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Gene Variant “Powerful Predictor” of Type 2 Diabetes

Jul 25, 2006

But lifestyle changes, such as exercise, counteract effects of this gene, study suggests. Results of a study confirm and extend the finding that polymorphisms in the transcription factor 7-like 2 gene (TCF7L2) increase the risk of type 2 diabetes in individuals with impaired glucose tolerance.

Investigators determined that the two most strongly associated TCF7L2 variants (rs12255372 and rs7903146) influence the risk of progression from impaired glucose tolerance to overt diabetes.

Lead author Dr. Jose Florez of Massachusetts General Hospital in Boston said, "This is the strongest genetic effect found in diabetes to date and it gives us the ability to predict the onset of diabetes better than just clinical characteristics and risk factors like obesity, sedentary lifestyle and glucose dysregulation,"

The findings come from genotyping 3,548 adults with impaired glucose tolerance enrolled in the Diabetes Prevention Program (DPP).

Launched in 1995, the DPP was designed to test whether a lifestyle intervention or treatment with metformin, compared with no intervention, would prevent or delay the development of diabetes in persons at risk for the disease. The trial ended in 2001, a year earlier than planned, based on the finding that lifestyle intervention and treatment with metformin reduced the incidence of diabetes by 58% and 31%, respectively, over an average of roughly three years.

In their DNA analysis of DPP participants, Dr. Florez and colleagues found that the 40% of subjects homozygous for the high-risk T allele (the rs7903146 polymorphism) had a 55% greater rate of progression to overt diabetes than those homozygous for the low-risk C allele. The 10% of people with the TT genotype had about an 80% higher risk of developing diabetes.

The results were similar for the rs12255372 variant. These TCF7L2 variants are associated with impaired beta-cell function but not with insulin resistance. "Our data, combined with previous longitudinal studies and genetic findings, show that type 2 diabetes can be triggered by decreased insulin production and not just by insulin resistance," Dr. Florez said.

A "major finding," Dr. Florez said, "is that lifestyle intervention to achieve a moderate degree of weight loss (7% of body weight) was just as effective, if not more, in people with two risk variants in preventing or delaying the onset of diabetes."

For now, however, routine genetic testing for these variants cannot be recommended until clinical trials show that it will lead to better patient outcomes and that it is cost-effective, Dr. Florez emphasized.

Dr. Stephen O’Rahilly, from Addenbrooke’s Hospital, and Dr. Nicholas J. Wareham, from the Medical Research Council Epidemiology Unit — both in Cambridge, UK – commented that, "Perhaps a more immediate use of this information, in combination with other genetic and nongenetic information," they suggest, "will be in refining a risk profile for diabetes in order to determine the need for and the intensity of follow-up or to influence decisions about staged implementation of preventive interventions with behavioral or drug therapy."

"At first glance," they add, "TCF7L2 is not the most attractive of drug targets, since it is closely involved in fundamental developmental processes. Nevertheless, the pharmaceutical industry will be looking carefully at agents that modulate the signaling pathways of TCF7L2."

N Engl J Med 2006;355:241-250.


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