Researchers narrow hunt for diabetes-causing gene

September 1996

Study finds link between DNA marker and diabetes in Mexican Americans
A multi-national team of 33 researchers 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, they report in the June 1996 issue of Nature Genetics.

Finding the DNA marker narrows the search from the three billion base pairs that make up the human genome down to a region of only about five million base pairs--about two percent of the total.

"Non-insulin-dependent diabetes is one of the most complex genetic diseases in the world," said Phillip Gorden, MD, director of the National Institute of Diabetes and Digestive and Kidney Diseases, a part of the National Institutes of Health and a major funder of the research. "These studies make an extremely important contribution towards identifying the genes that contribute to the cause of the disease."

Although genes responsible for rare sub-types of non-insulin-dependent diabetes have previously been reported, "this is the crucial first step toward finding a gene that is a major contributor to the common forms of this extremely prevalent disease," said Graeme Bell, PhD, Louis Block Professor of Biochemistry & Molecular Biology and of Medicine in the University of Chicago's Howard Hughes Medical Institute and an author of the study.

"We now have the first evidence for a gene that has a major effect on diabetes mellitus in Mexican Americans," said co-auther Craig Hanis, PhD, Professor of Genetics at the University of Texas Houston School of Public Health.

NIDDM, also known as type-II diabetes, affects an estimated 15 million people in the United States and is the seventh leading cause of death in this country.

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 lifespan, it has been difficult to gather the large multi-generational families typically amassed for genetic studies.

Rather than relying on a few muti-generational 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.

Hanis and colleagues at the U. T. Houston Human Genetic Center collected blood samples 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 U.T. Houston researchers since the late 1970s.

A consortium of four research centers, with grant support from the NIDDK, 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, perhaps five to ten, identifiable major genes increase the risk of developing NIDDM, and that these genes can be identified by genetic linkage studies."

Bell's University of Chicago team examined chromosomes 1-4 and 20 (where they had previously found a marker for an unusual from of NIDDM). Hanis and the U.T. Houston team studied chromosomes 12-17. A team led by Patrick Concannon, Ph.D., associate member of the Virginia Mason Research Center in Seattle, focused on chromosomes 5-11, and a team led by Richard S. Spielman, PhD, Professor of Human Genetics at the University of Pennsylvania, took 18, 19, 21, 22, and X.

Nancy Cox, PhD, assistant professor of medicine at the University of Chicago, 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. "Our next step is locate that gene."

Curiously, there are no likely candidates for a diabetes-causing gene--nothing that affects how insulin is produced or secreted, how glucose is taken up or metabolized, obesity, 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," explained Bell. "This finding may introduce us to a whole group of as yet unknown genes involved in regulating blood glucose levels.

"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. "It could point us toward new ways to predict who is at risk, prevent or delay onset, treat or even cure this common, chronic disorder."

"The normal function of this gene is also likely to be important," said Spielman. "This gene was identified because the disease-predisposing version of it appears to be relatively common in Mexican Americans. 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.

In addition to identifying NIDDM1, this study "provides a 'road map' of the human genome," said Concannon, "indicating where additional NIDDM susceptibility genes may be located."

As the effort to pinpoint the gene continues, the research team has also begun to look for biochemical differences between the diabetics in the study and their unaffected siblings.

Besides advancing our understanding about 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," said Bell.

NIDDM is a major public health problem, affecting 10 to 20 percent of the population older than age 45 in most developed countries. In the United States, the direct costs of medical care for people with diabetes are estimated at more than billion, with an additional billion lost to disability and premature mortality. Nearly 2,000 new cases are diagnosed every day in the U.S., 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 blood stream, 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.

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 Schröder 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-Meyers Squibb, and the Howard Hughes Medical Institute. Additional support for comparison with the Japanese and European populations was provided by the Ministries of Education, Science and Culture, and Health and Welfare, Japan; the Yoyoi Yoshioka Scholarship Fund of Tokyo Women's Medical College; and the Deutscher Akademischer Austauschdienst.

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