Variation in maturity-onset diabetes of the young genes influence response to interventions for diabetes prevention
Open accessAbstract
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.
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Billings, L. K., Jablonski, K. A., Pan, Q., Florez, J. C., Franks, P. W., Goldberg, R. B., Hivert, M.-F., Kahn, S. E., Knowler, W. C., Lee, C. G., et al. (2024) · Diabetes · doi:10.2337/db23-0761 · Cited by 11 · see citing works
Self-citation
- Authors
- Billings, L. K., Jablonski, K. A., Warner, A. S., Cheng, Y.-C., McAteer, J. B., Tipton, L., Shuldiner, A. R., Ehrmann, D. A., Manning, A. K., Dabelea, D., Franks, P. W., Kahn, S. E., Pollin, T. I., Knowler, W. C., Altshuler, D., Florez, J. C., & for the Diabetes Prevention Program Research Group
- Affiliations
- Endeavor Health (US)
- George Washington University (US)
- Massachusetts General Hospital (US)
- University of Maryland, Baltimore (US)
- University of Chicago (US)
- Broad Institute (US)
- Colorado School of Public Health (US)
- Lund University (SE)
- University of Washington (US)
- National Institutes of Health (US)
- Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2017-04-27
- Volume
- 102
- Issue
- 8
- Pages
- 2678-2689
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC5546852
- OpenAlex
- W2608826156
- Cited by
- 20
- References
- 49
- Citations by year
- 2025: 1 · 2024: 3 · 2023: 4 · 2021: 5 · 2020: 2 · 2019: 2 · 2018: 1 · 2017: 2
- FWCI
- 1.27
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- public-domain
- creativecommons.org/publicdomain/zero/1.0/ (vor)
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion, public-domain)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- Doris Duke Charitable Foundation
- Eli Lilly and Company
- Massachusetts General Hospital
- George Washington University
- NorthShore University HealthSystem
- Novo Nordisk Fonden (NNF14OC0011039)
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (U01DK048339, U01DK048375, U01DK048397, R01DK072041, U01DK048413, DK048489, U01DK048485, U01DK048400, L30 DK089944, K24DK110550, U01DK048380, U01DK048412, U01DK048437, U01DK048514, U01DK048489, U01DK048407, DK007028, U01DK048381, U01DK048443, U01DK048404, P30DK017047, T32DK007028)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Keywords
- maturity-onset diabetes of the young, MODY genes, genetic variation, diabetes prevention, metformin, lifestyle intervention, HNF4α, NeuroD1, beta-cell function, insulin secretion, genetic susceptibility, treatment response, single nucleotide polymorphisms, rare missense variants, Diabetes Prevention Program
- MeSH terms
- Diabetes Mellitus, Type 2, Exercise Therapy, Glucokinase, Humans, Metformin, Genetic Variation, Trans-Activators, Treatment Outcome, Homeodomain Proteins, Mutation, Missense, Polymorphism, Single Nucleotide, Risk Reduction Behavior, Hepatocyte Nuclear Factor 1-alpha, Hepatocyte Nuclear Factor 1-beta, Hepatocyte Nuclear Factor 4, Basic Helix-Loop-Helix Proteins, Weight Reduction Programs
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