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Variants in Three Genes Predict Development of Type 2 Diabetes

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Common variants in three genes have been found to predict development of type 2 diabetes, based on a study of 7,000 Swedes followed for an average of 22 years, according to a report presented at the American Diabetes Association's 66th Annual Scientific Sessions.

"Each of these genes are independent predictors of diabetes, which means that each acts via a different mechanism to increase risk of the disease, and that those who have two or more of the genes have added risk," explained Valeriya Lyssenko, MD, PhD, a fellow in diabetes and endocrinology at Lund University, Malmo, Sweden, in a recent interview.

"Type 2 diabetes is believed to be a disorder in which multiple genetic variants interact with environmental factors to unmask the disease," she explained.

"Common variants in a number of genes have been associated with the disease in cross-sectional studies, and we have now documented three."

The question of whether genetic variant information could be used to identify individuals at risk of developing future diabetes has been explored in research before, but because of limitations in the size and duration of the studies, relatively few individuals developed diabetes during the short follow-up periods.

In contrast, the Malmo Preventive Project offered sufficient power to test the hypothesis because 33,346 individuals have been followed for a median of 22 years.

For this genetic study, the researchers tested the ability of common variants in nine genes to predict overt type 2 diabetes in a subset of 7,061 individuals (4,392 men and 2,669 women) with DNA, follow-up medical history, and laboratory data available to date.

When these individuals were enrolled 22 years ago, their average age was 46 +/- 6 years, BMI was 24 +/- 3 kg (i.e. they were not overweight), and only 24.5% had impaired fasting glucose or impaired glucose tolerance (both measures of glucose are above normal but not yet high enough to be diagnostic of diabetes).

At the time of the follow-up examination, 422 (20.1%) individuals in the group had developed type 2 diabetes.

By looking at what genes were more common in those who developed diabetes - as opposed to those who did not - the scientists were able to define those genes that predict the disease.

The scientists identified the following genes that increased the risk of future type 2: the T-alleles of both TCF7L2 rs12255372 (odds ratio 1.40) and rs7903146 (odds ratio 1.52) - that is, two different polymorphisms (DNA sequence variations) on the same gene; KCNJ11 K-allele (odds ratio 1.23) and PPARG PP-genotype (odds ratio 1.20).

"While theoretically someone could now be tested to find out whether they have these risk-producing genes, that won't tell you for sure whether you will get diabetes because there are other genes that have yet to be identified - and genes must interact with environmental factors in order for the predisposition to be triggered and the disease to unfold," said Dr. Lyssenko.

"We need to identify what other genes are involved, which is underway in a genome scan that Lund University is conducting in collaboration with other institutions," she explained.

After further population-based studies to validate the findings, a screening test could then be developed to test a person to see if he/she is at significant risk for diabetes.