A study of 90,000 people has 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 research could lead to better ways of treating obesity.
The variants map close to a gene called MC4R: mutations in this gene are the most common genetic cause of severe familial obesity. The study also highlights the power of large collections of volunteer samples to uncover common variants that influence health.
The study also shows that the gene sequence is significantly more common in those with Indian Asian than European ancestry.
The team 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 They also had a tendency to become resistant to insulin, which can lead to type 2 diabetes. The sequence is found in 50% of the UK population.
“Until now, we have understood remarkably little about the genetic component of common problems linked with obesity, such as cardiovascular disease and diabetes,” said Professor Jaspal Kooner, the paper’s senior author from the National Heart and Lung Institute at Imperial College London. “Finding such a close association between a genetic sequence and significant physical effects is very important, especially when the sequence is found in half the population.”
The study shows that the sequence is a third more common in those with Indian Asian than in those with European ancestry. This could provide a possible genetic explanation for the particularly high levels of obesity and insulin resistance in Indian Asians, who make up 25% of the world’s population, but who are expected to account for 40% of global cardiovascular disease by 2020.
The new gene sequence sits close to a gene called MC4R, which regulates energy levels in the body by influencing how much we eat and how much energy we expend or conserve. The researchers believe the sequence is involved in controlling the MC4R gene, which has also been implicated in rare forms of extreme childhood obesity.
Previous research on finding the genetic causes of obesity has identified other energy-conserving genes. Combining knowledge about the effects of all these genes could pave the way for transforming how obesity is managed.
“A better understanding of the genes behind problems such as diabetes and cardiovascular disease means that we will be in a good position to identify people whose genetic inheritance makes them most susceptible,” added Professor Kooner. “We can’t change their genetic inheritance. But we can focus on preventative measures, including life-style factors such as diet and exercise, and identifying new drug targets to help reduce the burden of disease.“
The research was carried out as part of the London Life Sciences Population (LOLIPOP) study of environmental and genetic causes of cardiovascular disease, diabetes and obesity in approximately 30,000 UK citizens of Indian Asian and European ancestry. The scientists looked at the association between unique genetic markers, called single nuclear polymorphisms, and physical traits linked with obesity, such as waist circumference and insulin resistance.
“The studies we carry out through LOLIPOP are providing unique and important data,” explained lead author Dr John Chambers from the Department of Epidemiology and Public Health at Imperial College London. “The number of people involved, the comparisons between two ancestries, and the detail with which we can explore genetic and environmental effects are helping us identify crucial linkages.”
This research was carried out by scientists at Imperial College London, University of Michigan, USA, and the Pasteur Institute, France. Funded by the British Heart Foundation. Published in Nature Genetics.