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CHRM3 Gene Variation Is Associated With Decreased Acute Insulin Secretion and Increased Risk for Early-Onset Type 2 Diabetes in Pima Indians

From the Diabetes Molecular Genetics Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona

Address correspondence and reprint requests to Leslie J. Baier, PhD, Diabetes Molecular Genetics Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 445 N. 5th St., Suite 210, Phoenix, AZ 85004. E-mail: lbaier{at}phx.niddk.nih.gov

Abbreviations: AIR, acute insulin response; LD, linkage disequilibrium; M3, muscarinic acetylcholine receptor 3; mAch, muscarinic acetylcholine; NGT, normal glucose tolerant; OGTT, oral glucose tolerance test; SNP, single nucleotide polymorphism; UTR, untranslated region

The muscarinic acetylcholine receptor subtype M3 (CHRM3) gene is expressed in islet ß-cells and has a role in stimulating insulin secretion; therefore, CHRM3 was analyzed as a candidate gene for type 2 diabetes in Pima Indians. Ten variants were genotyped in a family-based sample (n = 1,037), and 1 variant (rs3738435) located in the 5' untranslated region of an alternative transcript was found to be modestly associated with both early-onset type 2 diabetes and the acute insulin response in a small subset of these subjects. To better assess whether this variant has a role in acute insulin secretion, which could affect risk for early-onset type 2 diabetes, rs3738435 was genotyped in a larger group of normal glucose-tolerant Pima Indians who had measures of acute insulin secretion (n = 282) and a larger case-control group of Pima Indians selected for early-onset type 2 diabetes (n = 348 case subjects with age of onset <25 years; n = 392 nondiabetic control subjects aged >45 years). Genotyping in these larger sets of subjects confirmed that the C allele of rs3738435 was associated with a reduced acute insulin response (adjusted P = 0.00006) and was also modestly associated with increased risk of early-onset type 2 diabetes (adjusted P = 0.02).

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