Impact of gamma-glutamyl carboxylase gene polymorphisms on warfarin dose requirement: a systematic review and meta-analysis

Abstract

Background: The Gamma-glutamyl carboxylase (GGCX) gene, as with Vitamin K Epoxide Reductase Complex Subunit 1 (VKORC1), CytochromeP450 Complex Subunit 14 F2 (CYP4F2) and CytochromeP450 Complex Subunit2C9 (CYP2C9), is a candidate predictor for appropriate maintenance warfarin dose. However, the association between GGCX gene polymorphisms and warfarin dose requirement is still controversial. To quantify the influence of GGCX polymorphisms on warfarin dose requirements, we performed a systematic review and meta-analysis.

Methods: According to PRISRM statement (Preferred reporting items for systematic reviews and meta-analyses), a comprehensive literature search was undertaken through August 2014 looking for eligible studies in Embase, Pubmed,Web of Science and the Cochrane Library. The impact of GGCX polymorphisms on mean daily warfarin dose (MDWD) was counted by means of Z test. RevMan 5.2.7 software (developed by the Cochrane Collaboration) was applied to analyze the relationship between GGCX gene polymorphisms and warfarin dose requirements.

Results: Nineteen articles including 21 studies with a total of 6957 patients were included in the meta-analysis. Among three investigated single nucleotide polymorphisms (SNPs), rs11676382 showed higher CC genotype frequencies in Asian than those in Caucasian (97.7% vs. 86.9%); patients who were "G carriers" (that is, carried the GGCX rs11676382 CG or GG genotypes) required 27% lower warfarin dose than CC genotype [95%Confidence Interval (CI)=17%-37%, P=0.000, I(2)%=82.0 and PQ=0.000], moreover, stratified analysis by ethnicity showed similar results in Caucasian (23% lower, 95%CI=12%-33%), but not in Asian. With respect to genetic variation of rs699664 and rs121714145 SNPs, no significant impact on warfarin dose requirements were demonstrated.

Conclusions: This meta-analysis suggested that GGCX rs11676382 polymorphism may be one of factors affecting the dose of warfarin requirement, and the effects are different in different ethnicities. Further studies about this topic in different ethnicities with larger samples are expected to be conducted to validate our results.

Keywords: Gamma-glutamyl carboxylase; Meta-analysis; Polymorphism; Warfarin.