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Variation within the Type 2 Diabetes Susceptibility Gene Calpain-10 and Polycystic Ovary Syndrome

Complex Traits Analysis Group (L.H., N.G., S.W., M.I.M.), Department of Medicine, Imperial College Genetics and Genomics Research Institute, and Medical Research Council Clinical Sciences Centre, Imperial College School of Medicine, London W12 0NN, United Kingdom; Department of Diabetes and Vascular Medicine (J.C.E., T.M.F., A.T.H.), School of Postgraduate Medicine and Health Sciences, University of Exeter, Exeter EX2 5AX, United Kingdom; Department of Reproductive Science and Medicine (C.R., K.R., S.F.), Institute of Reproductive and Developmental Biology, Imperial College of Science Technology and Medicine, Hammersmith Hospital, London W12 0NN, United Kingdom; Wellcome Trust Centre for Human Genetics (S.W.), Oxford OX3 7BN, United Kingdom; Plymouth Postgraduate Medical School (T.J.W., A.D., A.M.), Plymouth University, Plymouth PL6 8BH, United Kingdom; Department of Diabetes & Endocrinology (G.C.), the Middlesex Hospital, London W1T 3AA, United Kingdom; Department of Medicine and Human Genetics (N.J.C.), The University of Chicago, Chicago, Illinois 60637; Howard Hughes Medical Institute and Departments of Biochemistry and Molecular Biology (G.I.B.), Medicine and Human Genetics, the University of Chicago, Chicago, Illinois 60637

Address all correspondence and requests for reprints to: Prof. Mark I. McCarthy, Complex Traits Analysis Group, Imperial College Genetics and Genomics Research Institute, Imperial College School of Medicine, London W12 0NN, United Kingdom. E-mail: . m.mccarthy{at}ic.ac.uk

Abstract

Variation within the calpain-10 gene (CAPN10) has been proposed to account for linkage to type 2 diabetes on chromosome 2q in Mexican-Americans, and associations with diabetes have been reported in several other populations. Given the epidemiological, physiological, and genetic overlap between type 2 diabetes and polycystic ovary syndrome (PCOS), CAPN10 represents a strong candidate gene for a role in PCOS susceptibility. Using both family based and case-control association resources (146 parent-offspring trios; 185 additional PCOS cases; 525 control subjects, all of European ancestry), we sought association between CAPN10 variation and PCOS, focusing on four single nucleotide polymorphism (SNP) variants (SNP-44, SNP-43; SNP-19; SNP-63). On single-locus transmission disequilibrium analysis in the 146 trios, there was nominal evidence (P = 0.03) of excess transmission of the more common allele at SNP-63. This association was not, however, replicated in the case-control analysis. No other significant associations were observed at the single-locus or haplotype level in either the transmission-disequilibrium or case-control analyses. The relative risk for the high-risk diabetes susceptibility 112/121 genotype (SNPs 43–19-63) was 0.84 (95% confidence intervals, 0.40–1.71). No associations were seen with intermediate traits of relevance to diabetes and PCOS pathogenesis. We have found no evidence from these analyses that CAPN10 gene variation influences susceptibility to PCOS.

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