Geographic and haplotype structure of candidate type 2 diabetes-susceptibility variants at the calpain-10 locus
Geographic and haplotype structure of candidate type 2 diabetes-susceptibility variants at the calpain-10 locus
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DOI：
10.1086/339930
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发表时间：
2002-05-01
影响因子：
9.8
通讯作者：
Di Rienzo, A
中科院分区：
文献类型：
--
作者：
Fullerton, SM;Bartoszewicz, A;Di Rienzo, A
最近，一项位置克隆研究表明，在墨西哥裔美国人、芬兰人和德国人中，Calain-10基因(CAPN10)的单倍型与2型糖尿病或非胰岛素依赖型糖尿病的风险增加有关。为了解释最初的作图结果，并寻找自然选择对CAPN10起作用的证据，我们对候选易感变异进行了基于群体的基因分型调查。首先，我们对来自五大洲的11个群体的561个个体的43、19和63位(先前提出的定义单倍型的变体)和四个紧密连锁的SNPs进行了基因分型，并检查了它们之间的连锁不平衡。然后，我们通过对黑猩猩和猩猩CAPN10的同源部分进行测序，检查了这些位点的祖先状态(在其他类人猿和东半球和新大陆猴子的有限样本中，进一步研究了第43和19位点的身份)。我们的调查表明，CAPN10易感变异在非洲和非非洲人群中的分布差异大于预期，欧洲和亚洲样本中常见的派生单倍型(包括建议的两种风险单倍型之一)在非洲样本中罕见或不存在。这些结果表明，在该基因座上有一个积极的自然选择的历史，导致了多态频率的显著地理差异。讨论了这些差异与疾病风险的关系。
Recently, a positional cloning study proposed that haplotypes at the calpain-10 locus (CAPN10) are associated with increased risk of type 2 diabetes, or non-insulin-dependent diabetes mellitus, in Mexican Americans, Finns, and Germans. To inform the interpretation of the original mapping results and to look for evidence for the action of natural selection on CAPN10, we undertook a population-based genotyping survey of the candidate susceptibility variants. First, we genotyped sites 43, 19, and 63 (the haplotype-defining variants previously proposed) and four closely linked SNPs, in 561 individuals from 11 populations from five continents, and we examined the linkage disequilibrium among them. We then examined the ancestral state of these sites by sequencing orthologous portions of CAPN10 in chimpanzee and orangutan (the identity of sites 43 and 19 was further investigated in a limited sample of other great apes and Old World and New World monkeys). Our survey suggests larger-than-expected differences in the distribution of CAPN10 susceptibility variants between African and non-African populations, with common, derived haplotypes in European and Asian samples (including one of two proposed risk haplotypes) being rare or absent in African samples. These results suggest a history of positive natural selection at the locus, resulting in significant geographic differences in polymorphism frequencies. The relationship of these differences to disease risk is discussed.