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 beta-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).
Guo
Yan
Y
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, USA.
Traurig
Michael
M
Ma
Lijun
L
Kobes
Sayuko
S
Harper
Inge
I
Infante
Aniello M
AM
Bogardus
Clifton
C
Baier
Leslie J
LJ
Prochazka
Michal
M
D000273:Adipose Tissue / Q000033:anatomy & histology; D000328:Adult; D017668:Age of Onset; D000368:Aged; D001130:Arizona; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics*; D020869:Gene Expression Profiling; D014644:Genetic Variation; D005951:Glucose Tolerance Test; D006801:Humans; D007198:Indians, North American; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D016133:Polymerase Chain Reaction; D043587:Receptor, Muscarinic M3 / Q000235:genetics*; D012307:Risk Factors
D007328:Insulin; D043587:Receptor, Muscarinic M3