05 May 08

It's not just genes though - lifestyle contributes to body mass, too

New genetic variants that influence fat mass, weight and risk of obesity have been uncovered via an international investigation led by Oxford and Cambridge researchers.

A study of 90,000 people from seven countries found that these variants map close to a gene called MC4R. Mutations in this gene are the most common genetic cause of severe familial obesity and it is already known that rare, highly disruptive variants in the MC4R gene are responsible for very severe, genetic forms of obesity. The collaboration has now uncovered more common variants that affect more people.

The team, whose research is published in Nature Genetics, found that two copies of these 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. A 2007 study in which Oxford researchers also played a leading role 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 sets of variants were on average 3.8 kg (8.5 lb) heavier.

The 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 team suspect that the sequence variant changes activity of the MC4R gene, perhaps by disrupting DNA regions required for normal activity of MC4R.

‘We are increasingly finding that the genes known to play a role in severe – but rare – diseases are also implicated in much more common diseases,’ said Oxford’s Professor Mark McCarthy, Robert Turner Professor of Diabetic Medicine, who played a key role in both the FTO findings and the latest work.

Dr Cecilia Lindgren, joint first author (together with Dr. Ruth Loos and Dr. Shengxu Li), of the Wellcome Trust Centre for Human Genetics at the University of Oxford, added: ‘Several research groups had shown that rare variants in the MC4R gene are responsible for severe, genetic forms of obesity but this collaboration has uncovered variants that affect more people. This discovery was made possible by the pooling of research data from international teams of scientists. It highlights the power of large collections of samples from volunteers in looking for common genetic variants that can influence health.’

The team will now examine how DNA variants affect the way the MC4R protein orchestrates information from the body to control appetite and energy expenditure and hence keep body weight in balance.

The team emphasises 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.

The research programme was supported by the Medical Research Council, the Wellcome Trust, Diabetes UK, Cancer Research United Kingdom, BDA Research, UK National Health Service Research and Development, the European Commission, the Academy of Finland, the British Heart Foundation, the National Institutes of Health, the Novartis Institutes for BioMedical Research, GlaxoSmithKline, and the German National Genome Research Net.