title: 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.
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ lbaier@phx.niddk.nih.gov.
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Baier
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ.
authors.forename: Yunhua Li
authors.initials: YL
authors.lastname: Muller
authors.affiliation: Department of Cell Biology and Physiology, Washington University in St. Louis, St. Louis, MO.
authors.forename: Maria Sara
authors.initials: MS
authors.lastname: Remedi
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ.
authors.forename: Michael
authors.initials: M
authors.lastname: Traurig
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ.
authors.forename: Paolo
authors.initials: P
authors.lastname: Piaggi
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ.
authors.forename: Gregory
authors.initials: G
authors.lastname: Wiessner
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ.
authors.forename: Ke
authors.initials: K
authors.lastname: Huang
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ.
authors.forename: Alyssa
authors.initials: A
authors.lastname: Stacy
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ.
authors.forename: Sayuko
authors.initials: S
authors.lastname: Kobes
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Krakoff
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Bennett
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Nelson
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ.
authors.forename: William C
authors.initials: WC
authors.lastname: Knowler
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hanson
authors.affiliation: Department of Cell Biology and Physiology, Washington University in St. Louis, St. Louis, MO.
authors.forename: Colin G
authors.initials: CG
authors.lastname: Nichols
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ.
authors.forename: Clifton
authors.initials: C
authors.lastname: Bogardus
mesh_terms: D000328:Adult; D017668:Age of Onset; D019943:Amino Acid Substitution; D000818:Animals; D001130:Arizona / Q000453:epidemiology; D001724:Birth Weight; D019556:COS Cells; D002522:Chlorocebus aethiops; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D005260:Female; D047109:Fetal Development; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D007198:Indians, North American; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D011247:Pregnancy; D011994:Recombinant Proteins / Q000378:metabolism; D012306:Risk; D064233:Sulfonylurea Receptors / Q000235:genetics* / Q000378:metabolism
chemical_list: C577507:ABCC8 protein, human; D011994:Recombinant Proteins; D064233:Sulfonylurea Receptors