Study published in Nature Genetics uncovers new DNA variants that can help to pile on the pounds

01 May 2008

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.

Ends-

Contact details:
Alex Fernandes
Communications Office
Queen Mary, University of London
Tel: 020 7882 7910
email: a.fernandes@qmul.ac.uk

Notes to Editors:

Publications details

Loos RJF et al. (2008) Association studies involving over 90,000 people demonstrate that common variants near to MC4R influence fat mass, weight and risk of obesity. Nature Genetics Published online on Sunday 4 May 2008

A full list of participating groups can be found at http://www.nature.com/nature/index.html

The Cambridge Genetics of Energy Metabolism (GEM) consortium includes researchers from the Wellcome Trust Sanger Institute, MRC Epidemiology Unit and University of Cambridge Department of Clinical Biochemistry and brings together teams with diverse skills to tackle the task of understanding the genetics of both common polygenic forms and also rare monogenic forms of diabetes and obesity.

This 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.

Additional support was provided to individuals by the US National Institute of Diabetes and Digestive and Kidney Diseases, the Throne-Holst Foundation, the Vandervell Foundation, American Diabetes Association, Unilever Corporate Research and the British Heart foundation.

The Wellcome Trust Sanger Institute, which receives the majority of its funding from the Wellcome Trust, was founded in 1992 as the focus for UK sequencing efforts. The Institute is responsible for the completion of the sequence of approximately one-third of the human genome as well as genomes of model organisms such as mouse and zebrafish, and more than 90 pathogen genomes. In October 2005, new funding was awarded by the Wellcome Trust to enable the Institute to build on its world-class scientific achievements and exploit the wealth of genome data now available to answer important questions about health and disease. These programmes are built around a Faculty of more than 30 senior researchers. The Wellcome Trust Sanger Institute is based in Hinxton, Cambridge, UK.

http://www.sanger.ac.uk

www.ox.ac.uk

The Medical Research Council supports the best scientific research to improve human health. Its work ranges from molecular level science to public health medicine and has led to pioneering discoveries in our understanding of the human body and the diseases which affect us all.

http://www.mrc.ac.uk/

GlaxoSmithKline sponsored, in part, the CoLaus Study in Lausanne, Switzerland. This study is one of a large panel of academic-industry collaborations that GlaxoSmithKline has set up to decipher the genetic basis of common diseases. Scientists from GlaxoSmithKline and from Lausanne University Hospital collaborated closely with the MRC and Sanger scientists and were involved in the collection and the analysis of the data which led to the present publication.

The Wellcome Trust is the largest charity in the UK. It funds innovative biomedical research, in the UK and internationally, spending around £650 million each year to support the brightest scientists with the best ideas. The Wellcome Trust supports public debate about biomedical research and its impact on health and wellbeing. http://www.wellcome.ac.uk

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