BioWorld International Correspondent

LONDON - Two copies of a minor variation in a gene of unknown function is enough to put people at a 70 percent higher risk of obesity than those with no copies, a study has shown.

When researchers compared body mass index with inheritance of the genetic variant in more than 38,000 people, they found that 16 percent of adults have two copies of the variant, and that those people on average weighed 3 kilograms (6.6 lbs) more than those who had inherited no copies.

Mark McCarthy, the Robert Turner Professor of Diabetes at the Oxford Centre for Diabetes, Endocrinology and Metabolism in Oxford, UK, told BioWorld International: "This discovery reinforces the idea that genetics are important in the aetiology of obesity, and it is important because it is the first gene to be found that has such a convincing effect on the population at large."

Since the gene had never been identified as playing a role in obesity or weight regulation, he added, the hope is that it eventually will lead to completely new pathways for potential drug therapies.

The gene is called FTO and shows no homology with any other known gene. The researchers have shown that it is widely expressed in fetal and adult tissues, particularly the brain and pancreatic islets.

"There is no hard evidence about what it does, and it is all a bit of a mystery at the moment," McCarthy said. "Because it is quite highly expressed in the hypothalamus, where appetite, satiety and weight regulation is coordinated, my hunch would be that it is involved in this circuitry - particularly as some very rare genes known to cause obesity are known to work in this region."

He predicted a "frenzy of activity" over the coming months to find out what the gene does. "Many people have highly relevant datasets relating to, for example, appetite and diet, and they will now be working to fill in the gaps," he added.

His own group also will be working hard to understand the gene's role in normal weight regulation, and how the genetic variants influence weight regulation and obesity. Several groups are working to produce a knockout mouse lacking functional copies of FTO, in the hope of finding clues to its function.

McCarthy, together with Andrew Hattersley, professor of molecular medicine at Peninsula Medical School in Exeter, UK, and numerous collaborators, mainly from the UK, reported their findings in a paper in the April 12 Sciencexpress . The first author is Timothy Frayling. The title of the paper is: "A Common Variant in the FTO Gene is Associated with Body Mass Index and Predisposes to Childhood and Adult Obesity."

The discovery came about following a genome-wide search for genes predisposing to Type II diabetes. That identified a variant of the FTO gene as associating with obesity, which in turn puts people at higher risk of diabetes.

To confirm the finding, the collaborators examined the inheritance of the FTO variants in 13 cohorts including more than 38,000 people. "We found that one of the haplotypes of this gene was associated with higher weight, and one with lower weight. About 16 percent of Europeans have two copies of the higher-weight variant, about 50 percent have one copy, and about 35 percent have no copies," McCarthy said.

The difference in weight between those with two copies and those with no copies is about 3 kilograms, and the researchers have shown that the 3 kilograms is all fat.

"The result is about a 15 percent increase in fat mass for those with two of the higher-weight variants, and this translates into a 70 percent increased risk for obesity," McCarthy said. "There is also a 30 percent increased risk of being overweight for these people, and a 40 percent increased risk in Type II diabetes."

Mark Walport, director of the Wellcome Trust, which funded the study, said: "This is an exciting piece of work that illustrates why it was so important to sequence the human genome. Obesity is one of the most challenging problems for public health in the UK. The discovery of a gene that influences the development of obesity in the general population provides a new tool for understanding how some people appear to gain weight more easily than others. This discovery, along with further results expected from the Wellcome Trust Case Control Consortium later this year, will open up a wealth of new avenues to understand and treat common diseases."