Gamma-glutamyl carboxylase and its influence on warfarin dose.
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.
King
Cristi R
CR
Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri 63110, USA.
Deych
Elena
E
Milligan
Paul
P
Eby
Charles
C
Lenzini
Petra
P
Grice
Gloria
G
Porche-Sorbet
Rhonda M
RM
Ridker
Paul M
PM
Gage
Brian F
BF
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*
D054316:Biomarkers, Pharmacological; D014812:Vitamin K; D014859:Warfarin; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase