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

 描述（由申请人提供）：2型糖尿病（T2D）已成为印度和美国（US）的主要公共卫生问题。考虑到其流行病学负担和相关的人口健康差异，一直在继续努力了解其表型表达的潜在因素。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）和印度医学研究理事会（ICMR）共同宣布资助机会，以支持两国糖尿病研究合作伙伴关系（CRP）。印度缺乏T2D的遗传流行病学调查。为了响应这一倡议，我们已经形成了一个新的CRP涉及两个美国机构和三个印度机构，以评估T2D的遗传决定因素之间的四个同族通婚的民族（EEG）使用基于谱系的数据集，从两个北印度和两个南印度国家。这一联合试验/开发提案的具体目标详述如下，将由印度或美国合作伙伴或双方共同完成。作为目标1a的一部分，我们将从来自拉贾斯坦邦（Agarwal EEG）、泰米尔纳德邦（Chettiar EEG）和安得拉邦（Reddy EEG）的三个遗传和文化多样的EEG的约60个大家庭招募1500名个体;将从每个EEG的20个大家庭（每个家庭25名成员）中确定500名个体为T2 D先证者。已经收集了来自旁遮普州锡克教Khatri EEG的家族表型和基因型数据，并将用于本研究。与T2D相关的临床数据和环境协变量的信息（例如，饮食和体力活动）（目标1b）。通过目标2a和2b，将进行几项遗传分析，如确定T2D的遗传性，并在印度人群和美国多种族人群（包括欧洲裔美国人、非洲裔美国人和墨西哥裔美国人）之间进行比较分析，因为它们与T2D发病机制和病理生理学有关。最重要的是，我们将使用来自旁遮普锡克教EEG家族的样本（N = 336），通过进行靶向重测序，追踪先前在南亚人（包括旁遮普锡克教人群）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变异之间的关联（Aim 3a）。与T2D最相关的约200种遗传变异将在另外4，000名锡克教徒个体的样本中得到证实（目标3b）。作为目标4的一部分，将在作为目标1的一部分入组的3个EEG中确认来自目标3b的最佳相关的~100个SNP以及代表来自非印度人群的已确立T2D易感性基因座的~100个遗传变异。最大限度地发挥美国和印度合作团队的专业知识，研究经验和资源，我们的研究将奠定坚实的基础，批判性地研究印度脑电图之间的遗传，社会和文化差异。据我们所知，这是第一个印度-美国合作努力，应用基于谱系的设计和测序技术，以确定与T2D相关的新的致病基因和分子途径。

 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.