were used to estimate a pooled effect estimate for primary and secondary genetic models.ResultsA total of 17 studies met the inclusion criteria. A sex-specific meta-analysis applying a dominant model supported a protective effect of Ala147Thr on venous thrombosis in females (OR = 0.81, 95%CI: 0.68,0.97; p = 0.018), but not in males (OR = 1.06, 95%CI:0.96–1.16; p = 0.263). The Thr325Ile did not show a sex-specific effect but showed variation in allele frequencies by geographic region. A subgroup analysis of studies in European countries showed decreased risk, with a recessive model (OR = 0.83, 95%CI:0.71–0.97, p = 0.021) for venous thrombosis.ConclusionsA comprehensive literature review, including unpublished data, provided greater statistical power for the analyses and decreased the likelihood of publication bias influencing the results. Sex-specific analyses explained apparent discrepancies across genetic studies of Ala147Thr and venous thrombosis. While, careful selection of genetic models based on population genetics, evolutionary and biological knowledge can increase power by decreasing the need to adjust for testing multiple models.

Thrombin-Activatable Fibrinolysis Inhibitor Polymorphisms and Cerebral Venous Thrombosis in Mexican Mestizo Patients

“…Ethnic variation among TAFI haplotypes and SNPs should be analyzed based on genetic replication in the Mexican Mestizo population. Zwingerman et al 26 showed that the Thr325Ile polymorphism demonstrated allele frequency variation by geographical region among European, Asian, and African populations, a finding that has also been reported in other studies. 27,28 When analysis was limited to cases of European origin, a significant difference was observed associated with the risk of venous thrombosis (OR = 0.83; P < .021).…”

“…Sex subgroup analyses have found differences in SNP associations in CVT. In a meta-analysis, the minor allele of the rs3742264 SNP in a dominant model (AA+GA vs GG) was more frequent in female controls, and the Thr325Ile polymorphism was protective in Europeans independently of sex 26 ; despite this finding, 15% of SNPs have a sex-dependent susceptibility that could explain sexual dimorphism for thrombotic events. 33 In our sample, no differences in genotype, allele, or haplotype were observed between sexes in cases versus controls, which is similar the Ala147Thr and Thr325Ile SNPs and the risk of ischemic stroke in the Japanese population.…”

“…27,28 When analysis was limited to cases of European origin, a significant difference was observed associated with the risk of venous thrombosis (OR = 0.83; P < .021). 26 A previous meta-analysis examined the association between the Thr325Ile SNP and coronary artery disease, with an increased global risk association (OR = 1.25, 95% CI, 1.02-1.54) in mixed ethnic groups; however, in a subgroup analysis of European cases, this association did not reach statistical significance (OR = 1.13, 95% CI, 0.90-1.40). 29…”

“…30 In a previous report from Zorio et al, 31 Thr325Ile SNP frequencies were similar among cases with myocardial infarction and controls in a young Hispanic sample, with an increase in TAFI activity in cases not related to the SNP distribution. Moderate changes in TAFI plasma levels do not alter its function due to a threshold-dependent mechanism 26 ; therefore, TAFI activity analysis in Mexican Mestizo patients could be useful for explanatory evaluation of this association.…”

Carboxypeptidase U (CPU, TAFIa, CPB2) in Thromboembolic Disease: What Do We Know Three Decades after Its Discovery?

“…Subgroup analysis conducted based on ethnicity revealed similar results in different ethnic groups [ 117 ]. In accordance, the meta-analysis of Zwingerman and colleagues showed a decreased risk of VTE for the TT genotype versus the CT+CC genotype in both the overall and European study population, although not significant in the overall study population [ 118 ].…”