Obesity Gene Associated With Susceptibility To Polycystic Ovary Syndrome (PCOS)
17 Mar 2009
Researchers have shown that a gene implicated in the development of obesity is also associated with susceptibility to polycystic ovary syndrome (PCOS). The FTO gene has recently been shown to influence a person's predisposition to obesity, and is now the first gene to be associated convincingly with susceptibility to PCOS.
Carried out by Dr Tom Barber and colleagues from the Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford and Imperial College London, this research is the first evidence to show a genetic link between obesity and PCOS. The results are being presented at the annual Society for Endocrinology BES meeting in Harrogate.
PCOS is a common condition affecting up to 1 in 10 women of child-bearing age. PCOS affects the ovaries and is characterised by irregular periods, excessive hair growth and is a common cause of infertility. PCOS is strongly associated with obesity, and it is thought that the prevalence of PCOS will increase with rising levels of obesity. The FTO gene is known to influence weight. There are two versions of this gene, one of which is associated with increased weight gain and susceptibility to development of obesity.
Dr Tom Barber and colleagues are interested in working out the genetic causes of PCOS and its metabolic consequences. Given the association between PCOS and obesity, they investigated whether variants of the FTO gene also influence susceptibility to PCOS. To this end, they analysed the type of FTO gene carried by 463 PCOS patients and 1336 female population controls. They found that the type of FTO gene a person carried significantly influenced their susceptibility to PCOS. In fact, the version of the gene which is associated with increased weight gain is also associated with PCOS. The data suggest that FTO variants influence PCOS-susceptibility via an effect on fat mass. This is the first gene to be associated convincingly with susceptibility to PCOS and provides genetic evidence to corroborate the well established link between PCOS and obesity.
Researcher Dr Tom Barber said:
"Polycystic ovary syndrome is an incredibly common condition affecting 1 in 10 women of reproductive age and is a leading cause of infertility. It is a genetic condition and one that is strongly associated with obesity; it is therefore of huge relevance for women given today's obesity epidemic.
Our research shows that a variant of the FTO gene that has previously been shown to be associated with obesity also influences susceptibility to polycystic ovary syndrome. These data provide the first genetic evidence to corroborate the well documented association between these two conditions.
Our future work will focus on elucidating the underlying mechanisms of polycystic ovary syndrome and its metabolic consequences with the hope of understanding how this common condition develops. This in turn will instruct future therapeutic developments for women who suffer from polycystic ovary syndrome."
Notes
: 1. Barber TM, Bennett AJ, Groves CJ et al. (2008) Association of variants within the fat mass and obesity-associated (FTO) gene and polycystic ovary syndrome. Diabetologia 51:1153-1158.
2. Frayling TM, Timpson NJ, Weedon MN et al. (2007) A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316:889-894.
The paper will be presented at the Society for Endocrinology BES meeting at 17:45 on Monday 16 March 2009. The abstract for this work is reproduced below: see http://www.endocrine-abstracts.org/e.../ea0019s71.htm Note, this presentation has won the Society for Endocrinology Young Endocrinologist Clinical Prize Lecture 2009.
The Society for Endocrinology BES 2009 is Britain's biggest scientific meeting on hormones, and is taking place at the Harrogate International Centre, Harrogate, from 16-19 March 2009. For the full programme, please see here.
Please mention the Society for Endocrinology BES meeting in any story
The Society for Endocrinology is Britain's national organisation promoting endocrinology and hormone awareness. For general information, please visit our website: http://www.endocrinology.org
ABSTRACT
In search of the genetic basis of polycystic ovary syndrome and its metabolic consequences T Barber1, J Wass1, S Franks2 & M McCarthy1 1Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford, UK; 2Imperial College, Institute of Reproductive and Developmental Biology, London, UK.
Polycystic ovary syndrome (PCOS) is characterised by reproductive, hyperandrogenic and dysmetabolic features (including insulin resistance). There remain major questions about the basis of the metabolic dysfunction in PCOS and about its genetic aetiology. Having genotyped samples from >460 PCOS cases and >1300 female controls, I recently successfully identified the first genome-sequence variant (the FTO gene) to be implicated in susceptibility to PCOS [Barber et al., 2008, Diabetologia, 51, 1153-1158], providing the first genetic corroboration of the link between PCOS and obesity. Within the same cohort, I have also shown that variants implicated in T2D-susceptibility acting through adverse effects on beta-cell function, do not associate with PCOS. This is not consistent with the notion of a primary role of the beta-cell in the establishment of hyperinsulinaemia in PCOS.
