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

The muscarinic acetylcholine receptor subtype M3 ( CHRM3 ) gene is expressed in islet β-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 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).