Gene Variant Increases Obesity Risk

EXETER, England, April 12 -- The first clear genetic link to obesity for the common man or woman may have been nailed down by researchers here.

The British team that discovered the obesity-linked gene variant doesn't understand what it does or how it contributes to extra poundage. But the investigators are sure of the association.

In studies involving nearly 40,000 Europeans, the variant of a little-known gene on chromosome 16 increased the risk of being obese by up to 67%, according to Andrew Hattersley, D.M., of the Peninsula Medical School.

The 16% of adults with two copies of the variant weighed on average about three kilograms (6.6 pounds) more than counterparts with no copies, Dr. Hattersley and colleagues reported online today in Science.

"Our findings suggest a possible answer to someone who might ask, 'I eat the same and do as much exercise as my friend next door, so why am I fatter?'" Dr. Hattersley said. "There is clearly a component to obesity that is genetic."

The researchers said in a teleconference that this study is the best evidence yet of a relatively common genetic link to obesity. Other known genetic causes of obesity tend to be rare and affect a small number of people.

But they added that the finding shouldn't change the way doctors think about obesity.

"This gene is not the whole story," said co-author Mark McCarthy, M.B., of Oxford University. "This gene alone is not going to explain why some people are 10 or 20 or 30 kilograms heavier than people in the same environment."

Dr. McCarthy added there is no need to develop a genetic test for the gene variant, since it is "quite easy to see if someone is overweight."

Dr. Hattersley noted, "The best way forward for managing obesity is still what it was" -- exercise and lifestyle changes.

But the function of the gene -- dubbed FTO -- is not known, nor is it known how the variant alleles cause their bearers to gain more weight than those without, the researchers said.

The discovery began when the researchers scanned the genetic code of nearly 5,000 British volunteers looking for genes that were associated with type II diabetes.

A 47-kilobase stretch of the FTO gene was highly associated with the risk of diabetes, Dr. Hattersley and colleagues found, but the association vanished when the researchers controlled for body mass index.

That suggested that the link to diabetes was through increased body mass. So the researchers analyzed genetic data from several other European studies, involving an additional 19,424 adults and 10,172 children.

In all the studies, the risk of being overweight or obese was associated with having one or more copies of the so-called A allele of the FTO gene, they found.

Compared with those with two copies of the low-risk T allele -- about 37% of the population -- those with two copies of the A allele were:

• 38% more likely to be overweight (defined as a body mass index of at least 25 kg/m²). The odds ratio was 1.38, with a 95% confidence interval from 1.26 to 1.52, which was statistically significant at P=4x10^-11.
• 67% more likely to be overweight (defined as a body mass index of at least 30 25 kg/m²). The odds ratio was 1.67, with a 95% confidence interval from 1.47 to 1.89, which was statistically significant at P=1x10^-14.

To pin down when the effect starts to occur, the researcher examined two large birth cohorts, one in the United Kingdom and one in Finland. They found no significant differences in birth weight and height associated with the variant FTO gene.

However, in the British study, each copy of the A allele was associated with an extra 0.4 kilograms per meter by age 11, while the Finnish study showed an increase of 0.1 kilograms per meter squared by age 14.

The British study -- a longitudinal examination of nearly 7,500 children -- also included dual energy X-ray absorptiometry (DEXA)-derived measures of fat mass and non-fat mass, taken at age nine.

The link between the A allele and increased BMI was "almost exclusively attributable to changes in fat mass," the researchers said.