Why do some people get type 2 diabetes, while others who live the same lifestyle never do?
[Photo: Dr. Laura Scott]
For decades, scientists have tried to solve this mystery—and have found more than 80 tiny DNA differences that seem to raise the risk of the disease in some people, or protect others from the damagingly high levels of blood sugar that are its hallmark.
But no one “type 2 diabetes signature” has emerged from this search.
Now, a team of scientists has reported a discovery that might explain how multiple genetic flaws can lead to the same disease. They’ve identified something that some of those diabetes-linked genetic defects have in common: They seem to change the way certain cells in the pancreas “read” their genes.
The discovery could eventually help lead to more personalized treatments for diabetes. But for now, it’s the first demonstration that many type 2 diabetes-linked DNA changes have to do with the same DNA-reading molecule. Called Regulatory Factor X, or RFX, it’s a master regulator for a number of genes.
The team reporting the findings in a new paper in the Proceedings of the National Academy of Sciences comes from the University of Michigan, National Institutes of Health, Jackson Laboratory for Genomic Medicine, University of North Carolina and University of Southern California.
They report that many diabetes-linked DNA changes affect the ability of RFX to bind to specific locations in the genomes of pancreas cell clusters called islets. And that in turn changes the cells’ ability to carry out important functions.
Islets contain the cells that make hormones, including insulin and glucagon, which keep blood sugar balanced in healthy people. In people with diabetes, that regulation goes awry—leading to a range of health problems that can develop over many years.
“We have found that many of the subtle DNA spelling differences that increase risk of type 2 diabetes appear to disrupt a common regulatory grammar in islet cells,” says Dr. Stephen Parker, assistant professor of computational medicine and bioinformatics, and of human genetics, at the University of Michigan Medical School. “RFX is probably unable to read the misspelled words, and this disruption of regulatory grammar plays a significant role in the genetic risk of type 2 diabetes.”
Dr. Parker is one of four co-senior authors on the study, which also includes Dr. Michael Boehnke of the University of Michigan School of Public Health’s Department of Biostatistics; Dr. Francis Collins, director of the National Institutes of Health; and Dr. Michael Stitzel of the Jackson Laboratory.
“This work is part of an ongoing and very productive collaboration between statistical, computational and biological researchers,” says Dr. Laura Scott, research associate professor at the University of Michigan School of Public Health’s Department of Biostatistics and one of the study’s co-first authors. “We are starting to identify patterns of genetic variation in motifs that bind specific regulatory proteins and lead to increased type 2 diabetes risk.”