Researchers Discover Major Diabetes Susceptibility Gene

An international research team led by scientists at the University of Texas Health Science Center at Houston and the University of Chicago has identified a major susceptibility gene for type 2, or adult-onset diabetes in Mexican-Americans.

The discovery, published in the October 2000 issue of Nature Genetics, pinpoints a new and unexpected biochemical pathway leading to non-insulin-dependent diabetes mellitus (NIDDM), the most common form of diabetes. The finding marks the first time that a genome-wide linkage analysis has led to the identification of a gene responsible for a common genetically complex disorder such as diabetes, which is caused by interactions between genes and lifestyle factors such as obesity.

"To understand those interactions, you first have to have the gene. Now we have a gene," said Dr. Craig L. Hanis, professor of biological sciences at the UT-Houston School of Public Health Human Genetics Center. "This provides a whole new pathway to explore in preventing and treating diabetes."

"Finding this gene finally allows us to go after diabetes treatment strategies that address the underlying molecular defects rather than the symptoms," said research team leader Dr. Graeme Bell, Louis Block Professor of Biochemistry & Molecular Biology and of Medicine and an investigator in the Howard Hughes Medical Institute at the University of Chicago.

New analytical techniques developed by Dr. Bell's team were brought to bear on a unique data set compiled by Dr. Hanis during 19 years of research in Starr County, Texas, to locate the gene, called CAPN10, on chromosome 2. CAPN10 produces a newly identified protein called calpain 10.

"Dr. Bell and his colleagues' accomplishments are a tour-de-force," said Dr. Allen Spiegel, director of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDKD). "Actually identifying susceptibility genes for diseases such as diabetes with complex, as opposed to simple, Mendelian inheritance has proved exceedingly difficult. Identification of this gene, one that would not have leaped to mind as an obvious candidate, is exciting because it should lead to greater understanding of the pathogenesis of type 2 diabetes, and possibly to new forms of treatment. Identification also offers the prospect of genetic diagnosis, so those at increased risk can be identified early and prevention measures, such as appropriate diet and exercise, instituted."

Type 2 diabetes afflicts an estimated 135 million people worldwide, including 15 million Americans. It is caused by insulin deficiencies that allow a dangerous build up of the sugar glucose in the blood. The disease is the seventh leading cause of death in the United States and costs an estimated $98 billion a year to treat. It can lead to stroke, blindness, heart disease, kidney failure and limb amputations. The incidence of type-2 diabetes is on the rise worldwide.

Few are more aware of the disease's toll than the residents of Starr County, where the population is 98 percent Mexican-American, an ethnic group three times more likely to have the disease. The death rate from diabetes in the South Texas county on the Rio Grande is triple the rate for the rest of Texas.

Dr. Hanis has conducted research and screened area residents for diabetes through the university's Starr County Health Studies Field Office in Rio Grande City, which he and colleagues established in 1981. Dr. Hanis and his research team collected family histories, clinical data and DNA samples, while alerting many residents for the first time that they had the disease.

Because type-2 diabetes is typically diagnosed after age 40, reduces the life span of its victims, and involves multiple genes, it has been difficult to gather the extensive multi-generation family data usually required for genetic studies. Dr. Hanis allowed the team to get around this problem by providing extensive data on 346 sibling pairs from Starr County affected by diabetes.

In 1996, a team led by Drs. Hanis and Bell demonstrated a link between increased risk of diabetes among these siblings, and a gene located near one end of chromosome 2, a region that they named NIDDM1. No one studying a genetically complex disease had ever been able to take the next step of identifying the specific gene indicated by the linkage.

"People kept telling us it was impossible," Dr. Bell said.

Dr. Bell and University of Chicago colleague Dr. Nancy Cox developed new analytic techniques that enabled them to zero in on the gene in the Starr County samples. As the group's search narrowed, they relayed results to Dr. Hanis, who conducted confirming studies in his larger database. The CAPN 10 gene in the NIDDM1 region was pinpointed in 1998.

In an unusual development, Dr. Bell's team found that the variation in the gene that causes diabetes susceptibility occurred in an intron, a genetic component, sometimes referred to as junk DNA, that separates functional portions of a gene.

"Finding a significant mutation in an intron is almost, but not entirely, unheard of," Dr. Bell said.

Because the discovery was so surprising, the referees for Nature Genetics requested a series of supporting studies to help verify the finding, delaying publication by nearly eighteen months. These studies found the gene also plays a role in the incidence of type 2 diabetes in at least two separate European populations.

Drs. Bell and Hanis say that the gene accounts for about 14 percent of the prevalence of type 2 diabetes in the Mexican-American population, and about four percent in Europeans. They continue their research on other genes.

"There are other genes involved, and we know this gene interacts with another one we haven't yet identified on chromosome 15," Dr. Hanis said. "Between those two, we think we can probably explain about 50 percent of the genetic component for diabetes. It provides exciting avenues for study and research."

The team also continues to study the effect of the protein calpain 10 on type 2 diabetes. Forms of the protein have been found in the pancreas, muscle tissue and the liver, three crucial tissues involved in glucose regulation.

Even as the team follows up its own work, Dr. Hanis said the publication is expected to generate a flurry of studies by others examining the gene in different populations, its metabolism and its pharmaceutical potential.

Drs. Bell and Hanis say the techniques used in their research on type 2 diabetes can be applied to other genetically complex disorders such as hypertension, obesity, psychiatric diseases and asthma.

Other authors of the diabetes paper include researchers at the Virginia Mason Research Center in Seattle; NIDDKD, Phoenix; Tokyo Women's Medical University; the University of Lund in Sweden; and Technical University in Germany.

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©2006 Texas Medical Center

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