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Diabetes Susceptibility Gene Discovered

By Nancy Touchette

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An insulin-producing beta islet cell of pancreas.
Researchers have known for decades that diabetes runs in families and that that environmental factors, such as obesity and physical inactivity, also play a big role. But the specific genes that may cause or predispose a person to diabetes have long eluded researchers.

Several lines of research are coming together and point to a common culprit. Many cases of type 2, or adult onset, diabetes can now be traced, at least in part, to common variations near the same gene. This gene, known as HNF4α, serves as a master switch that controls many genes that are active in both the pancreas and liver.

“The genetic studies have nailed down HNF4α as a diabetes susceptibility gene,” says Duncan Odom of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, lead author of one of three recent studies. “Our study suggests a mechanism for why variations in this gene might cause diabetes.”

Two research teams used a traditional approach to look for genetic variations among families affected by the disease. Although the teams studied different ethnic groups, they found common variations near the same gene that are more prevalent in people with diabetes.

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Michael Boehnke of the University of Michigan in Ann Arbor, and colleagues including Francis Collins, director of the National Human Genome Research Institute, looked at variations in a region of chromosome 20 in people from Finland. They identified four variants near the HNF4α gene that occurred more frequently in people with type 2 diabetes than in those without the disease.

“It’s been tough sledding,” says Boehnke. “Although genes have been identified that cause rarer, simpler forms of diabetes, it’s been more difficult finding genes that cause type 2.”

In a similar study, M. Alan Permutt of Washington University in St. Louis, Missouri, found two additional variations near the same gene that were associated with diabetes in an Ashkenazi Jewish population.

Several years ago, researchers discovered that a rare mutation in the same gene can cause a simpler, more severe form of diabetes called Mature-Onset Diabetes of the Young, or MODY. While most forms of type 2 diabetes occur in older, overweight individuals, MODY tends to develop in younger individuals who are not necessarily overweight or sedentary.

Both MODY and type 2 diabetes occur when the pancreas doesn’t make enough insulin. Type 2 diabetes is also caused by a resistance of muscle and fat cells to the action of insulin. As a result of low insulin levels and insulin resistance, glucose cannot get into cells and accumulates in the blood.

An estimated 18 million people in the United States have diabetes, which can cause a heightened risk of heart disease and stroke, kidney disease, and vision impairment.

Although a single severe mutation in the HNF4α gene is enough to cause MODY, less severe, more common variations in the same gene do not in themselves cause diabetes. Rather, these variations, which occur in about 20 percent of the general population, appear to predispose individuals to type 2 diabetes. Other environmental or genetic factors, such as obesity or other genetic variations, are needed to trigger the disease.

Just why changes in the HNF4α gene predispose individuals to diabetes is unknown, but researchers studying the function of the normal gene now have some clues. It now appears that this gene codes for a protein that in turn regulates the activity of other important genes in the cell.

In a third study, Odom and his colleagues at the Whitehead Institute looked at the genes in different tissues that are controlled by the HNFα protein. They found that the protein binds to a whopping 40 percent of all liver and pancreas genes they examined. By contrast, most other known gene regulators bind to only two percent or less of all genes in a given cell or tissue.

“The big surprise was that HNF4α is so widely acting,” Odom says. “Almost half of all active genes in the liver and pancreas are bound to this protein.”

This suggests that the protein plays a key role in both the liver and the pancreas. With so many genes under its control, it is possible that variations in the protein could alter the activity of many genes and gene networks and cause disease.

But the finding also raises another question.

“If this protein is important for both liver and pancreas genes, why do we only see problems in the pancreas?” asks Odom.

The variations associated with diabetes found in the Fins and Ashkenazi Jews occur in the region of the gene required to make one of two different versions of the protein, which is only produced in the pancreas. Both forms of the protein are produced in the liver.

Next, researchers would like to find out whether diabetes in other population groups is also linked to variations in HNF4α. And they would like to understand better what genes it regulates.

“Variations in this protein could cause differences in 30 or 40 pathways in the cell,” says Rohit Kulkarni, of the Joslin Diabetes Center in Boston, Massachusetts. “There are a lot of permutations in these pathways that could lead to disease. That’s what makes this work so exciting.”

Although variations in HNF4α most severely affects the pancreas, which produces only one form of the protein, Kulkarni says there may be more subtle effects in the liver. The liver plays a big role in fat and carbohydrate metabolism and it’s the accumulation of fat in the body that is thought to trigger the resistance to insulin that occurs in obese and sedentary individuals.

“In the past we have only looked at individual genes and proteins,” says Kulkarni. “Now we have to look at the whole picture.”

Odom, D.T. et al. Control of pancreas and liver gene expression by HNF transcription factors. Science 303, 1378-1381 (February 27, 2004).
Kulkarni, R.N. and Kahn, C.R. HNFs—Linking the liver and pancreatic islets in diabetes. Science 303, 1311-1312 (February 27, 2004).
Silander, K. et al. Genetic variation near the hepatocyte nuclear factor-4α gene predicts susceptibility to type 2 diabetes. Diabetes 53, 1141-1149 (April 2004).

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