Diabetes mystery... Geneti clues

Researchers uncover new risk factors
Boston Globe

Decades after scientists first realized that the risk of getting diabetes was partially inherited, discoveries of real genetic defects are suddenly coming rapid-fire.

Thursday, four separate scientific teams, including one led by Harvard researchers, reported three new genetic risk factors and confirmed five others identified over the last few years. An additional risk factor identified by one group has not yet been confirmed by others.

The discoveries open up new avenues to explain what breaks down in the body to cause type 2 diabetes. More than 20 million Americans suffer from diabetes and another 54 million are at risk. In the future, scientists said, the genetic findings may also help predict who will get the illness and lead to treatments tailored to each individual's genetic makeup.

"This is a milestone," said Dr. Larry C. Deeb, president for medicine and science of the American Diabetes Association, who was not involved in the research. "We're moving out of the darkness into understanding a lot more about diabetes."

The researchers identified some genetic areas that are not connected to any known mechanism behind diabetes, which harms the body's ability to control blood sugar and can lead to heart disease, blindness, and early death.

"No one had the first clue that these genetic changes were involved in the disease," said David Altshuler, associate professor of genetics and medicine at Harvard Medical School and a leader of one of the three collaborating teams.

Some of the genetic changes are in what scientists previously called "junk DNA," he said, areas of the genetic code that they previously thought were meaningless. "Our whole view of which parts of the human genome contribute to disease is being augmented."

Genetics accounts for about half the risk of getting type 2 diabetes, according to Altshuler. Environment and such behaviors as obesity and lack of exercise account for the remaining risk.
The eight confirmed genetic defects together account for about 5 percent of the risk of getting the illness, he said. "The picture that is emerging is of multiple genes, each with a modest effect" on diabetes, he added.

However, scientists from the National Institutes of Health found that in one group of subjects, people with the most defects had a four times higher risk of having diabetes than people with the fewest defects.

Scientists said much work remains before genetic testing for diabetes becomes useful for patients. Researchers also expect it may be up to a decade before new treatments result from the work.

"The pharmaceutical industry is absolutely salivating at all of these studies" because they suggest targets for new drugs, said Dr. Francis Collins, director of the National Human Genome Research Institute and a leader of another of the teams. "But there is a long lead time."

The results were published Thursday in the online editions of the journals Science and Nature Genetics. They are based on a new research technique called genomewide association studies, in which scientists compare genetic samples from thousands of individuals who have a specific illness with those who don't.

The work is also unusual because three of the four scientific groups collaborated to confirm their results, drawing on the largest database of DNA ever used to study diabetes and making the findings extremely solid.

"Only five years ago this work would have been unthinkable," said Collins.

Each of the four groups used genetic material from a different population, totaling tens of thousands of subjects.

The three groups that coordinated to confirm each other's results were led by scientists from Britain; the National Institutes of Health and Finland; and the Broad Institute at Harvard and MIT, Sweden, and the pharmaceutical company Novartis.

The three variations they found are near genes that appear to be related to regulation of insulin, which controls blood sugar, and to growth of the cells in the pancreas that produce insulin. In diabetes, the body becomes resistant to insulin or fails to make enough insulin, causing a problematic build-up of sugar in the blood stream. The actual effect of the genetic defects has yet to be determined.