"Footprints" Help Scientists Get Warmer on Personalized Diabetes Care

Those who develop type 2 diabetes (T2D) tend to have poorer diets and less exercise, but not everyone who eats junk food or never works out suffers this fate.

The question is, why?

Scientists have studied more than 80 genetic differences that either raise the risk of T2D or shield people from high blood sugar. Understanding which of these differences matter—and how they work—could be key to unlocking a treatment for T2D or an effective prevention strategy.

Now, a team of luminaries from major research universities, along with Francis Collins, MD, PhD, the director of the National Institutes of Health, has published a paper in Proceedings of the National Academy of the Sciences that discusses a molecule that appears to act as a master switch in how pancreatic islet cells respond to the variants.

Many of the genetic variants linked to T2D limit the ability of the regulatory factor X (RFX) gene to bind to islets as expected, so that islet cells misinterpret the messages from these variants. When RFX binding is disrupted, so is normal cell activity, which affects the ability to create hormones like insulin and glucagon that regulate blood sugar.

“We have found that many of the subtle DNA spelling differences that increase the risk of type 2 diabetes appear to disrupt a common regulatory grammar in islet cells,” senior co-author Stephen C.J. Parker, PhD, an assistant professor of computational medicine and bioinformatics at the University of Michigan, said in a statement.

Because the study reveals how RFX affects the regulation of multiple genetic variants, it could lead to more personalized diabetes care. Clinicians now have multiple therapeutic options in T2D care, but it is less clear which of several drug classes work best in which patients.

Besides Parker and Collins, the other senior co-authors are Michael Boehnke, PhD, also of the University of Michigan, and Michael L. Stitzel, PhD, of the Jackson Laboratory of Genomic Medicine. Other authors on the paper come from the University of North Carolina and the University of Southern California.

The study started with a series of examinations of islet cell DNA from 112 people. Researchers looked not only at the DNA sequences, but also how they behaved in their genetic environment, which revealed how genes are interpreted. The common threat of RFX involvement emerged—the molecule was described by the University of Michigan as a “runway” that attaches near the gene. In their abstract, the authors describe RFX “footprints” alongside areas of “enriched” genetic variants.

“We find that T2D genetic variants are enriched in regions of the genome where transcription Regulatory Factor X (RFX) is predicted to bind in an islet-specific manner,” the authors wrote in introducing their paper. “Genetic variants that increase T2D risk are predicted to disrupt RFX binding, providing a molecular mechanism to explain how the genome can influence the epigenome, modulating gene expression and ultimately T2D risk.”

This, Parker said, shows how the DNA sequence affects the environment and can influence gene expression. The work may explain a unique and rare birth defect in which babies are born with a poorly formed pancreas and neonatal diabetes, caused by a rare mutation of RFX.

Reference

Varshney A, Scott LJ, Welch RP, et al. Genetic regulatory signatures underlying islet gene expression and type 2 diabetes. Proc Natl Acad Sci. 2017; 201621192. DOI: 10.1073/pnas.1621192114