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Variation in Maturity-Onset Diabetes of the Young Genes Influence Response to Interventions for Diabetes Prevention.

Citation
Billings, Liana K, et al. “Variation in Maturity-Onset Diabetes of the Young Genes Influence Response to Interventions for Diabetes Prevention”. 2017. The Journal of Clinical Endocrinology and Metabolism, vol. 102, no. 8, 2017, pp. 2678–2689.
Center University of Washington
Author Liana K Billings, Kathleen A Jablonski, 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, Diabetes Prevention Program Research Group
Abstract

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 × 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.

Year of Publication
2017
Journal
The Journal of clinical endocrinology and metabolism
Volume
102
Issue
8
Number of Pages
2678-2689
Date Published
12/2017
ISSN Number
1945-7197
DOI
10.1210/jc.2016-3429
Alternate Journal
J. Clin. Endocrinol. Metab.
PMID
28453780
PMCID
PMC5546852
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