ArchiveStudy published in Nature Genetics uncovers new DNA variants that can help to pile on the pounds
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Researchers at Barts and The London School of Medicine and Dentistry are among an international consortium of scientists to have uncovered new genetic variants that influence fat mass, weight and risk of obesity. The variants act in addition to the recently described variants of the FTO gene: adults carrying variants in both genes are, on average, 3.8 kg (or 8.5 lb) heavier. The study was published in Nature Genetics on Sunday 4 May 2008.
The variants map close to a gene called MC4R: mutations in which are the most common genetic cause of severe familial obesity. The study highlights the potential of large collections of volunteer samples to uncover common variants that influence health.
"By working together with many international groups we have been able to assemble a sample collection which was large enough to allow this finding to be made," explains Dr Ruth Loos, leading author from the Medical Research Council Epidemiology Unit. "Several groups had shown that rare, highly disruptive variants in the MC4R gene were responsible for very severe, genetic forms of obesity: this collaboration has uncovered more common variants that affect more people."
Among those groups were Professor Mark Caulfield, Professor Patricia Munroe, and Dr Chris Wallace of The William Harvey Research Institute at Barts and The London School of Medicine and Dentistry. The study, involving 90,000 people, was led by investigators from the Cambridge GEM consortium (Genetics of Energy Metabolism) and Oxford University and involved collaboration between 77 institutions from the UK, USA, France, Germany, Italy, Finland and Sweden.
The group studied more than 77,000 adults and found that two copies of genetic variants resulted in an average increase in weight of about 1.5 kg.
This is the second set of common variants that are associated with weight and obesity, following the study, involving many of the same team, published in April 2007 that uncovered a role for the FTO gene. People who carry two copies of an FTO variant are about 2–3 kg heavier than those who have no copies of the variant.
Importantly, the effects of the new gene add to those of FTO; people who carried both the FTO variant and new variants were on average 3.8 kg (8.5 lb) heavier.
MC4R protein plays a pivotal role in many aspects of physiology, including regulation of appetite and energy expenditure. The severe form of MC4R-related obesity is a consequence of alterations in the gene sequence, resulting in an inactive or less active MC4R protein.
By contrast, the new variants lie some distance from the MC4R gene. The group suspect that the sequence variant changes activity of the MC4R gene, perhaps by disrupting DNA regions required for normal activity of MC4R.
Professor Patricia Munroe said: "These results further exemplify how important studying large numbers of samples are for finding genes for common disorders."
Dramatically, in a study of almost 6000 children, the group found that the effects were almost double those seen in adults. Between the ages of four and seven, this additional increase in weight was the result, almost exclusively, of gain of fat tissue, and not due to gain in muscle or other solid tissues.
This more dramatic effect in young children reflects the more extreme consequences seen with rare variants of MC4R that severely disrupt its activity, suggesting that the novel variants do indeed exert their effect through action on MC4R.
"Our work to understand common disease, such as obesity, depends on the participation of thousands of people – members of the public who provide samples," explains Professor Nick Wareham, Director of the MRC Epidemiology Unit. "Without their willing participation, we could never achieve the power in our research to make striking findings like this.
"For each discovery, our efforts and the contribution of the participants will lead to improved healthcare for the population at large."
The group will now look to uncover how the DNA variants affect activity of the MC4R protein, which is a key player in orchestrating information from the body to control appetite and energy expenditure to keep body weight in balance. The team propose that altered activity of MC4R, imposed by the variants, might reduce its ability to carry out this important role.
The team emphasize that, although gene variants can affect weight, body mass index and obesity, they are only part of the story: lifestyle actions such as good diet and regular exercise are vital to control of weight.
Source: www.qmul.ac.uk
