Investigation of genetic variation underlying central obesity amongst Indian Asians.

世界卫生组织认为肥胖是一项重大的健康挑战，据估计，全世界有15亿人超重，5亿成年人肥胖。随着肥胖负担从高收入国家向印度和中国等中低收入国家转移，这些数字将在未来20年急剧恶化。肥胖是一种身体脂肪过多的医学状况。当多余的脂肪堆积在腰部时，不健康的风险是最大的。这被称为中心性肥胖。中枢性肥胖会导致异常高的血糖、胆固醇和脂肪，以及高血压，从而导致患糖尿病和心脏病的高风险。中心性肥胖在印度亚洲人中非常普遍，他们现在占世界人口的四分之一，患糖尿病和心脏病的风险是欧洲人的2-3倍。伦敦生命科学前瞻性人口研究（简称LOLIPOP）是英国最重要的一项研究，旨在调查心脏病、中风、糖尿病、肥胖和其他严重医疗问题的潜在机制，特别是在印度亚裔人群中。LOLIPOP的主要目标之一是确定导致这些疾病的生活方式和遗传因素，并开发保持良好健康的新方法。为了实现这一目标，LOLIPOP研究人员已经取得了一些重大发现。我从LOLIPOP研究中调查了印度亚裔中心性肥胖的原因。我在LOLIPOP的工作表明，饮食和生活方式的差异并不能解释印度亚裔中心性肥胖的风险。LOLIPOP先前的研究表明，印度亚洲人的基因构成在导致中心性肥胖方面起着重要作用。我发现印度亚洲人的中心性肥胖的遗传倾向不能用已知的基因变化来解释（主要在欧洲人身上发现）。这表明，印度亚洲人中枢性肥胖的遗传易感性是由基因变化引起的，而这种基因变化可能只有通过对印度亚洲人的研究才能发现。我的建议的总体目标是调查印度亚洲人中心肥胖背后的基因变化。为了实现这一点，我将使用一种利用“极端力量”的实验性策略；与瘦子相比，中心性肥胖患者的基因构成可能会发生更多有利于中心性肥胖的变化。我将使用一种被称为全外显子组测序的方法，对大约200名印度亚洲人进行分析，分析DNA中产生蛋白质的部分，以确定可能导致中枢性肥胖的基因变化。为了确认这些基因变化是否真的影响中心性肥胖，我将测试这些变化是否也发生在中心性肥胖不那么严重的印度亚洲人身上，他们来自LOLIPOP的大约18,000名印度亚洲人。然后，我将研究这些基因变化在多大程度上解释了印度亚裔中央性肥胖、糖尿病和心脏病的过度，以及它们是否也影响到其他人群。最后，我将分析这些基因变化如何转化为蛋白质功能的变化，并最终转化为疾病。我的工作将对澄清印度亚洲人中中心性肥胖的遗传基础，以及所有人群中中心性肥胖的基本生物学基础做出重要贡献。这可能最终导致对高危人群中心性肥胖及其后果的诊断、预防和治疗的改善。

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.