Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Diabetes (New York, N.Y.), 2015-12, Vol.64 (12), p.4322-4332

Ort / Verlag

United States: American Diabetes Association

Erscheinungsjahr

2015

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.