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J Clin Endocrinol Metab. 2017 Aug 1;102(8):2678-2689. doi: 10.1210/jc.2016-3429.

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

Author information

1
Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114.
2
Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114.
3
Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114.
4
Department of Medicine, NorthShore University HealthSystem, Evanston, Illinois 60201.
5
Department of Medicine, Pritzker School of Medicine, University of Chicago, Chicago, Illinois 60637.
6
Biostatistics Center, George Washington University, Rockville, Maryland 20852.
7
Department of Medicine, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland 21201.
8
Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142.
9
Department of Epidemiology, Colorado School of Public Health, University of Colorado, Denver, Colorado 80045.
10
Department of Clinical Sciences, Genetic, and Molecular Epidemiology Unit, Lund University Diabetes Center, Skåne University Hospital Malmö, SE-205 02 Malmö, Sweden.
11
Division of Metabolism, Endocrinology, and Nutrition, VA Puget Sound Health Care System and University of Washington, Seattle, Washington 98195.
12
Departments of Medicine (Division of Endocrinology, Diabetes, and Nutrition) and Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland 21201.
13
Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona 85014.
14
Vertex Pharmaceuticals, Boston, Massachusetts 02210.

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.

PMID:
28453780
PMCID:
PMC5546852
DOI:
10.1210/jc.2016-3429
[Indexed for MEDLINE]
Free PMC Article

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