Genetic and Environmental Determinants of Type 2 Diabetes in Chinese Singaporeans

描述（由申请人提供）：东南亚人群2型糖尿病（T2D）发病率高，但肥胖率低。这种“东南亚悖论”造成了极高的公共卫生和经济负担。虽然世界卫生组织（World Health Organization）设定的东南亚特定的较低肥胖定义阈值强调了这些民族对T2D的特殊易感性，但这些人群中糖尿病过多的潜在生物和环境原因尚不清楚。迄今为止，T2D的全基因组关联研究已在欧洲人群中完成，而在其他种族群体中尚未完成。这些最近的遗传发现只是增加了T2D的“东南亚悖论”，因为在欧洲人身上发现的几个风险等位基因在亚洲人身上的频率相对较低。我们的主要目的是确定新加坡华人T2D的遗传易感性因素，这里的T2D患病率很高。研究样本来自正在进行的新加坡华人健康研究，这是一项基于人群的前瞻性队列研究，在1993-1998年期间收集了63,257名成年男性和女性，并持续跟踪到目前为止的发病率和死亡率。新加坡华人健康研究从一开始就得到了国立卫生研究院的支持。新加坡国立大学一直并将继续承担大量费用。已经收集了所有生物样本并准备进行基因分型，并且在糖尿病病例发生之前，已在基线收集了所有环境因素。因此，我们在开展全基因组关联研究方面处于独特的地位，这在以下方面是迄今为止没有的：1)非常大的规模——6132例病例和6132例对照；2)嵌套病例对照设计——允许基因与环境相互作用；3)独特的高危人群，目前我们对2型糖尿病的病因知之甚少；4)由新加坡基因组研究所和新加坡国立大学广泛分担成本，导致科学发现与货币成本的比例很高；5)在两个外部亚洲队列研究中重复我们的发现。我们相信本申请中提出的研究将推动该领域向前发展，以了解许多亚洲人群中T2D的生物学和环境决定因素，并改善风险分层，以便识别风险最大的人群，以便进行早期预防或治疗。东南亚是世界上2型糖尿病发病率最高的地区之一，尽管肥胖率很低，但生物和环境决定因素仍不清楚。该项目的目的是在一项以新加坡华人为基础的大型人群研究中确定2型糖尿病的遗传和生活方式风险因素。这项研究具有巨大的潜力，可以提高我们对东南亚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.