Cluster of Genes Linked to Common Type of Diabetes

British researchers have identified a constellation of at least 18 genes that lead to the onset of insulin-dependent diabetes, a breakthrough that promises new hope for the prevention and treatment of the disabling disorder that afflicts nearly 1 million people in the United States.

The feat marks the first time researchers have used new technology developed for the human genome project--the ambitious effort to map the complete human genetic blueprint--to develop the genetic profile of a complex disorder in which multiple genes interact with environmental factors to produce disease.

“The technology we have developed here not only helps diabetes, but is also going to play a role in understanding (the genetic basis of) heart disease, asthma, rheumatoid arthritis and certain types of cancers,” said molecular geneticist Simon T. Bennett of Oxford University. “This is a major step forward.”

“If we can trace the genetics of diabetes, then hopefully we can find ways of preventing it from ever happening,” said Dr. Sarah King, director of research at the Juvenile Diabetes Foundation International. “Ultimately, prevention is the best cure.”

Diabetes is the fourth-leading cause of death by disease in the United States, accounting for an estimated 160,000 fatalities each year. Its complications include blindness, kidney disease, heart problems, strokes and amputations as a result of peripheral nerve damage. Diabetes is diagnosed in about 650,000 people each year.

Insulin-dependent, or Type 1, diabetes results when insulin-secreting cells of the pancreas are destroyed by the body’s immune system. Insulin helps cells use and store sugars in the diet, and in its absence an individual can quickly fall into a coma or die.

Short-term symptoms can be controlled by regular injection of insulin, but complications develop because of the wide swings of sugar concentration in the blood.

Type 2 diabetes, which afflicts at least 12 million Americans, occurs when the pancreas does not make enough insulin or when cells are unable to use it properly. It can usually be controlled with diet or drugs that stimulate insulin production. Its complications are the same as those for Type 1.

Researchers have long known that genes contribute to diabetes, but the role of genes is very different than in simpler genetic disorders, such as muscular dystrophy or Lou Gehrig’s disease. In those cases, there is a single gene involved. If both copies of the gene that a person carries--one from each parent--are defective, the disease will develop.

But diabetes, like heart disease, cancer and many other disorders, is polygenic--meaning that several genes, each of different importance, play a role in its onset. Also, the presence of the genes alone does not necessarily mean that the individual will develop the disease, but only that he or she is predisposed to developing it.

The individual must also be exposed to a trigger in the environment--a virus or a protein in cow’s milk, in the case of diabetes--before the disease occurs.

Tracking down the genes in a polygenic disease is a daunting and time-consuming task that requires an immense investment in research and supplies.

But molecular geneticist John Todd and his colleagues at Oxford used the modern techniques of high-speed replication of DNA (the PCR technique used in DNA fingerprinting), computerized control of the separation of DNA fragments and automation to speed up the process dramatically.

Using these techniques, they were able to identify 300 genetic markers in thousands of blood samples from the members of 300 U.S. and British families with a history of Type 1 diabetes, a process that would have required decades using conventional procedures.

From these studies, the researchers were able to show that 18 separate genes play a role in the onset of the disease. One of them, called IDDM1, is particularly crucial, accounting for 40% to 50% of the genetic contribution. Three others play a significant role, much like the supporting actors in a play, while the rest are, in effect, bit players.

The task now is to isolate each of the genes and identify the protein for which it is a blueprint. Once that is known, researchers say, it should be possible to fully understand how diabetes develops.

But that information is not necessarily essential to developing tests that indicate susceptibility to diabetes. That, said Oxford’s Bennett, could be accomplished in a couple of years. It should then be possible to identify diabetes-prone individuals at birth and take steps to minimize--and eventually eliminate--the possibility that they will develop the disorder.