Divisão de Farmacologia, Instituto Nacional do Câncer-INCA, Rio de Janeiro, Brazil.
Pharmacogenomics J. 2012 Jun;12(3):267-76. doi: 10.1038/tpj.2010.89. Epub 2010 Dec 21.
The impact of biogeographical ancestry, self-reported 'race/color' and geographical origin on the frequency distribution of 10 CYP2C functional polymorphisms (CYP2C82, 3, 4, CYP2C92, 3, 5, 11, CYP2C192, 3 and 17) and their haplotypes was assessed in a representative cohort of the Brazilian population (n=1034). TaqMan assays were used for allele discrimination at each CYP2C locus investigated. Individual proportions of European, African and Amerindian biogeographical ancestry were estimated using a panel of insertion-deletion polymorphisms. Multinomial log-linear models were applied to infer the statistical association between the CYP2C alleles and haplotypes (response variables), and biogeographical ancestry, self-reported Color and geographical origin (explanatory variables). The results showed that CYP2C193, CYP2C95 and CYP2C911 were rare alleles (<1%), the frequency of other variants ranged from 3.4% (CYP2C84) to 17.3% (CYP2C1917). Two distinct haplotype blocks were identified: block 1 consists of three single nucleotide polymorphisms (SNPs) (CYP2C1917, CYP2C192 and CYP2C92) and block 2 of six SNPs (CYP2C911, CYP2C93, CYP2C95, CYP2C82, CYP2C84 and CYP2C83). Diplotype analysis generated 41 haplotypes, of which eight had frequencies greater than 1% and together accounted for 96.4% of the overall genetic diversity. The distribution of CYP2C8 and CYP2C9 (but not CYP2C19) alleles, and of CYP2C haplotypes was significantly associated with self-reported Color and with the individual proportions of European and African genetic ancestry, irrespective of Color self-identification. The individual odds of having alleles CYP2C82, CYP2C83, CYP2C92 and CYP2C93, and haplotypes including these alleles, varied continuously as the proportion of European ancestry increased. Collectively, these data strongly suggest that the intrinsic heterogeneity of the Brazilian population must be acknowledged in the design and interpretation of pharmacogenomic studies of the CYP2C cluster in order to avoid spurious conclusions based on improper matching of study cohorts. This conclusion extends to other polymorphic pharmacogenes among Brazilians, and most likely to other admixed populations of the Americas.
在巴西人群的代表性队列中（n=1034），评估了生物地理起源、自我报告的“种族/肤色”和地理来源对 10 个 CYP2C 功能多态性（CYP2C82、3、4、CYP2C92、3、5、11、CYP2C192、3 和17）及其单倍型频率分布的影响。使用 TaqMan 测定法在每个 CYP2C 基因座上进行等位基因鉴别。使用插入缺失多态性的面板来估计个体的欧洲、非洲和美洲生物地理起源比例。应用多项逻辑线性模型推断 CYP2C 等位基因和单倍型（响应变量）与生物地理起源、自我报告的肤色和地理来源（解释变量）之间的统计关联。结果表明，CYP2C193、CYP2C95 和 CYP2C911 是罕见等位基因（<1%），其他变体的频率范围为 3.4%（CYP2C84）至 17.3%（CYP2C1917）。鉴定出两个不同的单倍型块：块 1 由三个单核苷酸多态性（SNP）（CYP2C1917、CYP2C192 和 CYP2C92）组成，块 2 由六个 SNP（CYP2C911、CYP2C93、CYP2C95、CYP2C82、CYP2C84 和 CYP2C83）组成。双等位基因分析产生了 41 种单倍型，其中 8 种的频率大于 1%，总共占总体遗传多样性的 96.4%。CYP2C8 和 CYP2C9（但不是 CYP2C19）等位基因的分布以及 CYP2C 单倍型与自我报告的肤色以及个体的欧洲和非洲遗传起源比例显著相关，而与肤色自我识别无关。个体携带 CYP2C82、CYP2C83、CYP2C92 和 CYP2C93 等位基因以及包含这些等位基因的单倍型的可能性随着欧洲血统比例的增加而连续变化。总的来说，这些数据强烈表明，在设计和解释 CYP2C 簇的药物基因组学研究时，必须承认巴西人群的固有异质性，以避免基于对研究队列的不当匹配得出虚假结论。这一结论适用于巴西人中的其他多态性药物基因，也很可能适用于美洲的其他混合人群。
