Two international research teams — one led by M. Alan Permutt, M.D., professor of medicine and of cell biology and physiology at Washington University School of Medicine in St. Louis — have found variations in a gene that may predispose people to type 2 diabetes, the most common form of the disease. The two research teams, which collaborated extensively, will report their findings in companion articles in the April issue of Diabetes.
Type 2 diabetes usually begins after age 40 in overweight, inactive people and is more common in those with a family history of diabetes. In the United States, type 2 diabetes disproportionately affects African-Americans, Hispanic/Latino Americans and Native Americans. Affecting about 17 million people nationwide, this form of diabetes accounts for 90 to 95 percent of all diabetes cases in the United States. Its prevalence has been steadily rising over the past 30 years, and it is increasingly being seen in younger people, even in children. Hallmarks of the disease are insulin resistance — the inability of target tissues to respond to insulin — and a gradual failure of islet cells in the pancreas to produce enough insulin.
Studying two distinct populations and homing in on a wide stretch of chromosome 20 that had been flagged in earlier studies as a likely location for a type 2 diabetes susceptibility gene, the teams identified four genetic variants, called single nucleotide polymorphisms (SNPs), which are strongly associated with type 2 diabetes in Finnish and Ashkenazi Jewish populations.
All four SNPs cluster in the regulatory region of a single gene, hepatocyte nuclear factor 4 alpha (HNF4A), a transcription factor that acts as a “master switch” regulating the expression of hundreds of other genes. HNF4A turns genes on and off in many tissues, including the liver and pancreas. In the beta cells of the pancreas, the gene influences the secretion of insulin in response to glucose.
Permutt’s team studied 100 SNPs in 275 Ashkenazi Jewish adults in Israel with type 2 diabetes and 342 non-diabetic adults. They found diabetes-related associations for SNPs in a region of DNA that regulates the gene’s expression in the insulin-secreting cells of the pancreas.
“We believe these variants are marking a regulatory region that determines the level of expression of HNF4A,” Permutt says. “We’re now looking to see if this region of DNA is affecting gene expression in some way.”
The other international research team examined genetic variants in 793 Finnish adults diagnosed with type 2 diabetes and 413 non-diabetic adults. Those researchers identified a total of 10 SNPs within and near the HNF4A gene that are associated with type 2 diabetes in the Finnish population. Their most significant results were in the same region of HNF4A. Individuals who inherited the risk variant tended to have higher levels of blood glucose at fasting and two hours after ingesting food or drinks designed to raise their blood glucose levels.
“It’s a nice coalescence of findings,” says Francis S. Collins, M.D., Ph.D., director of the National Human Genome Research Institute (NHGRI) and senior author of the article describing the Finnish study results. “What we found is a common variation in this gene. If you have this variation, it appears to raise your risk of type 2 diabetes about 30 percent. The variation isn’t going to cause diabetes unless you have it in combination with other yet-to-be-identified genetic susceptibility factors, together with certain environmental influences such as obesity and lack of physical exercise.”
Translating the discovery into a treatment that benefits people with diabetes or those at risk is still years away. “We need to learn much more about this gene and how to modulate its function,” Collins cautioned.
Permutt and Collins also stress that other groups still need to confirm their results, and scientists already are looking for the variants in other populations.
For years, scientists have known that single-gene mutations, most affecting beta cell function, contribute to rare forms of diabetes, including the six types of Maturity Onset Diabetes of the Young or MODY. Such mutations account for about 2 to 3 percent of all diabetes cases. A mutation in the coding region of HNF4A causes MODY type 1, a rare form of diabetes that begins before age 25 in people of normal weight.
Scientists have come a long way in understanding the basis for diseases arising from single-gene mutations. Understanding the genetic basis of the more common diseases like diabetes, which involve many genes, has been much more difficult.
“We could have scoured the coding region of every gene on chromosome 20 by sequencing it in many patients and not come up with anything,” Permutt says. “That’s because the problem isn’t in the gene itself but in a regulatory region far from the gene. This study suggests that perhaps the level of expression of candidate genes will expand our understanding of genetic risk factors. It also shows us that if we scrutinize the gene itself from beginning to end, we haven’t done a complete job. We need to look at markers surrounding the gene for differences in those markers in affected individuals and healthy controls.”
Latisha D. Love-Gregory, Ph.D., post-doctoral fellow in medicine at the School of Medicine was the lead author on the study in the Ashkenazi Jewish population, which was conducted in collaboration with The Hadassah-Hebrew University in Israel.
The FUSION (Finland-United States Investigation of NIDDM Genetics) study was conducted by researchers from the National Human Genome Research Institute; University of Michigan; University of Southern California; National Public Health Institute in Finland; and The Wellcome Trust Sanger Institute in the United Kingdom.
The studies were funded by the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) and by NHGRI. The Academy of Finland, Burroughs Wellcome and the American Diabetes Association provided additional support.