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

  • 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
Publishing year: 2017-08-01
Language: English
Pages: 2678-2689
Publication/Series: Journal of Clinical Endocrinology and Metabolism
Volume: 102
Issue: 8
Document type: Journal article
Publisher: The Endocrine Society

Abstract english

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.


  • Endocrinology and Diabetes


  • Genetic and Molecular Epidemiology
  • ISSN: 0021-972X
Paul Franks
E-mail: paul [dot] franks [at] med [dot] lu [dot] se

Principal investigator

Genetic and Molecular Epidemiology

+46 40 39 11 49



Lund University Diabetes Centre, CRC, SUS Malmö, Entrance 72, House 91:12. SE-205 02 Malmö. Telephone: +46 40 39 10 00