ABCC8 R1420H Loss-of-Function Variant in a Southwest American Indian Community: Association With Increased Birth Weight and Doubled Risk of Type 2 Diabetes

Abstract

Missense variants in KCNJ11 and ABCC8, which encode the KIR6.2 and SUR1 subunits of the β-cell KATP channel, have previously been implicated in type 2 diabetes, neonatal diabetes, and hyperinsulinemic hypoglycemia of infancy (HHI). To determine whether variation in these genes affects risk for type 2 diabetes or increased birth weight as a consequence of fetal hyperinsulinemia in Pima Indians, missense and common noncoding variants were analyzed in individuals living in the Gila River Indian Community. A R1420H variant in SUR1 (ABCC8) was identified in 3.3% of the population (N = 7,710). R1420H carriers had higher mean birth weights and a twofold increased risk for type 2 diabetes with a 7-year earlier onset age despite being leaner than noncarriers. One individual homozygous for R1420H was identified; retrospective review of his medical records was consistent with HHI and a diagnosis of diabetes at age 3.5 years. In vitro studies showed that the R1420H substitution decreases KATP channel activity. Identification of this loss-of-function variant in ABCC8 with a carrier frequency of 3.3% affects clinical care as homozygous inheritance and potential HHI will occur in 1/3,600 births in this American Indian population.

Complex Genetics of Type 2 Diabetes and Effect Size: What have We Learned from Isolated Populations?

“…The clinical course of this individual included hypoglycemia, with seizures at the age of 4 months due to hyperinsulinemia, and a diagnosis of diabetes at 3.5 years of age [121]. The R1420H also associated with birth weight where newborns who carried this mutation were approximately 170 grams heavier than noncarriers [121]. This is consistent with the hypothesis of fetal hyperinsulinemia, resulting in increased birth weight.…”

“…One novel R1420H variant was significantly associated with T2D in Pima Indians where heterozygous carriers had twice the risk for T2D as non-carriers (OR = 2.02, p = 3.6 × 10 -5 ) [121]. In a community-based study of Pima Indians, 3.3% of the population carried this mutation, and the mean age of diabetes onset was, on average, 7 years earlier for carriers compared with non-carriers (HR = 2.05).…”

“…Among the 7,528 individuals genotyped, only one individual was homozygous for this mutation. The clinical course of this individual included hypoglycemia, with seizures at the age of 4 months due to hyperinsulinemia, and a diagnosis of diabetes at 3.5 years of age [121]. The R1420H also associated with birth weight where newborns who carried this mutation were approximately 170 grams heavier than noncarriers [121].…”

“…Whole genome sequencing in Pima Indians led to the identification of several novel variants in ABCC8 which encodes the SUR1 subunit of the K ATP channel [121]. One novel R1420H variant was significantly associated with T2D in Pima Indians where heterozygous carriers had twice the risk for T2D as non-carriers (OR = 2.02, p = 3.6 × 10 -5 ) [121].…”

Dissecting the Etiology of Type 2 Diabetes in the Pima Indian Population

“…In this issue of Diabetes, Baier et al (5) report on the results of a targeted sequencing project focusing on the genes encoding the two subunits of the b-cell K ATP channel. Variants identified by whole-genome sequencing in ABCC8 and KCNJ11 in 335 Pima Indians are genotyped in 7,710 individuals of full Pima Indian heritage or mixed American Indian heritage (;4/8th Pima Indian).…”