Variation In Maturity-Onset Diabetes Of The Young Genes Influence Response To Interventions For Diabetes Prevention

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 beta-cell function, insulinogenic index, and oral disposition index. Analyses were stratified by treatment group for significant single-nucleotide polymorphism x treatment interaction (P-int < 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 beta-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.