Established dogma dictates that body fat distribution (visceral adiposity) is implicated in the inherent, fat-mass independent insulin resistance that characterizes many women with PCOS. Using axial MRI images, I recently demonstrated that groups of PCOS cases and BMI/fat mass-matched control women are indistinguishable with respect to distribution of fat within visceral, abdominal and gluteo-femoral subcutaneous depots, despite significant differences in measures of insulin resistance between the groups [Barber, 2008, JCEM, 93, 999-1004]. Therefore, insulin resistance in PCOS is less closely linked to eutopic fat distribution than has previously been thought, and ectopic fat may play an important role. To corroborate the notion of adipo-normality in PCOS, I have shown that adipokine levels (adiponectin and retinol-binding protein 4) are indistinguishable between PCOS cases and BMI/fat mass-matched control women [Barber, 2008, JCEM, 93, 2859-2865].
In conclusion, adipose tissue (both distribution and function) appears to behave normally in women with PCOS. Although the link between obesity and PCOS (probably mediated via effects on insulin resistance) has been genetically corroborated for the first time recently, our understanding of this association remains incomplete.
UK researchers have discovered a commonly occuring gene variant that may explain why some people become overweight while others do not. However, they point out that it is unlikely to be the cause of the global obesity epidemic.
The findings are published in Science, the journal of the American Association for the Advancement of Science.
A UK research team, led by Dr Andrew Hattersley of Peninsula Medical School in Exeter, have discovered a gene variant that occurs in over half of people of European descent that they think helps to regulate the amount of fat in the body.
The scientists discovered the gene, known as FTO, in a study of 2,000 diabetics when they were doing a genome-wide search for susceptibility to type 2 diabetes. They found there was a strong link between the FTO variant and body mass index (BMI).
So they conducted another study on 13 cohorts of 38,759 Britons, Finns and Italians aged 7 and above where they found a similar link between the FTO variant and body weight.
The strength of the genetic influence depends on whether an individual has inherited one or two copies of the FTO gene variant.
A person with two copies of the FTO variant is likely on average to weigh 3 kilos (6.6 pounds) more than a person who does not have the FTO variant at all, and if they have only one copy they are likely on average to weigh 1.2 kilos (2.6 pounds) more.
About 16 per cent, or one sixth, of Europeans are likely to have both copies of the variant, according to the study. And around half will have one or two.
This is not to be confused with the estimated genetic predisposition to severe obesity which is around 1 in 10,000 people.
Commenting on the study, the team said it reinforces findings from twin studies that suggest obesity is driven partly by genes. However, they added that lifestyle and environment are also strong factors. The genetics has not changed in the last 100 years, but lifestyle and environment has, they said.
They are particularly excited by the fact this is the first study to identify a particular gene.
The scientists want to find out if other ethnic groups outside of Europe also have the FTO variant. They are planning to study the DNA of South Asians and black Americans because diabetes and obesity are more prevalent in these groups than the general population.
While the study did not help them work out the biological mechanism behind the FTO gene and weight control, they suspect it has to do with fat regulation. FTO is known to play a role in the hypothalamus which regulates appetite.
The World Health Organization (WHO) estimates that about 2 billion people worldwide are obese or overweight, that is about one third of all people over the age of 15. It also estimates that about 20 million children under 6 are in the same category.
"Once considered a problem only in high-income countries, overweight and obesity are now dramatically on the rise in low and middle-income countries, particularly in urban settings", says the WHO.
There has been a mixed reaction to this study. Some are saying they hope this does not cause overweight people to be fatalistic about obesity and give up trying to get their weight down, while others say that this could mean people will be even more determined to take care of themselves if they think they have a genetic risk factor for obesity.
The impact on the research and development community is likely to be significant, with scientists curious to find out exactly what role FTO plays in fat regulation, and pharma companies looking at opportunites for new weight control drugs.
"A Common Variant in the FTO Gene Is Associated with Body Mass Index and Predisposes to Childhood and Adult Obesity."
