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首页> 外文OA文献 >Similarity in recombination rate and linkage disequilibrium at CYP2C and CYP2D cytochrome P450 gene regions among Europeans indicates signs of selection and no advantage of using tagSNPs in population isolates
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Similarity in recombination rate and linkage disequilibrium at CYP2C and CYP2D cytochrome P450 gene regions among Europeans indicates signs of selection and no advantage of using tagSNPs in population isolates

机译：欧洲人中CYP2C和CYP2D细胞色素P450基因区域的重组率和连锁不平衡的相似性表明选择的迹象并且在人群分离物中没有使用tagSNP的优势

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[OBJECTIVE] Linkage disequilibrium (LD) and recombination rate variations are known to vary considerably between human genome regions and populations mostly because of the combined effects of mutation, recombination, and demographic history. Thus, the pattern of LD is a key issue to disentangle variants associated with complex traits. Here, we aim to describe the haplotype structure and LD variation at the pharmacogenetically relevant cytochrome P450 CYP2C and CYP2D gene regions among European populations. [METHODS] To assess the haplotype structure, LD pattern, and recombination rate variations in the clinically significant CYP2C and CYP2D regions, we genotyped 143 single-nucleotide polymorphisms (SNPs) across these two genome regions in a diverse set of 11 European population samples and one sub-Saharan African sample. [RESULTS] Our results showed extended patterns of LD and in general a low rate of recombination at these loci, and a low degree of allele differentiation for the two cytochrome P450 regions among Europeans, with the exception of the Sami and the Finns as European outliers. The Sami sample showed reduced haplotype diversity and higher LD for the two cytochrome P450 regions than the other Europeans, a feature that is proposed to enhance the LD mapping of underlying common complex traits. However, recombination hotspots and LD blocks at these two regions showed highly consistent structures across Europeans including Finns and Sami. Moreover, we showed that the CEPH sample has significantly higher tag transferability among Europeans and a more efficient tagging of both the rare CYP2C9 and the common CYP2C19 functional variants than the Sami. Our data set included CYP2C9*3 (rs1057910) and CYP2C19*2 (rs4244285) enzyme activity-altering variants associated in a recent genome-wide study with acenocoumarol-induced and warfarin-induced anticoagulation or to the antiplatelet effect of clopidogrel, respectively. Including these known activity-altering variants, we showed the haplotype variation and high derived allele frequencies of novel recently identified acenocoumarol genome-wide associated SNPs at CYP2C9 (rs4086116) and CYP2C18 (rs12772169, rs1998591, rs2104543, rs1042194) loci in a comprehensive set of 11 European populations. Furthermore, a significant frequency difference of a CYP2C19*2 gene mutation causing variable drug reactions was observed among Europeans. [CONCLUSION] The CEPH sample representing the general European population as such in the HapMap project seems to be the optimal population sample for the LD mapping of common complex traits among Europeans. Nevertheless, it is still argued that the unique pattern of LD in the Sami may offer an advantage for further association mapping, especially if multiple rare variants play a role in disease etiology. However, besides the activity-altering CYP2C9*3 (rs1057910) and CYP2C19*2 (rs4244285) variants, the high derived allele frequencies of novel recently identified acenocoumarol genome-wide associated SNPs at CYP2C9 (rs4086116) and CYP2C18 (rs12772169, rs1998591, rs2104543, rs1042194) loci variants indicated that the CYP2C region may have been influenced by selection. Thus, this fine-scale haplotype map of the CYP2C and CYP2D regions may help to choose markers for further association mapping of complex pharmacogenetic traits at these loci. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.
机译：[目的]众所周知，人类基因组区域和种群之间的连锁不平衡（LD）和重组率差异很大，这主要是由于突变，重组和人口统计学的综合影响。因此，LD的模式是解开与复杂性状相关的变异的关键问题。在这里，我们旨在描述欧洲人群中与药物遗传学相关的细胞色素P450 CYP2C和CYP2D基因区域的单倍型结构和LD变异。 [方法]为了评估具有临床意义的CYP2C和CYP2D区域的单倍型结构，LD模式和重组率变异，我们对11个欧洲人群样本中这两个基因组区域的143个单核苷酸多态性（SNP）进行了基因分型。一份撒哈拉以南非洲样本。 [结果]我们的结果显示，欧洲人中两个细胞色素P450区的LD扩展模式以及这些位点的重组率通常较低，等位基因分化程度较低，但萨米人和芬兰人是欧洲异常值。 Sami样品显示出两个细胞色素P450区域的单倍型多样性降低，而LD高于其他欧洲人，这是为了增强潜在的常见复杂性状的LD作图而提出的功能。但是，这两个区域的重组热点和LD区块在包括Finns和Sami在内的整个欧洲人中显示出高度一致的结构。此外，我们表明，CEPH样品在欧洲人中的标记转移能力明显更高，稀有CYP2C9和常见CYP2C19功能变体的标记效率均高于Sami。我们的数据集包括CYP2C9 * 3（rs1057910）和CYP2C19 * 2（rs4244285）改变酶活性的变体，该变体在最近的全基因组研究中分别与乙酰香豆酚诱导的和华法林诱导的抗凝作用或与氯吡格雷的抗血小板作用有关。包括这些已知的可改变活性的变体，我们在一组完整的基因组中显示了CYP2C9（rs4086116）和CYP2C18（rs12772169，rs1998591，rs2104543，rs1042194）位点的新近鉴定的新的乙酰香豆酚全基因组相关SNP的单倍型变异和高衍生等位基因频率11个欧洲人口。此外，在欧洲人中观察到引起可变药物反应的CYP2C19 * 2基因突变的显着频率差异。 [结论]代表HapMap项目中的欧洲普通人群的CEPH样本似乎是欧洲人群中常见复杂性状LD映射的最佳人群样本。然而，仍然有争议的是，萨米语中LD的独特模式可能为进一步的关联作图提供优势，特别是如果多种罕见变体在疾病病因中起作用。但是，除了可改变活性的CYP2C9 * 3（rs1057910）和CYP2C19 * 2（rs4244285）变体外，新近鉴定出的新的乙酰香豆酚全基因组关联的SNPs在CYP2C9（rs4086116）和CYP2C18（rs12772169，rs1998543， （rs1042194）基因座变体表明CYP2C区可能已受到选择的影响。因此，CYP2C和CYP2D区域的这种精细单倍型图谱可能有助于选择标记物，以进一步在这些基因座上绘制复杂的药物遗传学特征的关联图。 ©2012 Wolters Kluwer Health |版权所有。利平科特·威廉姆斯和威尔金斯。

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