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 U.S. 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 one-year beta-cell function, insulinogenic index (InsIndex) and oral disposition index (DIo). Analyses were stratified by treatment group for significant SNP×treatment interaction (Pint<0.05). Sequence kernel association tests examined the association between an aggregate of rare missense variants and insulinogenic traits. RESULTS: After one year, the minor allele of rs3212185 (HNF4A) was associated with improved beta-cell function in the metformin and lifestyle, but not placebo groups; 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.