Gene variants may increase susceptibility to type 2 diabetes 11/3/04. By NHGRI International research teams studying two distinct populations have found variants in the HNF4A gene that may predispose people to type 2 diabetes, the most common form of the disease.

The researchers, who collaborated extensively in their work, report their findings in companion articles in the April 2004 issue of Diabetes.

Homing in on a wide stretch of chromosome 20 - flagged by 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, it influences the secretion of insulin in response to glucose.

"It's a nice coalescence of findings," said Dr Francis Collins, 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 per cent. 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."

The Finnish study identified a total of ten SNPs within and near the HNF4A gene that are associated with type 2 diabetes in the Finnish population. The most significant results were found in a region of DNA (called the promoter) that regulates the gene's expression in the insulin-secreting cells of the pancreas.

The other international team of researchers, led by Dr M Alan Permutt of the Washington University School of Medicine in St Louis, studied Ashkenazi Jewish adults in Israel. They found diabetes-related associations for SNPs in the same region of HNF4A.

"We believe these four variants are marking a regulatory region that determines the level of expression of HNF4A," Dr Permutt said. "We're now looking to see if this region of DNA is affecting gene expression in some way."

Other groups still need to confirm their results, Drs Collins and Permutt stress. In fact, scientists are already looking for the variants in other populations. "We've e-mailed our findings in precise detail to scientists in the International Type 2 Diabetes Linkage Analysis Consortium," said Dr. Boehnke, who co-leads the National Institute of Diabetes and Digestive and Kidney Diseases-funded consortium, a group of scientists around the world who are mapping type 2 diabetes susceptibility genes. "This approach will substantially increase the speed with which we see our results confirmed or contradicted," he added. Other studies will see if people with the risk variants have signs of beta cell impairment and will look at HNF4A's function in animals.

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 per cent 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.

Adapted from a press release by the National Human Genome Research Institute .

Further reading

Latisha D et al. A Common Polymorphism in the Upstream Promoter Region of the Hepatocyte Nuclear Factor-4 Gene on Chromosome 20q Is Associated With Type 2 Diabetes and Appears to Contribute to the Evidence for Linkage in an Ashkenazi Jewish Population. Diabetes 2004 53:1134-1140. Abstract ; Full text

Kaisa Silander K, et al. (2004) Genetic Variation Near the Hepatocyte Nuclear Factor-4 Gene Predicts Susceptibility to Type 2 Diabetes. Diabetes 2004 53: 1141-1149. Abstract ; Full text