Genetic and Environmental Determinants of Type 2 Diabetes in Chinese Singaporeans

描述(申请人提供)：尽管肥胖率较低，但东南亚人口的2型糖尿病(T2D)发病率很高。这一“东南亚悖论”造成了极高的公共卫生和经济负担。尽管世界卫生组织为定义肥胖设定了针对东南亚的较低门槛，强调了这些民族对T2D的特殊易感性，但这些人群中过度糖尿病的潜在生物和环境原因尚不清楚。到目前为止，T2D的全基因组关联研究已经在欧洲人群中完成，而在其他种族群体中还没有。这些最新的基因发现只是增加了T2D的“东南亚悖论”，因为在欧洲人中发现的几个风险等位基因在亚洲人中的频率相对较低。我们的主要目标是确定居住在新加坡的中国人中T2D的遗传易感因素，新加坡是T2D的高发区。研究样本来自正在进行的新加坡华人健康研究，这是一个基于人群的前瞻性队列，在1993-1998年间收集了63,257名成年男性和女性，并持续跟踪调查其发病率和死亡率。美国国立卫生研究院自新加坡华人健康研究项目开展以来一直支持该项目。新加坡国立大学一直并将继续大量分担费用。已经收集了所有生物样本，并准备好进行基因分型，所有环境因素都已在发生糖尿病病例之前的基线上收集。因此，我们在以下方面处于独特的地位，可以进行迄今为止前所未有的全基因组关联研究：1)非常大的规模-6,132个病例和6,132个对照；2)嵌套病例对照设计-允许基因x环境交互作用；3)独特的高危人群，我们目前对T2 DM病因缺乏了解；4)新加坡基因组研究所和新加坡国立大学的广泛成本分担，导致科学发现与货币成本的高比率；以及5)在两项外部亚洲队列研究中复制我们的发现。我们相信，这项申请中提出的研究将推动该领域在了解许多亚洲人群中T2D的生物学和环境决定因素方面取得进展，并改善风险分层，以便能够识别出风险最高的人，以便及早预防或治疗。与公共健康相关东南亚人是世界上2型糖尿病发病率最高的国家之一，尽管肥胖率很低，这是一个悖论，其生物和环境决定因素尚不清楚。该项目的目标是通过对新加坡华裔成年人的大规模人群研究，确定2型糖尿病的遗传和生活方式危险因素。这项研究具有巨大的潜力，可以提高我们对东南亚人2型糖尿病风险的了解，从而改善预防工作。

DESCRIPTION (provided by applicant): Southeast Asian populations have high rates of type 2 diabetes (T2D) despite low rates of obesity. This "Southeast Asian Paradox" has caused an extremely high public health and economic burden. While Southeast Asian-specific lower thresholds for defining obesity, set by the World Health Organization, underscore the particular susceptibility of these ethnic groups to T2D, the underlying biological and environmental causes for the excess diabetes in these populations are unknown. To date, genome-wide association studies of T2D have been completed in European populations, with none in other ethnic groups. These recent genetic findings only add to a "Southeast Asian Paradox" of T2D because several of the risk alleles found in Europeans have relatively low frequencies in the Asians. Our main aim is the identification of genetic susceptibility factors for T2D in Chinese living in Singapore, where there is a high prevalence of T2D. The study samples are derived from the ongoing Singapore Chinese Health Study, a population-based prospective cohort of 63,257 adult men and women assembled during 1993-1998 and continuously followed to date for incident morbidity and mortality. The NIH has been supporting the Singapore Chinese Health Study since its inception. There has been and continues to be significant cost- sharing by the National University of Singapore. All biological samples have already been collected and are ready for genotyping, and all environmental factors have been collected at baseline prior to the accrual of incident diabetes cases. Thus, we are in a unique position of conducting a genome-wide association study like none other to date in the following respects: 1) Very large size - 6,132 cases and 6,132 controls; 2) Nested case-control design - allowing for gene x environment interactions; 3) Unique, high risk population for which we currently have a weak understanding of T2DM etiology; 4) Extensive cost-sharing by the Genome Institute of Singapore and National University of Singapore, resulting in a high ratio of scientific discovery to monetary cost; and 5) Replication of our findings in two external Asian cohort studies. We believe the study proposed in this application will move the field forward in understanding the biological and environmental determinants of T2D in many Asian populations, and improve risk stratification so that those at greatest risk can be identified for early prevention or treatment. PUBLIC HEALTH RELEVANCE Southeast Asians have among the world's highest rates of type 2 diabetes despite low rates of obesity, a paradox for which the biological and environmental determinants remain unclear. The objective of this project is to identify the genetic and lifestyle risk factors for type 2 diabetes in a large population-based study of Singaporean Chinese adults. The study has tremendous potential to improve our understanding of type 2 diabetes risk in Southeast Asians, leading to improved prevention efforts.