Genome, Metabolome, Ancestry and Diabetes Health Disparity

基因组、代谢组、血统和糖尿病健康差异

基本信息

项目摘要

ABSTRACT Our genome-metabolome investigations of type 2 diabetes (T2D) and the associated cardiometabolic (CM) complications are one of the high-priority research areas for the NIH to understand the causes of disparities in health in underserved populations of the US. T2D prevalence is projected to increase from 10% currently to 33% by the year 2050 in the US. South Asians (SAs) are a rapidly growing ethnic minority group, and have a well-documented high predisposition to T2D and cardiovascular diseases. Although it is well known that genetic and environmental factors influence T2D, the underlying mechanisms are poorly characterized in SAs. Recent studies performed in European populations have identified genetic factors influencing metabolite concentrations in patients with a wide spectrum of cardiometabolic diseases using metabolome-wide/genome-wide technologies. However, no such study has ever been performed in any population from India despite the fact that about one in four people in the global population are part of the SA population. Unlike conventional genome-wide association studies (GWAS), the metabolome GWAS (mGWAS) has higher statistical power to capture common genetic variation. Given the promise of the genome-metabolome approaches in elucidating underlying genetic causes for disease, such investigations in other non-white ethnic cohorts are critical to achieve advances in precision medicine. Essentially, such studies will help characterize unique metabolites linked with the “non- obese/metabolically-obese” phenotype of T2D in SAs and others. Therefore in this investigation, using existing resources of already collected family and population-based samples (n=5,250) from the Asian Indian Diabetic Heart Study (AIDHS), our strategy is to cost-effectively integrate phenotypic, metabolomic, and genomic data to investigate the underlying genetic mechanisms regulating T2D pathophysiology. We propose these three specific aims for this proposal: AIM 1: Generate global (untargeted) metabolome profiles to identify and characterize small heritable molecules genetically correlated with T2D and related cardiometabolic traits using GCxGC-MS; AIM 2: Perform mGWAS to identify mQTLs and variants simultaneously associated with T2D, metabolites, and other traits; Replicate association of the top mQTL variants and ~15-20 of most significant metabolites in additional independent SA samples; AIM 3: Determine differences and similarities of putative biomarkers for T2D by performing look-up analysis in US multiethnic families, and perform preliminary functional characterization of a few of the most interesting mQTL loci by using zebrafish and knockout mouse models. OVERALL IMPACT: No comparable study has ever been undertaken in people of Asian Indian descent. With our outstanding team, a unique high-risk homogenous Sikh population, and cost-effective utilization of existing resources, our project has high potential to identify novel biomarkers of therapeutic importance. Of these, some may predict a subtype of T2D risk linked to early onset at lower obesity thresholds in relevance to multi-ethnic US populations.
摘要 我们对2型糖尿病(T2 D)和相关心脏代谢(CM)的基因组-代谢组研究 并发症是NIH了解健康差异原因的高度优先研究领域之一 在美国服务不足的人群中。T2 D患病率预计将从目前的10%增加到33%。 2050年在美国。南亚人(SA)是一个快速增长的少数民族群体,并有充分的记录, 2型糖尿病和心血管疾病易感性高。虽然众所周知,遗传和环境 影响T2 D的因素,其潜在机制在SA中的特征很差。 最近在欧洲人群中进行的研究已经确定了影响代谢物的遗传因素 使用全代谢组/全基因组方法, 技术.然而,从未在印度的任何人群中进行过此类研究, 全球人口中约有四分之一是SA人口的一部分。与传统的全基因组 关联研究(GWAS),代谢组GWAS(mGWAS)具有更高的统计能力,以捕获常见的 遗传变异鉴于基因组-代谢组方法在阐明潜在遗传原因方面的前景 对于疾病,在其他非白人种族群体中进行此类调查对于实现精确度的进步至关重要 药从本质上讲,这些研究将有助于表征与“非代谢物”相关的独特代谢物。 在SA和其他人中的T2 D的“肥胖/代谢性肥胖”表型。 因此在本次调查中,利用现有的资源,以已收集的家庭和人口为基础, 样本(n= 5,250)来自亚洲印度糖尿病心脏研究(AIDHS),我们的策略是成本有效地整合 表型、代谢组学和基因组学数据,以研究调节T2 D的潜在遗传机制 病理生理学我们为这个提议提出了三个具体目标:目标1:生成全局(无目标) 代谢组谱,以鉴定和表征与T2 D和相关疾病遗传相关的小遗传分子 使用GCxGC-MS的心脏代谢性状; AIM 2:进行mGWAS以同时鉴定mQTL和变体 与T2 D、代谢物和其他性状相关;顶部mQTL变体的重复关联和大多数mQTL变体的约15-20个重复关联。 其他独立SA样本中的显著代谢物;目的3:确定推定的 通过在美国多种族家庭中进行查找分析, 通过使用斑马鱼和基因敲除小鼠模型表征一些最有趣的mQTL基因座。 总体影响:在亚洲印度裔人群中从未进行过类似的研究。与我们 杰出的团队,独特的高风险同质锡克教人口,以及对现有资源的成本效益利用, 我们的项目具有很高的潜力,以确定新的生物标志物的治疗重要性。其中,有些人可能会预测, 与多种族美国人群相关的T2 D风险亚型与较低肥胖阈值下的早发性相关。

