Investigation of genetic variation underlying central obesity amongst Indian Asians.

The World Health Organisation recognises obesity as a major health challenge, with estimates of 1.5 billion overweight, and 500 million obese adults worldwide. These figures are set to worsen dramatically in the next two decades with the burden of obesity shifting profoundly from high income to low and middle income countries, such as India and China. Obesity is a medical condition of excess body fat. The risk of ill-health is greatest when surplus fat is found around the waist. This is called central obesity. Central obesity causes abnormally high blood sugar, cholesterol and fat, and high blood pressure, with consequent high risk of diabetes and heart disease. Central obesity is highly prevalent in Indian Asians, who now comprise a quarter of the world's population, and have a 2-3 times greater risk of diabetes and heart disease compared to Europeans.

The London Life Sciences Prospective Population Study (abbreviated to LOLIPOP) is a foremost UK research study investigating the mechanisms underlying heart disease, stroke, diabetes, obesity and other serious medical problems, particularly amongst people of Indian Asian ancestry. One of the main aims of LOLIPOP is to identify the lifestyle and inherited factors that contribute to these diseases, and to develop new ways to preserve good health. Towards this aim, the LOLIPOP investigators have already been responsible for a number of major discoveries.

I have investigated the causes of central obesity in Indian Asians from the LOLIPOP study. My work within LOLIPOP shows that differences in diet and lifestyle do not account for the risk of central obesity amongst Indian Asians. Previous work in LOLIPOP has shown that the genetic make-up of Indian Asians plays an important role in causing central obesity. I find that this hereditary predisposition to central obesity in Indian Asians is not explained by known genetic changes (identified predominantly in Europeans). This suggests that the hereditary predisposition to central obesity in Indian Asians is caused by genetic changes which may only be found by study of Indian Asians.

The general objective of my proposal is to investigate the genetic changes that underlie central obesity in Indian Asians. To achieve this I will use an experimental strategy that takes advantage of the "power of extremes"; individuals with extreme central obesity are likely to have a greater number of changes in their genetic-make up that favour central obesity compared to the lean. I will use an approach called whole exome sequencing in around 200 Indian Asians, which analyses the parts of DNA which make proteins, to identify genetic changes that may underlie central obesity. To confirm whether these genetic changes truly influence central obesity, I will test whether these changes also occur in Indian Asians with less extreme central obesity in a large group of around 18,000 Indian Asians from LOLIPOP. I will then examine the extent to which these genetic changes explain the excess of central obesity, diabetes and heart disease in Indian Asians, and whether they also affect other populations. Lastly, I will analyse how these genetic changes translate into change in function of proteins, and ultimately disease.

My work will make an important contribution to clarifying the inherited basis of central obesity in Indian Asians, and in turn the basic biology underlying central obesity in all populations. This may ultimately lead to improvements in diagnosis, prevention and treatment of central obesity and its consequences, for at risk people.

Indian Asians have high prevalence of central obesity, which is causally linked to their 2-3 fold excess risk of the metabolic syndrome of insulin resistance, T2D and CHD, compared to Europeans. Improved understanding of the mechanisms underlying central obesity and associated diseases in Indian Asians is of great importance for improving health in this population. Central obesity has been shown to be heritable amongst Indian Asians though the underlying genetic mechanisms are not well understood. My preliminary studies in LOLIPOP show that genetic variants linked to obesity in Europeans do not account for the excess risk of central obesity in Indian Asians. The goal of my proposal is to investigate genetic variation underling central obesity in Indian Asians. I propose WES in 200+ Indian Asians at extremes of central obesity, selected as the top and bottom 0.5% of the population distribution for WHR in the LOLIPOP cohort (n~18,000). Genetic variants associated with WHR at P<10-3 will be taken forward for replication testing in a two stage design. In stage one, >100 genetic variants will be tested in ~1800 Indian Asians (selected as the top and bottom 5% of the population distribution for WHR among the remaining LOLIPOP participants). In stage two, variants identified from stage 1 at P<0.01 will be tested for association with WHR in the remaining ~16,000 Indian Asian participants in LOLIPOP. Significance will be inferred at P<5x10-8. The extent to which confirmed genetic variants contribute to the excess of central obesity and the increased risk of T2D and CHD in Indian Asians will be established. Indian Asian data will be compared with 1000 Genomes data to identify whether the associated variants in Indian Asians are population specific or cosmopolitan. Pathways to disease will be evaluated using bioinformatic approaches.

The Department of Health and Government White Paper 10.2011 - Healthy Lives, Healthy People / Equality Analysis: A call to action on obesity in England - commits to tackling the major public health challenge presented by high levels of overweight and obesity in the UK. Special attention is given to ethnic minorities, including Indian Asians, with their high risk of obesity related diseases. The paper identifies the critical need for building an evidence base through research, and for reducing health inequalities. The MRC independently stresses the need for research into 'Genetics and Disease' (Strategic Aim 1, Research Priority Theme 2: Leading a Long and Health Life).

The main initial outcome of my research will be new knowledge of genetic and molecular mechanisms underlying central obesity and its associated disease cluster in Indian Asians. The immediate benefits will therefore be greatest in the academic community (above). After the discovery and analysis phases, wide-spread and timely dissemination of my research and downstream translational findings has the potential for diverse impacts on society, people and the economy, in preventing disease and reducing health inequalities.

SOCIETAL IMPACTS - POLICY MAKERS: my research and consequent opportunities for translation may help to inform future policy of government agencies and public sector providers including the NHS, about the deleterious effects of central obesity, with a view to improving UK and global health. This is of special importance in Indian Asians who are at high risk of central obesity and its consequences, represent 5% of the UK and 1/4 of the world's population, and are exposed to major heath inequalities. Policy on central obesity may also have broad implications in the general adult population and for children.

SOCIETAL IMPACTS - PUBLIC SECTOR, THIRD SECTOR & OTHER BENEFICIARIES: policy in relation to central obesity can be implemented through public sector, third sector and other beneficiaries, who will provide life-style education in schools and for adults, disseminate positive healthcare messages through the NHS and media, and support affected individuals and families through voluntary sector, charity and social enterprises, towards reducing the burden of central obesity.

SOCIETAL IMPACTS - HEALTHCARE, WELL BEING & QUALITY OF LIFE: my research may lead to increased understanding of molecular mechanisms underlying central obesity, laying the foundation for improvements in diagnosis and treatment, to the benefit of UK and global health-care providers, patients and their families. The identification of novel genetic markers may also aid the development of new prediction tools for central obesity, which may empower people to make healthy lifestyle decisions and reduce individual stigma related to central obesity.

ECONOMIC IMPACTS - THE BURDEN OF OBESITY: overweight and obesity and their consequences are predicted to cost the NHS ~£5.1bn per annum, though the estimated annual cost to the economy is ~£16bn (2007 figures). Increased understanding of genetic and molecular mechanisms in relation to central obesity may help in the future development and implementation of new therapeutic strategies, which will ultimately improve health and reduce health-care costs and indirect economic costs.

ECONOMIC IMPACTS - UK & INTERNATIONAL PROSPERITY: my research has the potential to identify new genetic and molecular mechanisms underlying central obesity in Indian Asians. This may help scientists to identify new disease biomarkers and drug targets, advancing healthcare diagnostics and pharmaceutical enterprise. New knowledge may also assist the development of risk prediction tools, ultimately helping food and recreation industries to target at risk groups with healthier consumables and new health facilities. Overall these may aid UK competitiveness, and increase the role of business in improving national health, a key UK government goal.