The association between EPCR gene p.Ser219Gly polymorphism and venous thromboembolism risk: a case-control study, meta-analysis, and a reproducibility study.

Background: The rs867186 single-nucleotide polymorphism in the gene (g.6936A > G, c.4600A > G) results in a serine-to-glycine substitution at codon 219 of endothelial protein C receptor (EPCR). We performed a case-control study followed by an updated meta-analysis of the association between this polymorphism and the risk of venous thromboembolism (VTE).

Objective And Methods: We enrolled 263 VTE patients and 320 unrelated healthy controls for the case-control study. The total number of cases and controls for the meta-analysis were 5,768 and 30,017, respectively. A new online MetaGenyo Statistical Analysis System software was used to perform the current meta-analysis. Furthermore, a reproducibility study was conducted to validate our results.

Results: Among well-defined thrombosis risk factors, Factor V Leiden was more frequent in the VTE group ( < 0.001), while there was no difference in mutation frequency of prothrombin 20210G>A polymorphism between the two groups. There was no difference in the mutation frequency of Factor V Leiden and prothrombin 20210G>A between cases with and without provoking factors and cases with and without VTE recurrence. The rs867186 "G" carriership did not influence the risk of VTE [odds ratio (OR) 1.339; 95% confidence interval (CI): 0.904-1.984] in our study. No significant differences could be demonstrated among the rs867186 genotype frequencies between VTE cases with and without provoking factors ( = 0.430). rs867186 was associated with an OR of 1.72 (95% CI: 0.95-3.13,  = 0.075) in terms of VTE recurrence. In the meta-analysis, a significant association was found between EPCR Ser219Gly polymorphism and VTE under the dominant model (OR = 1.27, 95% CI: 1.11-1.46,  = 0.0006), the recessive model (OR = 1.60, 95% CI: 1.26-2.04,  = 0.0001), the GG vs. AA contrast model (OR = 1.64, 95% CI: 1.28-2.09,  = 0.0001), and the GA vs. AA contrast model (OR = 1.24, 95% CI: 1.08-1.43,  = 0.002).

Conclusion: The rs867186 was not associated with the first VTE risk in our case-control study; however, a tendency to VTE recurrence was observed. Based on the results of our reproducibility study, MetaGenyo is acceptable for meta-analysis in case of genetic epidemiology studies. Although the risk conferred by the rs867186 is mild in all meta-analyses, including ours, identifying patients carrying the minor allele might have an impact on personalized VTE risk assessment, risk-score calculation, and patient management.