Association of the GGCX (CAA)16/17 repeat polymorphism with higher warfarin dose requirements in African Americans

Larisa H Cavallari,Minoli Perera,Nancy L Shapiro,Shitalben R Patel,Mia Wadelius,Gelson Taube,Keston Aquino-Michaels,Marlos A.G Viana,Panos Deloukas,Edith A Nutescu

doi:10.1097/fpc.0b013e32834f288f

Abstract

Little is known about genetic contributors to higher than usual warfarin dose requirements, particularly for African Americans. This study tested the hypothesis that the γ-glutamyl carboxylase (GGCX) genotype contributes to warfarin dose requirements greater than 7.5 mg/day in an African American population. A total of 338 African Americans on a stable dose of warfarin were enrolled. The GGCX rs10654848 (CAA)n, rs12714145 (G>A), and rs699664 (p.R325Q); VKORC1 c.-1639G>A and rs61162043; and CYP2C9*2, *3, *5, *8, *11, and rs7089580 genotypes were tested for their association with dose requirements greater than 7.5 mg/day alone and in the context of other variables known to influence dose variability. The GGCX rs10654848 (CAA)16 or 17 repeat occurred at a frequency of 2.6% in African Americans and was overrepresented among patients requiring greater than 7.5 mg/day versus those who required lower doses (12 vs. 3%, P=0.003; odds ratio 4.0, 95% confidence interval, 1.5-10.5). The GGCX rs10654848 genotype remained associated with high dose requirements on regression analysis including age, body size, and VKORC1 genotype. On linear regression, the GGCX rs10654848 genotype explained 2% of the overall variability in warfarin dose in African Americans. An examination of the GGCX rs10654848 genotype in warfarin-treated Caucasians revealed a (CAA)16 repeat frequency of only 0.27% (P=0.008 compared with African Americans). These data support the GGCX rs10654848 genotype as a predictor of higher than usual warfarin doses in African Americans, who have a 10-fold higher frequency of the (CAA)16/17 repeat compared with Caucasians.

Highlights

Warfarin is the most widely prescribed oral agent for the prophylaxis of thromboembolic events
The gene encoding γ-glutamyl carboxylase (GGCX) rs10654848 (CAA) 16 or 17 repeat occurred at a frequency of 2.6% in African Americans and was overrepresented among patients requiring >7.5mg/day versus those who required lower doses (12% vs 3%, p=0.003; odds ratio 4.0, 95% CI, 1.5–10.5)
The GGCX rs10654848 genotype remained associated with high dose requirements on regression analysis including age, body size, and vitamin K epoxide reductase complex 1 (VKORC1) genotype

Summary

Introduction

Warfarin is the most widely prescribed oral agent for the prophylaxis of thromboembolic events. Clinical factors are well known to influence the dose of warfarin required to produce therapeutic anticoagulation, with higher doses often necessary in those who are young, obese, taking medications that induce warfarin metabolism, or consuming large amounts of vitamin K-containing foods [3, 4]. Common CYP2C9 and VKORC1 variants have been associated with warfarin dose requirements across populations [7,8,9,10,11,12]. The CYP2C9*2, CYP2C9*3, and VKORC1 -1639G>A variants were identified as major contributors to warfarin dose requirements within the usual range of 0.5 mg to 7.5 mg per day, especially in Caucasian and Asian populations [13,14,15]

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Conclusion