Timothy M. Frayling, Nicholas J. Timpson, Michael N. Weedon, Eleftheria Zeggini, Rachel M. Freathy, Cecilia M. Lindgren, John R. B. Perry, Katherine S. Elliott, Hana Lango, Nigel W. Rayner, Beverley Shields, Lorna W. Harries, Jeffrey C. Barrett, Sian Ellard, Christopher J. Groves, Bridget Knight, Ann-Marie Patch, Andrew R. Ness, Shah Ebrahim, Debbie A. Lawlor, Susan M. Ring, Yoav Ben-Shlomo, Marjo-Riitta Jarvelin, Ulla Sovio, Amanda J. Bennett, David Melzer, Luigi Ferrucci, Ruth J. F. Loos, Inês Barroso, Nicholas J. Wareham, Fredrik Karpe, Katharine R. Owen, Lon R. Cardon, Mark Walker, Graham A. Hitman, Colin N. A. Palmer, Alex S. F. Doney, Andrew D. Morris, George Davey-Smith, The Wellcome Trust Case Control Consortium, Andrew T. Hattersley, and Mark I. McCarthy.
Science Published Online April 12, 2007.
DOI: 10.1126/science.1141634
Click here for Abstract.
Click here for the Association for the Study of Obesity (UK).
Written by: Catharine Paddock
Writer: Medical News Today
Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today
Obesity Gene Trumped by Healthy Diet With a Healthy Diet, Kids With Obesity Gene Not Destined to Be Fat
By Daniel J. DeNoon
WebMD Health News
Reviewed by Louise Chang, MD
March 5, 2009 -- Children born with a gene linked to obesity don't have to get fat. A healthy diet trumps the obesity gene's unhealthy effects.
People who inherit a variant version of the FTO gene tend to have to eat more to satisfy their appetites. As a result, they gain excess fat. That's why FTO has been dubbed the " obesity gene."
The seeds of obesity are planted early in life. But kids with the obesity gene are not doomed to be fat, says University College London researcher Laura Johnson, PhD, and colleagues. Children with the FTO variant aren't any more vulnerable than other kids to the fat-increasing effects of energy-dense, high-calorie foods.
"Obesity is not inevitable if your genes give you a higher risk," Johnson said in a news release. "Those with high-risk genes can, in some cases, resist their genetic lot if they alter their lifestyle in the right way -- in this case, their diet."
The findings reinforce what child obesity expert David S. Ludwig, MD, PhD, told WebMD last year.
"We know that genes affect our body weight set point. But so does our environment and our diet," Ludwig told WebMD. "We can’t change our genes, but we can change our diet, and by doing so in a sophisticated way, we may be able to adjust that body weight set point in our favor."
Energy-Dense Foods, Children, and the Obesity Gene
Energy-dense foods, such as cheese, are dry and/or fatty. They contain more calories per bite than leaner, more watery foods such as soup.
Adults tend to eat the same amount of food, regardless of its energy density. Eating a diet rich in energy-dense foods increases obesity risk for grown-ups.
That's not true for kids, Johnson notes. When younger kids eat energy-dense foods, they generally eat less at the next meal. As they get older, though, they get more and more like adults.
Might the obesity gene make young children particularly vulnerable to energy-dense foods? It's an important question, as nearly one in five U.S. kids aged 6 to 11 years is overweight. So is nearly one in three British kids aged 10 to 11 years.
To get answers, Johnson's team looked at data collected during a long-term study of 2,275 children who were tested for the FTO gene.
Information on what the kids ate at age 10 was used to determine the energy density of their diets. Then the researchers looked at how much fat mass the children had accumulated by the time they reached age 13.
The 13-year-olds tended to be fatter if they had the FTO gene variant. And they tended to be fatter if they ate an energy-dense diet at age 10. But there was no sign that the obesity gene made energy-dense diets extra risky for children.
That, Johnson and colleagues conclude, means that kids can offset the risk of having the obesity gene if their parents feed them fewer energy-dense foods.
How? By doing what they're supposed to do anyway: Replacing high-fat foods with low-fat foods and giving kids more fruits and vegetables.
The study findings appear in the March 2009 issue of the online journal PloS One.
