ABCC8 R1420H loss-of-function variant in a southwest American Indian community: Association with increased birth weight and doubled risk of type 2 diabetes

Leslie J. Baier, Yunhua Li Muller, Maria Sara Remedi, Michael Traurig, Paolo Piaggi, Gregory Wiessner, Ke Huang, Alyssa Stacy, Sayuko Kobes, Jonathan Krakoff, Peter H. Bennett, Robert G. Nelson, William C. Knowler, Robert L. Hanson, Colin G. Nichols, Clifton Bogardus

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22 Scopus citations

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.

Original languageEnglish
Pages (from-to)4322-4332
Number of pages11
JournalDiabetes
Volume64
Issue number12
DOIs
StatePublished - Dec 2015

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    Baier, L. J., Muller, Y. L., Remedi, M. S., Traurig, M., Piaggi, P., Wiessner, G., Huang, K., Stacy, A., Kobes, S., Krakoff, J., Bennett, P. H., Nelson, R. G., Knowler, W. C., Hanson, R. L., Nichols, C. G., & Bogardus, C. (2015). ABCC8 R1420H loss-of-function variant in a southwest American Indian community: Association with increased birth weight and doubled risk of type 2 diabetes. Diabetes, 64(12), 4322-4332. https://doi.org/10.2337/db15-0459