项目成果

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RAVINDRANATH DUGGIRALA其他文献

RAVINDRANATH DUGGIRALA的其他文献

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{{ truncateString('RAVINDRANATH DUGGIRALA', 18)}}的其他基金

Genome, Metabolome, Ancestry and Diabetes Health Disparity
基因组、代谢组、血统和糖尿病健康差异
  • 批准号:
    10241268
  • 财政年份:
    2019
  • 资助金额:
    $ 61.01万
  • 项目类别:
Genetics of Type 2 Diabetes in Indian Populations: US-India Collaboration Project
印度人群 2 型糖尿病的遗传学:美印合作项目
  • 批准号:
    9258433
  • 财政年份:
    2016
  • 资助金额:
    $ 61.01万
  • 项目类别:
Genetics of Type 2 Diabetes in Indian Populations: US-India Collaboration Project
印度人群 2 型糖尿病的遗传学:美印合作项目
  • 批准号:
    8929918
  • 财政年份:
    2016
  • 资助金额:
    $ 61.01万
  • 项目类别:
The Metabolic Syndrome in Mexican American Children
墨西哥裔美国儿童的代谢综合症
  • 批准号:
    7935117
  • 财政年份:
    2009
  • 资助金额:
    $ 61.01万
  • 项目类别:
The Metabolic Syndrome in Mexican American Children
墨西哥裔美国儿童的代谢综合症
  • 批准号:
    7570683
  • 财政年份:
    2005
  • 资助金额:
    $ 61.01万
  • 项目类别:
The Metabolic Syndrome in Mexican American Children
墨西哥裔美国儿童的代谢综合症
  • 批准号:
    7365259
  • 财政年份:
    2005
  • 资助金额:
    $ 61.01万
  • 项目类别:
The Metabolic Syndrome in Mexican American Children
墨西哥裔美国儿童的代谢综合症
  • 批准号:
    6876383
  • 财政年份:
    2005
  • 资助金额:
    $ 61.01万
  • 项目类别:
The Metabolic Syndrome in Mexican American Children
墨西哥裔美国儿童的代谢综合症
  • 批准号:
    7024501
  • 财政年份:
    2005
  • 资助金额:
    $ 61.01万
  • 项目类别:
The Metabolic Syndrome in Mexican American Children
墨西哥裔美国儿童的代谢综合症
  • 批准号:
    7189139
  • 财政年份:
    2005
  • 资助金额:
    $ 61.01万
  • 项目类别:
Genetics of Birth Weight in Mexican Americans
墨西哥裔美国人出生体重的遗传学
  • 批准号:
    6536421
  • 财政年份:
    2001
  • 资助金额:
    $ 61.01万
  • 项目类别:

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Drug Abuse and Crime Across the Life Course in an African American Population
非裔美国人一生中的药物滥用和犯罪
  • 批准号:
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  • 财政年份:
    2008
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    $ 61.01万
  • 项目类别:
Drug Abuse and Crime Across the Life Course in an African American Population
非裔美国人一生中的药物滥用和犯罪
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Drug Abuse and Crime Across the Life Course in an African American Population
非裔美国人一生中的药物滥用和犯罪
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Drug Abuse and Crime Across the Life Course in an African American Population
非裔美国人一生中的药物滥用和犯罪
  • 批准号:
    7586197
  • 财政年份:
    2008
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    $ 61.01万
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Molecular and Genetic Signatures of Perturbed Diabetic Pathways with Hepatitis C Virus infection and Co-morbidity Risks in African American Population
丙型肝炎病毒感染引起的糖尿病通路紊乱的分子和遗传特征以及非洲裔美国人的共病风险
  • 批准号:
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  • 财政年份:
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    $ 61.01万
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Molecular and Genetic Signatures of Perturbed Diabetic Pathways with Hepatitis C Virus infection and Co-morbidity Risks in African American Population
丙型肝炎病毒感染引起的糖尿病通路紊乱的分子和遗传特征以及非洲裔美国人的共病风险
  • 批准号:
    10331060
  • 财政年份:
    1997
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    $ 61.01万
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Molecular and Genetic Signatures of Perturbed Diabetic Pathways with Hepatitis C Virus infection and Co-morbidity Risks in African American Population
丙型肝炎病毒感染引起的糖尿病通路紊乱的分子和遗传特征以及非洲裔美国人的共病风险
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Molecular and Genetic Signatures of Perturbed Diabetic Pathways with Hepatitis C Virus infection and Co-morbidity Risks in African American Population
丙型肝炎病毒感染引起的糖尿病通路紊乱的分子和遗传特征以及非洲裔美国人的共病风险
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    10178913
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