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Exercise Can Overcome Obesity Gene Study Shows Physical Activity Can Offset Genetic Predisposition for Obesity
By Caroline Wilbert
WebMD Health News
Reviewed by Louise Chang, MD
Sept. 8, 2008 -- Though genetics do play a role in obesity, a new study shows regular physical activity can blunt the impact of a genetic predisposition to being overweight.
Variations of a particular gene, known as the fat mass and obesity associated (FTO) gene, are widely acknowledged to be linked with a high body mass index, according to background material in the study, which is published in the Archives of Internal Medicine.
Evadnie Rampersaud, MSPH, PhD, then of the University of Maryland School of Medicine and now of the University of Miami, and colleagues examined how lifestyle affected the weight of people with a genetic predisposition to being overweight.
Researchers studied DNA samples of 704 healthy Amish adults, collected between 2003 and 2007. Participants also underwent physiological tests, including a seven-day measurement of physical activity using an accelerometer, which participants wore on their body. The instrument measured activity level at 15-second intervals.
The participants had an average age of 44 years; 53% were men. Fifty-four percent of the men were overweight and 10% were obese. About 64% of the women were overweight and 31% were obese.
The group was divided into people with high activity levels and low activity levels. The highly active group burned about 900 more calories per day than the lower activity group. That equals about three to four hours of moderately intensive physical activity, such as brisk walking, house cleaning, or gardening, according to the researchers.
The study showed, as past research has, that people with certain variations of the FTO gene were more likely to be overweight. However, the researchers found that being genetically predisposed to obesity "had no effect on those with above average physical activity scores."
As obesity increasingly becomes a global health concern, understanding all aspects of the FTO gene is important, the researchers say. Variants of the FTO gene are prevalent -- about 30% of European populations have such variants, according to the study. The gene variants are associated with a greater than 20% risk for obesity, write the researchers.
Study authors conclude, "These findings emphasize the important role of physical activity in public health efforts to combat obesity, particularly in genetically susceptible individuals."
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Julie Steenhuysen
Reuters Tuesday, 9 September 2008
Overweight people can no longer blame it all on their genes, with a US study finding that physical activity can help people genetically prone to obesity keep the weight off.
The study of a group of Amish people found those who had an obesity-related gene called FTO, but were very physically active weighed about the same as others who did not carry the gene.
"When we looked at the Amish who were the most active, there is suddenly no effect of that gene," says Dr Soren Snitker of the University of Maryland, whose study appears in the Archives of Internal Medicine.
The findings, which suggest physical activity can overcome a genetic predisposition for obesity, may help inform the debate over whether changes in diet or physical activity will make the biggest difference in fighting obesity.
Researchers focused their study on a group of 704 Old Order Amish men and women in Pennsylvania, a religious group whose members often do not drive cars or have electricity in their homes.
Snitker says the group offered a unique mix of activity levels, with some farmers in the community still using horse-drawn ploughs while others holding more conventional jobs, including factory work.
He and colleague Assistant Professor Evadnie Rampersaud of the University of Miami were looking to see if physical activity in this group might offset the effects of the fat mass and obesity associated with the FTO gene, found in more than half of all people of European descent.
Risk of obesity
People with two copies of the FTO gene on average weigh nearly 3 kilograms more and are about 70% more likely to be obese than those who do not have the gene.
The volunteers wore a device called an accelerometer to track motion for a week.
The researchers compared body mass index or BMI, a measure of weight to height, and found those who were less active and had the FTO gene variant were significantly more likely to be overweight or obese.
But among the most physically active, the FTO gene made no difference.
Snitker says the study gives some perspective on how the obesity epidemic has evolved, as modern conveniences have reduced the need and opportunity for physical activity.
People in the most physically active group expended about 3700 more kilojoules per day than the low-activity group. That would equal three to four hours of moderately intense physical activity such as brisk walking, house cleaning or gardening.
"We probably carry genes that 150 years ago were not risk factors for obesity, but because of changes in our environment, they become liabilities," he says.
Snitker believes societies should step in to make more opportunities for what he called "free" exercise, making it easier to walk or bike to work, or to use public transportation that requires some walking.
The World Health Organization estimates 1.6 billion adults worldwide are overweight and at least 400 million adults are obese.
Genetic Link between PCOS and Obesity Found 
