Department of Genetics & Genomic Sciences, Mount Sinai School of Medicine of New York University, New York, NY 10029, USA.
Pharmacogenomics. 2009 Aug;10(8):1243-55. doi: 10.2217/pgs.09.71.
Although the frequencies of pharmacogenetic variants differ among racial groups, most pharmacogenetic algorithms for genotype-guided warfarin dosing only include two CYP2C9 alleles (*2 and *3) and a single VKORC1 allele (g.-1639G>A or g.1173C>T) commonly found among Caucasians. Therefore, this study sought to identify other CYP2C9 and VKORC1 alleles important in warfarin dose variability and to determine their frequencies in different racial and ethnic groups.
MATERIALS & METHODS: The CYP2C9 and VKORC1 genes were sequenced in selected sensitive (< 21 mg/week) and resistant (> 49 mg/week) individuals with discrepant therapeutic and algorithm-predicted warfarin doses based on prior CYP2C9 and VKORC1 genotyping. The CYP2C9 and VKORC1 allele frequencies were determined in healthy, racially self-identified blood donors.
Sequencing identified an African-American male with a lower than predicted therapeutic warfarin dose (14.4 mg/week), previously genotyped as CYP2C91/1, who was homozygous for CYP2C98 (c.449G>A; p.R150H). Genotyping 600 African-American alleles identified CYP2C98 as their most frequent variant CYP2C9 allele (0.047), and the combined allele frequency of CYP2C9*2, *3, *5, *6, 8 and 11 was 0.133. Given most warfarin pharmacogenetic dosing algorithms only include CYP2C92 and 3, the inclusion of CYP2C98 alone could reclassify the predicted metabolic phenotypes of almost 10% of African-Americans, or when combined with CYP2C95, *6 and *11, more than 15%. In addition, the African-American VKORC1 g.-1639A allele frequency was 0.108 and three g.1331G>A (p.V66M) carriers were identified.
CYP2C98 is prevalent among African-Americans ( approximately 1 in 11 individuals). Thus, in this racial group, the incorporation of CYP2C98 into genotyping panels may improve dose prediction of CYP2C9-metabolized drugs, including warfarin.
尽管药物遗传学变异的频率在不同种族群体中存在差异，但大多数基于基因型指导华法林剂量的药物遗传学算法仅包括两个 CYP2C9 等位基因（*2 和 *3）和一个常见于白种人的单一 VKORC1 等位基因（g.-1639G>A 或 g.1173C>T）。因此，本研究旨在确定其他在华法林剂量变异性中起重要作用的 CYP2C9 和 VKORC1 等位基因，并确定它们在不同种族和族群中的频率。
根据之前的 CYP2C9 和 VKORC1 基因分型，选择治疗效果和算法预测的华法林剂量差异较大（<21mg/周和>49mg/周）的敏感（<21mg/周）和耐药（>49mg/周）个体，对 CYP2C9 和 VKORC1 基因进行测序。在健康的、自我认定为种族的献血者中确定 CYP2C9 和 VKORC1 等位基因的频率。
测序发现一名非洲裔美国男性的华法林治疗剂量低于预测值（14.4mg/周），之前的 CYP2C9 基因型为1/1，为 CYP2C98（c.449G>A；p.R150H）纯合子。对 600 名非洲裔美国人的等位基因进行基因分型，确定 CYP2C98 是其最常见的变异 CYP2C9 等位基因（0.047），CYP2C92、3、5、6、8 和11 的联合等位基因频率为 0.133。鉴于大多数华法林药物遗传学剂量算法仅包括 CYP2C92 和3，如果单独纳入 CYP2C98，可能会重新分类近 10%的非洲裔美国人的预测代谢表型，或者当与 CYP2C95、6 和11 联合使用时，超过 15%。此外，非洲裔美国人 VKORC1 g.-1639A 等位基因的频率为 0.108，发现了 3 名 g.1331G>A（p.V66M）携带者。
CYP2C98 在非裔美国人中较为常见（约每 11 个人中就有 1 人）。因此，在这个种族群体中，将 CYP2C98 纳入基因分型面板可能会改善 CYP2C9 代谢药物（包括华法林）的剂量预测。
