Researchers take giant step toward finding diabetes-causing gene

Study finds link between DNA marker and diabetes in Mexican-Americans A multinational team of 33 researchers -- including a group led by geneticist Graeme Bell at Chicago -- is one step closer to identifying a gene that has a major effect on non-insulin-dependent diabetes mellitus, or NIDDM, in Mexican-Americans. The gene, which they named NIDDM1, has been mapped to one end of chromosome 2, the researchers report in the June 1996 issue of Nature Genetics.

"Once we isolate this gene and determine how it interacts with environmental factors to trigger diabetes in this population, it should provide insights about the cause of this disease and its complications," said Bell, Louis Block Professor in Biochemistry & Molecular Biology and an author of the study. "It could point us toward new ways to predict who is at risk, prevent or delay onset, and treat or even cure this common, chronic disorder."

NIDDM, also known as type II diabetes, affects 10 percent to 20 percent of the population older than 45 in most developed countries and an estimated 15 million people in the United States. It is the seventh leading cause of death in this country, with nearly 2,000 new cases of NIDDM diagnosed every day, for a total of 625,000 each year.

In NIDDM, the body either cannot produce enough insulin or does not use it effectively. If this goes untreated, glucose -- a form of sugar -- accumulates in the bloodstream, slowly damaging the cardiovascular system, kidneys, eyes and nerves. This places diabetics at much higher risk for heart disease, kidney failure, blindness, pain and weakness in the arms and legs, and amputation of extremities.

Finding the DNA marker narrows the search from the 3 billion base pairs that make up the human genome down to a region of only about 5 million base pairs.

Although genes responsible for rare subtypes of non-insulin-dependent diabetes have been reported previously, "this is the crucial first step toward finding a gene that is a major contributor to the common forms of this extremely prevalent disease," Bell said.

Abnormalities in the NIDDM1 gene are thought to account for at least 30 percent -- and as much as 75 percent -- of the familial clustering of non-insulin-dependent diabetes mellitus in Mexican-Americans, a population with a high incidence of this most common type of diabetes. It appears to be less important in non-Hispanic whites or Japanese.

Hereditary factors, along with environmental influences such as obesity and a sedentary lifestyle, have long been recognized as playing an important role in the development of NIDDM. But since the disease does not generally follow a known inheritance pattern, and because of the late age of onset -- generally only after age 40 -- and shortened life span, it has been difficult to gather the large, multigenerational families typically amassed for genetic studies.

Rather than relying on a few multigenerational families, the research team decided to analyze DNA from hundreds of ethnically similar "affected sibling pairs," adult brothers and sisters with a common genetic heritage and NIDDM. Blood samples were collected from 330 pairs of Mexican-American adult siblings, all with NIDDM, who are residents of Starr County, Texas. Starr County has the highest number of diabetes-related deaths of any county in Texas. It has been the site of long-term genetic and epidemiologic studies of diabetes by University of Texas-Houston researchers since the late 1970s.

A consortium of four research centers, with grant support from the National Institute of Diabetes and Digestive and Kidney Diseases, a part of the National Institutes of Health, then screened the entire genome (except for the male-only Y chromosome) of each research subject.

"Our working hypothesis," explained Bell, "was that a small number of identifiable major genes, perhaps five to 10, increase the risk of developing NIDDM, and that these genes can be identified by genetic linkage studies."

Bell and a team of researchers at Chicago examined chromosomes 1 through 4 and 20, where they had previously found a marker for an unusual form of NIDDM. The remaining chromosomes were divided up and studied by teams led by Craig Hanis, professor of genetics at the University of Texas-Houston School of Public Health; Patrick Concannon, associate member of the Virginia Mason Research Center in Seattle; and Richard Spielman, professor of human genetics at the University of Pennsylvania. Nancy Cox, Assistant Professor in Medicine, carried out the statistical analysis of the genetic data.

The search involved testing nearly 500 DNA markers, small bits of DNA that vary from person to person, on the DNA from each individual -- a process that required almost 30 months. Several regions of interest were identified, but one marker on chromosome 2 stood out.

"We now believe that late-onset NIDDM in Mexican-Americans results from the action of at least one relatively major susceptibility gene on chromosome 2," said Hanis, who headed the University of Texas team. "Our next step is to locate that gene."

Curiously, there are no likely candidates for a diabetes-causing gene -- nothing that affects obesity, how insulin is produced or secreted, how glucose is taken up or metabolized, or any other abnormalities associated with diabetes -- in this target region of chromosome 2. In fact, there are no known genes nearby.

"That means we're onto something new, something unexpected," said Bell. "This finding may introduce us to a whole group of as yet unknown genes involved in regulating blood glucose levels."

The normal function of this gene is also likely to be important, the researchers pointed out. "This gene was identified because the disease-predisposing version of it appears to be relatively common in Mexican-Americans," said Spielman, leader of the University of Pennsylvania team. "But of course some version of this gene is present in all humans. Figuring out its normal function will be of considerable interest in its own right."

The researchers estimate that the gene could be identified in as little as two years. Once this gene has been isolated, it will provide a useful clue -- "a foot in the door," said Bell -- for identifying the major genes responsible for susceptibility to NIDDM in other populations.

Besides advancing our understanding of the perplexing genetics of diabetes, this landmark paper also demonstrates that "the same approach can be used to find genes responsible for other complex, multi-gene disorders such as hypertension or cardiovascular disease," Bell said.

In addition to the four genome-scan teams, research participants included professors Neil Risch from Stanford University, Yasue Omori and Naoko Iwasaki from Tokyo Women's Medical College, and Hans-Egbert Schrider and Jan Schulze from the Technical University of Dresden, Germany.

Support for this project was provided by the National Institutes of Health, the American Diabetes Association, the Canadian Diabetes Association, the state of Texas, Bristol-Myers Squibb and the Howard Hughes Medical Institute. Additional support for comparison with the Japanese and European populations was provided by Japan's Ministry of Education, Science and Culture and Ministry of Health and Welfare; the Yoyoi Yoshioka Scholarship Fund of Tokyo Women's Medical College; and the Deutscher Akademischer Austauschdienst.