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Meta-Analysis
. 2017 May 26;12(5):e0177768.
doi: 10.1371/journal.pone.0177768. eCollection 2017.

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

Nora Zwingerman  1 , Alejandra Medina-Rivera  2   3 , Irfahan Kassam  1 , Michael D Wilson  2   4 , Pierre-Emmanuel Morange  5   6 , David-Alexandre Trégouët  7   8   9 , France Gagnon  1
Affiliations
Meta-Analysis

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

Nora Zwingerman et al. PLoS One. .

Abstract

Background: Thrombin 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.

Methods: A 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.

Results: A 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.

Conclusions: A comprehensive literature review, including unpublished data, provided greater statistical power for the analyses and decreased the likelihood of publication bias influencing the results.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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Flow-chart of the selection process for inclusion into the systematic review.
Outline of the selection process used to identify studies from a comprehensive literature search that investigated the CPB2 variants and venous thrombosis.
Fig 2
Fig 2. Sex-specific meta-analysis of the CPB2 Ala147Thr variant using the dominant model and risk of venous thrombosis.
The analysis was stratified by sex. The solid squares represent the ORs from the individual studies; horizontal lines represent corresponding CIs; the diamonds show the combined ORs.
Fig 3
Fig 3. Meta-analysis results of the CPB2 Thr325Ile variant and risk of venous thrombosis using a recessive model.
The solid squares represent the ORs from the individual studies; horizontal lines represent corresponding CIs; the diamonds show the combined ORs.
Fig 4
Fig 4. Meta-analysis results of the CPB2 Thr325Ile variant and risk of venous thrombosis in European study populations.
The solid squares represent the ORs from the individual studies; horizontal lines represent corresponding CIs; the diamonds show the combined ORs.
See this image and copyright information in PMC

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