PAT PROTEINS: GENE-DIET INTERACTIONS OBESITY RISK AND HEALTH

描述(申请人提供)：肥胖已被认定为“当今最明显但最被忽视的公共健康问题之一”。像大多数影响整体人群福祉的疾病一样，肥胖是一种复杂的状况，在这种情况下，多种决定因素相互作用，产生不希望看到的终点。全世界有超过11亿人属于超重或肥胖。世界是怎么变得这么胖的，又是为什么呢？全球的答案可能很简单：卡路里太多，锻炼太少。然而，在个人层面上，答案更为复杂，减肥疗法取得的长期成功非常有限。我们知道，在个人层面上，肥胖是由环境和遗传因素共同决定的。肥胖的遗传率估计在0.37到0.52之间。然而，关于特定基因在当前肥胖症流行中的确切作用，我们知道的要少得多。虽然已经通过不同的代谢途径鉴定了数百个肥胖候选基因，但肥胖的根本基础在于脂肪组织中三酰甘油酯(Tag)的过度储存。控制TAG在脂滴中储存和释放的机制复杂且知之甚少；然而，它们可能对于理解能量代谢和体重的调节至关重要。在这方面，由蛋白质序列相似性定义的进化相关的PAT蛋白家族(Perilipin(Plin)，Adiophlin，TIP47，S3-12)可能在肥胖中起关键作用。我们最近从几项大规模人群研究中发现，plin基因的常见变异与女性的BMI和肥胖风险有关，这些研究包括白人、中国人、印度人和马来人。然而，关于其他PAT基因对肥胖的贡献，我们一无所知。此外，关于PAT基因在现代社会老龄化期间BMI纵向变化中可能发挥的作用的信息缺乏。最后，这些基因和饮食因素之间的潜在相互作用可能有助于揭示饮食摄入量和个体体重变化之间的复杂关系。因此，这项应用的主要目标是利用这项研究中提供的大量横断面和纵向数据，识别PAT家族基因的常见遗传变异，并将这些变异与人体测量指标(BMI、腰围、内脏脂肪和全身脂肪)以及它们随时间的变化联系起来，来自弗雷明翰心脏研究的2600名男性和女性。此外，我们将评估基因变异和饮食习惯之间的相互作用，作为肥胖的调节因素和相关的人体测量指标。这项研究有可能将遗传关联和相互作用的结果转化为根据遗传特征选择的特定群体的饮食建议，以增加旨在抗击肥胖症流行的饮食措施的成功。

DESCRIPTION (provided by applicant): Obesity has been identified as "one of today's most blatantly visible - yet most neglected - public health problems." Like most disorders affecting the well-being of the population at-large, obesity is a complex condition in which multiple determinants interact to produce the undesired end-point. More than 1.1 billion people worldwide fall within the classification of overweight or obese. How and why did the world get so fat? The global answer may be simple: Too many calories and too little exercise. However, at the individual level the answer is more complex as shown by the very limited long term success achieved by weight-reducing therapies. We know that at the individual level obesity is determined by a combination of environmental and genetic factors. The heritability of obesity is estimated to range from 0.37 to 0.52. However, much less is known about the precise contribution of specific genes to the current obesity epidemic. Although hundreds of obesity candidate genes have been identified through different metabolic pathways, the fundamental basis of obesity resides with excessive storage of triacylglycerides (TAG) in adipose tissue. The mechanisms that control the storage and release of TAG in lipid droplets are complex and poorly understood; yet, they are likely to be crucial to the understanding of the regulation of energy metabolism and body weight. In this regard, the evolutionarily related family of PAT proteins (Perilipin (PLIN), Adipophilin, TIP47, S3-12) defined by protein sequence similarity and their association with lipid droplets, may play key roles in obesity. We have recently shown that common variants at the PLIN locus were associated with BMI and obesity risk in females from several large population studies, including Whites, Chinese, Indians and Malays. However, nothing is known about the contributions of other PAT genes to obesity. Moreover, information is lacking about the role that PAT genes may play on the longitudinal changes in BMI that take place in modern societies during aging. Finally, the potential interactions between these genes and dietary factors may shed light on the complex relation between dietary intake and body weight changes observed on an individual basis. Therefore, the primary objective of this application is to identify common genetic variants of the PAT family of genes and to relate those variants with anthropometric measures (BMI, waist circumference, visceral and total body fat) and their changes over time in -2600 men and women from the Framingham Heart Study, using the wealth of cross-sectional and longitudinal data available in this study. Moreover, we will evaluate interactions between genetic variants and dietary habits as modulators of obesity and related anthropometric measures. This research has the potential of translating findings of genetic associations and interactions into dietary recommendations for specific groups selected according to their genetic characteristics in order to increase the success of dietary measures aimed to fight the obesity epidemic.