Association of the GGCX (CAA)16/17 repeat polymorphism with higher warfarin dose requirements in African Americans.
Association of the GGCX (CAA)16/17 repeat polymorphism with higher warfarin dose requirements in African Americans.
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DOI：
10.1097/fpc.0b013e32834f288f
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发表时间：
2012-02
影响因子：
2.6
通讯作者：
Nutescu EA
中科院分区：
文献类型：
--
作者：
Cavallari LH;Perera M;Wadelius M;Deloukas P;Taube G;Patel SR;Aquino-Michaels K;Viana MA;Shapiro NL;Nutescu EA
关于遗传因素导致华法林剂量要求高于通常剂量要求的情况知之甚少，特别是对非裔美国人。本研究检验了γ-谷氨酰羧化酶（GGCX）基因型导致非裔美国人人群华法林剂量需求>7.5 mg/天的假设。共有338名接受稳定剂量华法林的非洲裔美国人入组。GGCX rs10654848（CAA）n、rs12714145（G>A）和rs699664（p.R325Q）; VKORC 1 c. 1639 G>A和rs61162043;以及CYP 2C 9 *2、*3、*5、*8、*11和rs7089580基因型，测试其与单独>7.5 mg/天的剂量需求的相关性以及在已知影响剂量变异性的其他变量的背景下。GGCX rs 10654848（CAA）16或17重复发生在非裔美国人中的频率为2.6%，并且在需要> 7.5 mg/天的患者与需要较低剂量的患者中的代表性过高（12% vs 3%，p=0.003;比值比4.0，95% CI，1.5-10.5）。在包括年龄、体型和VKORC 1基因型的回归分析中，GGCX rs 10654848基因型仍然与高剂量需求相关。在线性回归中，GGCX rs 10654848基因型解释了非裔美国人华法林剂量总体变异的2%。在华法林治疗的高加索人中对GGCX rs 10654848基因型的检查显示，（CAA）16重复等位基因频率仅为0.27%（与非裔美国人相比，p=0.008）。这些数据支持GGCX rs 10654848基因型作为非洲裔美国人华法林剂量高于常规剂量的预测因子，非洲裔美国人的（CAA）16/17重复频率是白人的10倍。
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 >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 tested for their association with dose requirements >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 >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 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 allele frequency of only 0.27% (p=0.008 compared to 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 to Caucasians.