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MODY gene variants may influence response to insulin-sensitizing interventions for diabetes

Stephen Padilla
07 Sep 2017

Genetic variation among maturity-onset diabetes of the young (MODY) genes appears to affect response to insulin-sensitizing interventions, a recent study has found.

“[S]elect MODY gene variants annotated to HNF4A, HNF1B and NEUROD1 are associated with response to insulin-sensitizing interventions on either diabetes incidence and/or insulinogenic traits,” according to researchers.

A secondary analysis of a multicentre, randomized clinical trial, the Diabetes Prevention Program (DPP), involving 27 US academic institutions was conducted. Researchers genotyped 22 missense and 221 common variants in the MODY-causing genes among 2,806 DPP participants randomly assigned to receive intensive lifestyle intervention (n=935), metformin (n=927) or placebo (n=944).

Analyses were stratified by treatment group for significant single-nucleotide polymorphism x treatment interaction (p<0.05 for interaction).  The association between an aggregate of rare missense variants and insulinogenic traits was examined using sequence kernel association tests.

The primary outcomes were the association of MODY genetic variants with diabetes incidences at a median of 3 years and measures of 1-year β-cell function, insulinogenic index and oral disposition index.

The minor allele of rs3212185 (HNF4A) correlated with improved β-cell function in the lifestyle and metformin groups but not the placebo group after 1 year. Moreover, the minor allele of rs6719578 (NEUROD1) correlated with an increase in insulin secretion in the metformin group but not in the placebo and lifestyle groups. [J Clin Endocrinol Metab 2017;102:2678–268]

“We have examined genetic variation among six canonical MODY genes for association with insulinogenic traits and diabetes incidence in response to diabetes preventive interventions,” researchers said. “Our key findings show that genetic variation within HNF4AHNF1B and NEUROD1 is associated with a differential response to lifestyle and/or metformin interventions in insulinogenic traits and diabetes development.”

These findings support previous studies showing that variations in genes where pathogenic mutations are known to cause MODY contribute to the risk of diabetes and variation in insulinogenic traits. [Diabetes 2006;55:2534–2540; Diabetes 2007;56:685–693; Diabetes 2008;57:1738–1744; Nat Genet 2010;42:579–589; Diabetologia 2011;54:2038–2046; Nat Genet 2011;43:984–989; Nat Genet 2011;44:67–72; Nat Genet 2007;39:977–983]

Furthermore, researchers demonstrated how insulin-sensitizing intervention modified the influence of variation in MODY genes.

“Among common variants in MODY genes previously associated with type 2 diabetes from candidate gene studies and [genome-wide association studies), we replicated rs757210 in HNF1B for association with diabetes incidence,” researchers said. [Diabetes 2007;56:685–693]

“We reported an association between rs11868513 in HNF1B and diabetes incidence among the placebo group participants, but rs11868513 and rs757210 are not in linkage disequilibrium (r2<0.009) and appear to be exerting independent effects on diabetes incidence,” they added.

Further genotype-centred studies are warranted to determine whether carriers of the aforementioned gene variants respond differently to insulin-sensitizing and, moreover, insulin secretagogue therapy, according to researchers.

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