Strong Parent-of-Origin Effects in the Association of KCNQ1 Variants with Type 2 Diabetes Mellitus in American Indians
Parent-of-origin effects were observed in an Icelandic population for several genetic variants associated with type 2 diabetes, including those in KLF14 (rs4731702), MOB2 (rs2334499) and KCNQ1 (rs2237892, rs231362). We analyzed parent-of-origin effects for these variants, along with two others in KCNQ1 identified in previous genome-wide association studies (rs2237895, rs2299620), in 7351 Pima Indians from 4549 nuclear families; 34% of participants had diabetes. In a subset of 287 normoglycemic individuals, acute insulin secretion was measured by an intravenous glucose tolerance test. Statistically significant (P<0.05) parent-of-origin effects were seen for association with type 2 diabetes for all variants. The strongest effect was seen at rs2299620 in KCNQ1: the C allele was associated with increased diabetes when maternally-derived (odds ratio=1.92, P=4.1x10-12), but not when paternally-derived (odds ratio=0.93, P=0.47; P=9.9x10-6 for difference in maternal and paternal effects). A maternally-derived C allele was also associated with a 28% decrease in insulin secretion (P=0.002). This study confirms parent-of-origin effects in the association with type 2 diabetes for variants in KLF14, MOB2 and KCNQ1. In Pima Indians the effect of maternally-derived KCNQ1 variants appears to be mediated through decreased insulin secretion, and is particularly strong, accounting for 4% of the variance in liability to diabetes.
- Received December 14, 2012.
- Accepted April 20, 2013.
- © 2013 by the American Diabetes Association.
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