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A major risk factor for severe obesity in women


Researchers, in one small step in the fight against obesity, have identified a region of chromosome 4 likely to contain a major risk factor for severe obesity in females. The risk factor—probably a single gene—is present in nearly half the families in the study.

"The gene is a major player in obesity," according to Steven Stone, of Myriad Genetics in Salt Lake City, Utah, who co-led the study. The Myriad team, in collaboration with researchers at the University of Utah, analyzed the DNA of families with very severe obesity. The project's long-term goal is to develop new drugs to treat the disease.

"Obesity is a raging epidemic, and there is a pressing need for new drugs," says Stone, noting that none of the existing drugs are effective over the long term. "If we can understand the underlying genetic predisposition, we'll be in a better position to develop drugs."

The surprise of the study, says Stone, was the magnitude of the statistical signal indicating the presence of a disease gene. A statistically significant measure of genetic linkage, known as a LOD score, is about 3.6; Stone's team obtained a score of 11.3 for the region.

"A higher score gives you more confidence in the result, and the chances are greater that you'll actually find a gene," says Stone. "And that's what everyone is trying to do—find the gene." Despite Stone's enthusiasm, the gene has not been identified, and the draft human genome sequences do not contain any obvious obesity-related genes at this location.

As with other complex diseases, pinpointing genes involved in obesity has proved a challenge. To improve their odds of detecting relevant chromosomal regions, the researchers focused on an extreme form of the disease. Families in the study had at least three closely related members with very severe obesity. Severe obesity is defined as a body mass index (BMI) of 40 or more. BMI is calculated by taking weight in kilograms and dividing it by height in meters squared.

The researchers also used different data sets for males and females. The sex-specific strategy was inspired by genetic linkage studies of obesity in mice, says Stone. Researchers have identified regions of the mouse genome that contribute to obesity in one sex but not the other. Why this strategy worked is not entirely clear. One reason may be that the sex-specific approach eliminates confounding factors during the statistical analysis of the data.

The findings, which appear in The American Journal of Human Genetics, are the first published data on the chromosome 4 region and obesity. The paper notes, however, that researchers last year gave a presentation at a scientific meeting implicating the same region in obesity among Mexican Americans.

More studies are needed to determine the region's possible contribution to obesity in males and in the general population.

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Stone, S. et al. A major predisposition locus for severe obesity, at 4p15-p14. Am J Hum Genet 70, 1459-1468 (June 2002).

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