Department of Pharmacy Practice, University of Illinois, Chicago, IL 60612-7230, USA.
Pharmacogenet Genomics. 2012 Feb;22(2):152-8. doi: 10.1097/FPC.0b013e32834f288f.
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.
对于非裔美国人，人们对导致华法林剂量高于常规的遗传因素知之甚少。本研究检测了一个假设，即γ-谷氨酰羧化酶（GGCX）基因型会导致非裔美国人华法林剂量需求高于 7.5mg/天。
共纳入 338 名正在服用稳定剂量华法林的非裔美国人。检测 GGCX rs10654848（CAA）n、rs12714145（G>A）和 rs699664（p.R325Q）；VKORC1 c.-1639G>A 和 rs61162043；CYP2C9*2、*3、*5、*8、*11 和 rs7089580 基因型与单独及与其他已知影响剂量变异性的变量相结合时，与剂量需求大于 7.5mg/天的关联。
GGCX rs10654848（CAA）16 或 17 重复在非裔美国人中的频率为 2.6%，且在需要大于 7.5mg/天的患者中比需要较低剂量的患者更为常见（12%比 3%，P=0.003；比值比 4.0，95%置信区间，1.5-10.5）。在包括年龄、体型和 VKORC1 基因型在内的回归分析中，GGCX rs10654848 基因型仍与高剂量需求相关。在线性回归中，GGCX rs10654848 基因型解释了非裔美国人华法林剂量总变异性的 2%。在华法林治疗的白种人中检查 GGCX rs10654848 基因型，发现（CAA）16 重复频率仅为 0.27%（与非裔美国人相比，P=0.008）。
这些数据支持 GGCX rs10654848 基因型是导致非裔美国人华法林剂量高于常规的一个预测因素，非裔美国人（CAA）16/17 重复的频率比白种人高 10 倍。
