ABCMdb

PMID: 17259403

Florez JC, Jablonski KA, Kahn SE, Franks PW, Dabelea D, Hamman RF, Knowler WC, Nathan DM, Altshuler D
Type 2 diabetes-associated missense polymorphisms KCNJ11 E23K and ABCC8 A1369S influence progression to diabetes and response to interventions in the Diabetes Prevention Program.
Diabetes. 2007 Feb;56(2):531-6., [PubMed]

Sentences

No. Mutations Sentence Comment

0 ABCC8 p.Ala1369Ser ABCC8 p.Ala1369Ser Brief Report Type 2 Diabetes-Associated Missense Polymorphisms KCNJ11 E23K and ABCC8 A1369S Influence Progression to Diabetes and Response to Interventions in the Diabetes Prevention Program Jose C. Florez,1,2,3,4 Kathleen A. Jablonski,5 Steven E. Kahn,6 Paul W. Franks,7,8 Dana Dabelea,9 Richard F. Hamman,9 William C. Knowler,8 David M. Nathan,2,3 and David Altshuler1,2,3,4,10 for the Diabetes Prevention Program Research Group* The common polymorphisms KCNJ11 E23K and ABCC8 A1369S have been consistently associated with type 2 diabetes. Login to comment 6 ABCC8 p.Ala1369Ser Results for ABCC8 A1369S were essentially identical to those for KCNJ11 E23K. Login to comment 15 ABCC8 p.Ala1369Ser ABCC8 p.Ala1369Ser Interestingly, this variant is in strong linkage disequilibrium with the upstream missense single nucleotide polymorphism (SNP) A1369S in the adjacent gene ABCC8, which encodes the functionally related sulfonylurea receptor SUR1 (7,8,13); thus, in all examined populations, lysine carriers at KCNJ11 E23K almost invariably carry the alanine allele at ABCC8 A1369S, and it remains possible that either or both variants are actually required to mediate these effects. Login to comment 66 ABCC8 p.Ala1369Ser In this study, we addressed five distinct hypotheses, limiting subsequent analyses to their further refinement: 1) genotype at KCNJ11 E23K (or at ABCC8 A1369S, as both are highly correlated) influences diabetes incidence, 2) this genetic effect is modified by a lifestyle intervention or 3) by metformin treatment, 4) genotype at KCNJ11 E23K affects insulin secretion, and 5) genotype at KCNJ11 E23K does not affect insulin resistance. Login to comment 77 ABCC8 p.Ala1369Ser We found strong linkage disequilibrium between ABCC8 A1369S and the downstream variant KCNJ11 E23K in the five ethnic groups: Lewontin`s DЈ (25) and r2 were 0.97/0.93, 0.98/0.93, 0.99/ 0.95, 0.99/0.88, and 0.97/0.95 in U.S. Caucasians, African Americans, Hispanic Americans, Asian Americans, and American Indians, respectively. Login to comment 78 ABCC8 p.Ala1369Ser Thus, not surprisingly, our findings in carriers of the alanine allele at ABCC8 A1369S were essentially the same as those for lysine carriers at KCNJ11 E23K in all of the analyses reported below. Login to comment 106 ABCC8 p.Ala1369Ser ABCC8 p.Ala1369Ser ABCC8 p.Ala1369Ser TABLE 2 Baseline measures of insulin secretion and sensitivity according to KCNJ11 E23K and ABCC8 A1369S genotypes in the DPP KCNJ11 E23K E/E E/K K/K P value (E/E vs. E/K)* P value (E/E vs. K/K)* n 1,658 1,445 364 Ins index ͓(␮U/ml)/(mg/dl)͔ 1.07 (0.94) 1.04 (0.87) 0.97 (0.79) 0.046 0.003 ISI ͓(␮U/ml) ϫ (mmol/l)͔-1 0.161 (0.121) 0.162 (0.124) 0.169 (0.144) 0.98 0.76 Fasting insulin (␮U/ml) 24 (16) 24 (17) 23 (18) 0.85 0.73 ABCC8 A1369S S/S A/S A/A P value (S/S vs. A/S)* P value (S/S vs. A/A)* n 1,635 1,424 378 Ins index ͓(␮U/ml)/(mg/dl)͔ 1.07 (0.95) 1.03 (0.86) 0.97 (0.81) 0.02 Ͻ0.01 ISI ͓(␮U/ml) ϫ (mmol/l)͔-1 0.162 (0.121) 0.162 (0.123) 0.172 (0.145) 0.87 0.67 Fasting insulin (␮U/ml) 24 (17) 24 (17) 22 (17) 0.73 0.88 Data are median (interquartile range). Login to comment