title: Gamma-glutamyl carboxylase and its influence on warfarin dose.
abstract: Via generation of vitamin K-dependent proteins, gamma-glutamyl carboxylase (GGCX) plays a critical role in the vitamin K cycle. Single nucleotide polymorphisms (SNPs) in GGCX, therefore, may affect dosing of the vitamin K antagonist, warfarin. In a multi-centered, cross-sectional study of 985 patients prescribed warfarin therapy, we genotyped for two GGCX SNPs (rs11676382 and rs12714145) and quantified their relationship to therapeutic dose. GGCX rs11676382 was a significant (p=0.03) predictor of residual dosing error and was associated with a 6.1% reduction in warfarin dose (95% CI: 0.6%-11.4%) per G allele. The prevalence was 14.1% in our predominantly (78%) Caucasian cohort, but the overall contribution to dosing accuracy was modest (partial R2 = 0.2%). GGCX rs12714145 was not a significant predictor of therapeutic dose (p = 0.26). GGCX rs11676382 is a statistically significant predictor of warfarin dose, but the clinical relevance is modest. Given the potentially low marginal cost of adding this SNP to existing genotyping platforms, we have modified our non-profit website (www.WarfarinDosing.org) to accommodate knowledge of this variant.
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri 63110, USA.
authors.forename: Cristi R
authors.initials: CR
authors.lastname: King
authors.forename: Elena
authors.initials: E
authors.lastname: Deych
authors.forename: Paul
authors.initials: P
authors.lastname: Milligan
authors.forename: Charles
authors.initials: C
authors.lastname: Eby
authors.forename: Petra
authors.initials: P
authors.lastname: Lenzini
authors.forename: Gloria
authors.initials: G
authors.lastname: Grice
authors.forename: Rhonda M
authors.initials: RM
authors.lastname: Porche-Sorbet
authors.forename: Paul M
authors.initials: PM
authors.lastname: Ridker
authors.forename: Brian F
authors.initials: BF
authors.lastname: Gage
mesh_terms: D000368:Aged; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D019735:Carbon-Carbon Ligases / Q000235:genetics* / Q000378:metabolism; D002985:Clinical Protocols; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D020246:Venous Thrombosis / Q000097:blood / Q000175:diagnosis* / Q000188:drug therapy* / Q000235:genetics; D014812:Vitamin K / Q000037:antagonists & inhibitors; D014859:Warfarin / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D054316:Biomarkers, Pharmacological; D014812:Vitamin K; D014859:Warfarin; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase