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Variation in maturity-onset diabetes of the young genes influence response to interventions for diabetes prevention

By Liana K. Billings, Kathleen A Jablonski, A. Sofia Warner, Yu Chien Cheng, Jarred B. McAteer, Laura Tipton, Alan R. Shuldiner, David A Ehrmann, Alisa K. Manning, Dana Dabelea, Paul W. Franks, Steven E Kahn, Toni I Pollin, William C Knowler, David Altshuler, Jose C. Florez and Diabetes Prevention Program Research Group


Context: Variation in genes that cause maturity-onset diabetes of the young (MODY) has been associated with diabetes incidence and glycemic traits. Objectives: This study aimed to determine whether genetic variation in MODY genes leads to differential responses to insulin-sensitizing interventions. Design and Setting: This was a secondary analysis of a multicenter, randomized clinical trial, the Diabetes Prevention Program (DPP), involving 27 US academic institutions. We genotyped 22 missense and 221 common variants in the MODY-causing genes in the participants in the DPP. Participants and Interventions: The study included 2806 genotyped DPP participants randomized to receive intensive lifestyle intervention (n = 935), metformin (n = 927), or placebo (n = 944). Main Outcome Measures: Association of MODY genetic variants with diabetes incidence at a median of 3 years and measures of 1-year β-Cell function, insulinogenic index, and oral disposition index. Analyses were stratified by treatment group for significant single-nucleotide polymorphism 3 treatment interaction (Pint, 0.05). Sequence kernel association tests examined the association between an aggregate of rare missense variants and insulinogenic traits. Results: After 1 year, the minor allele of rs3212185 (HNF4A) was associated with improved β-Cell function in the metformin and lifestyle groups but not the placebo group; the minor allele of rs6719578 (NEUROD1) was associated with an increase in insulin secretion in the metformin group but not in the placebo and lifestyle groups. Conclusions: These results provide evidence that genetic variation among MODY genes may influence response to insulin-sensitizing interventions

Topics: Endocrinology and Diabetes
Publisher: 'The Endocrine Society'
Year: 2017
DOI identifier: 10.1210/jc.2016-3429
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