Department of Genetics & Genomic Sciences, Box 1498, Mount Sinai School of Medicine of New York University, Fifth Avenue at 100th Street, New York, NY 10029, USA.
Pharmacogenomics. 2010 Jun;11(6):781-91. doi: 10.2217/pgs.10.49.
CYP4F2*3 (p.V433M) has been associated with higher warfarin dose requirements; however, its frequency, like other CYP2C9 and VKORC1 variants, has not been systematically assessed in major racial/ethnic populations. Thus, we determined the individual and combined frequencies of important CYP2C9, VKORC1 and CYP4F2 variants in several racial/ethnic groups.
MATERIALS & METHODS: Healthy African-American, Asian, Caucasian, Hispanic and Ashkenazi Jewish (AJ) blood donors were genotyped for CYP2C9 (*2, *3, *4, *5, *6, *8, *11 and *13), VKORC1 (g.-1639G>A) and CYP4F2 (*3 [p.V433M] and rs2189784).
The combined frequencies of variant CYP2C9 alleles were 0.133, 0.078, 0.212, 0.178 and 0.212 among African-American, Asian, Caucasian, Hispanic and AJ individuals, respectively. CYP4F23 frequencies were prevalent (0.233-0.342) among Asian, Caucasian, Hispanic and AJ individuals, while significantly less frequent among African-Americans (0.117; p < 0.0001). In addition, CYP4F23 was in linkage disequilibrium with rs2189784, an allele recently associated with time-to-therapeutic international normalized ratio, among all studied populations. Importantly, 87-95% of Asian, Caucasian, Hispanic and AJ individuals had a variant CYP2C9, VKORC1 and/or CYP4F2*3 allele, compared with only 53% of African-Americans (p < 0.0001).
Compared with other racial/ethnic populations studied, only approximately one in 80 African-Americans were CYP4F2*3 homozygous, indicating that this population would benefit less from dosing algorithms that include this variant. In addition, the unique allele frequency profiles identified among the different populations partly explain why genotype-guided warfarin dosing algorithms perform less well for African-Americans and suggest that other unidentified genetic and/or nongenetic factors that influence warfarin dosage may exist in this population.
CYP4F2*3（p.V433M）与华法林剂量需求较高有关；然而，与其他 CYP2C9 和 VKORC1 变体一样，其频率尚未在主要种族/族群中进行系统评估。因此，我们确定了几个种族/族群中重要的 CYP2C9、VKORC1 和 CYP4F2 变体的个体和组合频率。
对非裔美国人、亚洲人、高加索人、西班牙裔和阿什肯纳兹犹太人（AJ）健康献血者进行 CYP2C9（*2、*3、*4、*5、*6、*8、*11 和 *13）、VKORC1（g.-1639G>A）和 CYP4F2（*3[p.V433M]和 rs2189784）的基因分型。
非裔美国人、亚洲人、高加索人、西班牙裔和 AJ 个体中，变异 CYP2C9 等位基因的组合频率分别为 0.133、0.078、0.212、0.178 和 0.212。CYP4F23 频率在亚洲人、高加索人、西班牙裔和 AJ 个体中普遍存在（0.233-0.342），而非裔美国人则明显较低（0.117；p<0.0001）。此外，CYP4F23 与 rs2189784 呈连锁不平衡，rs2189784 是最近与治疗国际标准化比值时间相关的等位基因，存在于所有研究人群中。重要的是，与非裔美国人相比，87-95%的亚洲人、高加索人、西班牙裔和 AJ 个体具有变异 CYP2C9、VKORC1 和/或 CYP4F2*3 等位基因，而非裔美国人仅有 53%（p<0.0001）。
与其他研究的种族/族群相比，只有大约 1/80 的非裔美国人是 CYP4F2*3 纯合子，这表明该人群从包含此变体的剂量算法中获益较少。此外，不同人群中鉴定出的独特等位基因频率谱部分解释了为什么基因型指导的华法林剂量算法对非裔美国人的效果较差，并表明该人群中可能存在其他未识别的影响华法林剂量的遗传和/或非遗传因素。
