Strong Parent-of-Origin Effects in the Association of KCNQ1 Variants With Type 2 Diabetes 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 7,351 Pima Indians from 4,549 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 [OR], 1.92; P = 4.1 × 10⁻¹²), but not when paternally derived (OR, 0.93; P = 0.47; P = 9.9 × 10⁻⁶ for difference in maternal and paternal effects). A maternally derived C allele also was 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.Several single nucleotide polymorphisms (SNPs) reproducibly associated with type 2 diabetes recently have been identified (1–4). Many of these are in regions of the genome that are imprinted, and studies of an Icelandic population suggest that there are parent-of-origin effects at four of these variants (5); in other words, the extent of association with the risk allele depends on whether it is inherited from the mother or from the father. The SNPs for which parent-of-origin effects have been observed include one in KLF14 (rs4731702), one near MOB2 (rs2334499), and two independent SNPs in KCNQ1 (rs231362 and rs2237892) (5). The presence of parent-of-origin effects at these SNPs is consistent with imprinting and may have important implications for the mechanisms by which variants in or near these genes confer susceptibility to type 2 diabetes. However, for some of the SNPs, the current statistical evidence for parent-of-origin effects is modest. Furthermore, to our knowledge, these effects have not been replicated in other ethnic groups, nor have parent-of-origin effects been analyzed for metabolic traits that underlie the risk of type 2 diabetes, perhaps because few large studies have family data. In the current study, we have analyzed parent-of-origin effects at these SNPs in Pima Indians, an American Indian population in which the prevalence of type 2 diabetes is extraordinarily high (6) and in which family and detailed metabolic data were obtained.