TY - JOUR
T1 - Studies of association between the gene for calpain-10 and type 2 diabetes mellitus in the United Kingdom
AU - Evans, Julie C.
AU - Frayling, Timothy M.
AU - Cassell, Paul G.
AU - Saker, Philip J.
AU - Hitman, Graham A.
AU - Walker, Mark
AU - Levy, Jonathan C.
AU - O’rahilly, Stephen
AU - Subba Rao, Pamidighantam V.
AU - Bennett, Amanda J.
AU - Jones, Elizabeth C.
AU - Menzel, Stephan
AU - Prestwich, Philip
AU - Simecek, Nikol
AU - Wishart, Marie
AU - Dhillon, Ranjit
AU - Fletcher, Chris
AU - Millward, Ann
AU - Demaine, Andrew
AU - Wilkin, Terence
AU - Horikawa, Yukio
AU - Cox, Nancy J.
AU - Bell, Graeme I.
AU - Ellard, Sian
AU - McCarthy, Mark I.
AU - Hattersley, Andrew T.
PY - 2001/9
Y1 - 2001/9
N2 - Variation in CAPN10, the gene encoding the ubiquitously expressed cysteine protease calpain-10, has been associated with type 2 diabetes in Mexican Americans and in two northern-European populations, from Finland and Germany. We have studied CAPN10 in white subjects of British/Irish ancestry, using both family-based and case-control studies. In 743 sib pairs, there was no evidence of linkage at the CAPN10 locus, which thereby excluded it as a diabetes-susceptibility gene, with an overall sib recurrence risk, λs, of 1.25. We examined four single-nucleotide polymorphisms (SNP-44, -43, -19, and -63) previously either associated with type 2 diabetes or implicated in transcriptional regulation of calpain-10 expression. We did not find any association between SNP-43, -19, and -63, either individually or as part of the previously described risk haplotypes. We did, however, observe significantly increased (P =. 033) transmission of the less common C allele at SNP-44, to affected offspring in parents-offspring trios (odds ratio 1.6). An independent U.K. case-control study and a small discordant-sib study did not show significant association individually. In a combined analysis of all U.K. studies (P =. 015) and in combination with a Mexican American study (P =. 004), the C allele at SNP-44 is associated with type 2 diabetes. Sequencing of the coding region of CAPN10 in a group of U.K. subjects revealed four coding polymorphisms - L34V, T504A, R555C, and V666I. The T504A polymorphism was in perfect linkage disequilibrium with the diabetes-associated C allele at SNP-44, suggesting that the synthesis of a mutant protein and/or altered transcriptional regulation could contribute to diabetes risk. In conclusion, we were not able to replicate the association of the specific calpain-10 alleles identified by Horikawa et al. but suggest that other alleles at this locus may increase type 2 diabetes risk in the U.K. population.
AB - Variation in CAPN10, the gene encoding the ubiquitously expressed cysteine protease calpain-10, has been associated with type 2 diabetes in Mexican Americans and in two northern-European populations, from Finland and Germany. We have studied CAPN10 in white subjects of British/Irish ancestry, using both family-based and case-control studies. In 743 sib pairs, there was no evidence of linkage at the CAPN10 locus, which thereby excluded it as a diabetes-susceptibility gene, with an overall sib recurrence risk, λs, of 1.25. We examined four single-nucleotide polymorphisms (SNP-44, -43, -19, and -63) previously either associated with type 2 diabetes or implicated in transcriptional regulation of calpain-10 expression. We did not find any association between SNP-43, -19, and -63, either individually or as part of the previously described risk haplotypes. We did, however, observe significantly increased (P =. 033) transmission of the less common C allele at SNP-44, to affected offspring in parents-offspring trios (odds ratio 1.6). An independent U.K. case-control study and a small discordant-sib study did not show significant association individually. In a combined analysis of all U.K. studies (P =. 015) and in combination with a Mexican American study (P =. 004), the C allele at SNP-44 is associated with type 2 diabetes. Sequencing of the coding region of CAPN10 in a group of U.K. subjects revealed four coding polymorphisms - L34V, T504A, R555C, and V666I. The T504A polymorphism was in perfect linkage disequilibrium with the diabetes-associated C allele at SNP-44, suggesting that the synthesis of a mutant protein and/or altered transcriptional regulation could contribute to diabetes risk. In conclusion, we were not able to replicate the association of the specific calpain-10 alleles identified by Horikawa et al. but suggest that other alleles at this locus may increase type 2 diabetes risk in the U.K. population.
UR - http://www.scopus.com/inward/record.url?scp=0034894047&partnerID=8YFLogxK
U2 - 10.1086/323315
DO - 10.1086/323315
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C2 - 11481585
AN - SCOPUS:0034894047
SN - 0002-9297
VL - 69
SP - 544
EP - 552
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 3
ER -
