期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 70, 期 5, 页码 1096-1106出版社
UNIV CHICAGO PRESS
DOI: 10.1086/339930
关键词
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资金
- NIDDK NIH HHS [P60 DK020595, P30 DK020595, DK20595, DK56670, DK47486, R01 DK056670, R01 DK055889, R01 DK047486, DK55889] Funding Source: Medline
- NIGMS NIH HHS [GM57672, P01 GM057672] Funding Source: Medline
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.
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