Genetics of Type 2 Diabetes in Indian Populations: US-India Collaboration Project

 描述(由申请人提供)：在印度和美国，2型糖尿病(T2D)已经成为一个主要的公共卫生问题。考虑到它的流行病学负担和相关的人群健康差异，人们一直在努力了解其表型表达背后的因素。鉴于其作为两国医疗保健问题的重要性，美国国立卫生研究院(NIH RFA-DK-14-006)和印度医学研究委员会(ICMR)联合宣布了资助机会，以支持糖尿病研究的两国合作研究伙伴关系(CRPS)。印度缺乏T2D的遗传流行病学调查。为了响应这一倡议，我们成立了一个新的CRP，包括两个美国机构和三个印度机构，利用来自两个北印度邦和两个南印度邦的谱系数据集，评估四个内婚制种族群体(EEGs)中T2D的遗传决定因素。这一联合实验/发展提案的具体目标详述如下，将由印度或美国合作伙伴或两者共同实现。作为目标1a的一部分，我们将从拉贾斯坦邦(Agarwal EEG)、泰米尔纳德邦(Chettiar EEG)和安得拉邦(Reddy EEG)三个遗传和文化不同的脑电波中招募来自约60个大家庭的1500人；将在T2D先驱身上确定来自20个大家庭(每个家庭25名成员)的500人。来自旁遮普邦的锡克·哈特里人脑电波的家系表型和基因数据已经收集完毕，将用于这项研究。将收集与T2D有关的临床数据和关于环境协变量(例如，饮食和体力活动)的信息(目标1b)。通过AIMS 2a和2b，将进行几项遗传分析，如T2D遗传力的测定，并将在印度人群和美国多民族人群(包括欧洲裔美国人、非裔美国人和墨西哥裔美国人)之间进行与T2D发病机制和病理生理学相关的比较分析。最重要的是，我们将利用旁遮普锡克教徒脑电波家族的样本(N=336)，通过进行有针对性的重测序，追踪先前在包括旁遮普锡克教徒在内的南亚人中发现的8个T2D易感基因座的遗传区域，并评估T2D与通过测序检测到的罕见和低频率变异之间的关联(AIM 3a)。与T2D相关的最好的约200个遗传变异将在额外的4,000名锡克教徒个体样本中得到确认(AIM 3b)。作为目标4的一部分，来自目标3b的最相关的~100个SNPs以及代表来自非印度人群的已建立的T2D易感基因座的~100个遗传变异将在作为目标1的一部分登记的三个脑电组中得到确认。我们的研究将最大限度地利用美国和印度合作团队的专业知识、研究经验和资源，为批判性地检查印度脑电组之间的遗传、社会和文化差异奠定坚实的基础。据我们所知，这是印度和美国第一次合作，应用基于系谱的设计和测序技术来识别与T2D相关的新原因基因和分子途径。

 DESCRIPTION (provided by applicant): Type 2 diabetes (T2D) has become a major public health issue in both India and the United States (US). In consideration of its epidemiological burden and the related population health disparities, there have been continued efforts to understand the factors underlying its phenotypic expression. Given its significance as a binational healthcare problem, the National Institutes of Health (NIH RFA-DK-14-006) and the Indian Council: of Medical Research (ICMR) have come together to announce funding opportunities to support Binational Collaborative Research Partnerships (CRPs) on diabetes research. There is a paucity of genetic epidemiologic investigations of T2D in India. In response to this initiative, we have formed a new CRP involving two US institutions and three Indian institutions to evaluate genetic determinants of T2D among four endogamous ethnic groups (EEGs) using pedigree-based data sets from two North and two South Indian states. The specific aims of this joint experimental/developmental proposal are detailed below, which will be accomplished by Indian or US partners or both of them jointly. As part of Aim 1a, we will recruit 1500 individuals from ~60 large families from three genetically and culturally diverse EEGs from the states of Rajasthan (Agarwal EEG), Tamil Nadu (Chettiar EEG), and Andhra Pradesh (Reddy EEG); 500 individuals from 20 large families (25 members per family) from each EEG will be ascertained on T2D probands. The family- phenotypic- and genotypic data, from a Sikh Khatri EEG from the state of Punjab are already collected and will be available for this study. Clinical data related to T2D and information on environmental covariates (e.g., diet and physical activity) will be collected (Aim 1b). Through Aims 2a and 2b, several genetic analyses will be conducted such as determination of heritability of T2D, and comparative analyses will be performed between Indian populations and the US multi-ethnic populations including European Americans, African Americans, and Mexican Americans as they relate to T2D pathogenesis and pathophysiology. Most importantly, we will pursue genetic regions harboring 8 T2D susceptibility loci previously identified in South Asians including the Punjabi Sikh population by performing targeted resequencing, using samples (N=336) from the Punjabi Sikh EEG families and assess associations between T2D and rare and low frequency variants detected through sequencing (Aim 3a). The best associated ~200 genetic variants with T2D will be confirmed in an additional sample of 4,000 Sikh individuals (Aim 3b). As part of Aim 4, the best associated ~100 SNPs from Aim 3b together with ~100 genetic variants representing the established T2D susceptibility loci from non-Indian populations will be confirmed in the three EEGs enrolled as part of Aim 1. Maximizing the expertise, research experience, and resources of the US and Indian collaborative teams, our study will lay a strong foundation to critically examine genetic, social and cultural differences among the Indian EEGs. To our knowledge, this is the first Indo-US collaborative effort to apply pedigree-based design and sequencing technologies to identify novel causal genes and molecular pathways associated with T2D.