Journal Article

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

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

2017

Overview

ContextVariation in genes that cause maturity-onset diabetes of the young (MODY) has been associated with diabetes incidence and glycemic traits.ObjectivesThis study aimed to determine whether genetic variation in MODY genes leads to differential responses to insulin-sensitizing interventions.Design and SettingThis 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 InterventionsThe study included 2806 genotyped DPP participants randomized to receive intensive lifestyle intervention (n = 935), metformin (n = 927), or placebo (n = 944).Main Outcome MeasuresAssociation 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.ResultsAfter 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.ConclusionsThese results provide evidence that genetic variation among MODY genes may influence response to insulin-sensitizing interventions.Genetic variation in MODY genes was associated with response to diabetes prevention interventions as measured by β-cell function and diabetes incidence.

• Publisher: Endocrine Society,Copyright Oxford University Press,Oxford University Press
• Subject: Alleles / Basic Helix-Loop-Helix Transcription Factors - genetics / Beta cells / Beta2 protein / Clinical Medicine / Clinical s / Clinical trials / Diabetes / Diabetes mellitus / Diabetes Mellitus, Type 2 - genetics / Diabetes Mellitus, Type 2 - prevention & control / Editor's Choice / Endocrinology and Diabetes / Endokrinologi och diabetes / Exercise Therapy / Genetic analysis / Genetic diversity / Genetic Variation / Glucokinase - genetics / Hepatocyte Nuclear Factor 1-alpha - genetics / Hepatocyte Nuclear Factor 1-beta - genetics / Hepatocyte nuclear factor 4 / Hepatocyte Nuclear Factor 4 - genetics / Homeodomain Proteins - genetics / Humans / Insulin / Insulin secretion / Klinisk medicin / Lifestyles / Medical and Health Sciences / Medicin och hälsovetenskap / Metformin / Metformin - therapeutic use / Mutation, Missense / Placebos / Polymorphism, Single Nucleotide / Risk Reduction Behavior / Secretion / Single-nucleotide polymorphism / Trans-Activators - genetics / Treatment Outcome / Weight Reduction Programs