Original Research

August, 2017

Variation in Maturity-Onset Diabetes of the Young genes influence response to interventions for diabetes prevention

J Clin Endocrinol Metab. 2017 Aug 1;102(8):2678-2689

Billings LK, Jablonski KA, Warner AS, Cheng YC, McAteer JB, Tipton L, Shuldiner AR, Ehrmann DA, Manning AK, Dabelea D, Franks PW, Kahn SE, Pollin TI, Knowler WC, Altshuler D, Florez JC

Variation in genes that cause Maturity-Onset Diabetes of the Young (MODY) has been associated with diabetes incidence and glycemic traits.
This study aimed to determine whether genetic variation in MODY genes leads to differential responses to insulin-sensitizing interventions.
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.
The study included 2806 genotyped DPP participants randomized to receive intensive lifestyle intervention (N=935), metformin (N=927), or placebo (N=944).
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.