Whole-exome Sequencing Study of Diabetic Nephropathy

糖尿病肾病全外显子组测序研究

• 批准号: 8818102
• 负责人: Tanika Nicole Kelly
• 金额: $ 52.03万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-21 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8818102
• 关键词: Accounting; African; African American; Age; Aging; Albumins; American; Antihypertensive Agents; Architecture; Atherosclerosis; Bioinformatics; Biological; Chronic Kidney Failure; Chronic Kidney Insufficiency; Clinical; Cohort Studies; Communities; Data; Development; Diabetes Mellitus; Diabetic Nephropathy; End stage renal failure; Epidemiology; European; Excretory function; Exons; Frequencies; Gender; Genes; Genetic; Genetic study; Genomics; Genotype; Glomerular Filtration Rate; Health; Hour; Individual; Injury; Kidney; Kidney Diseases; LDL Cholesterol Lipoproteins; Lipids; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Open Reading Frames; Participant; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenotype; Play; Population; Predisposition; Prevalence; Prevention; Protocols documentation; Public Health Practice; Race; Recording of previous events; Renal function; Research; Risk; Risk Factors; Role; Sampling; Statistical Methods; Technology; Testing; Untranslated RNA; Variant; Women' s Health; Work; case control; cohort; cost effective; diabetes mellitus genetics; exome; exome sequencing; follow-up; gene therapy; genetic variant; innovation; insight; next generation; next generation sequencing; non-diabetic; novel; phase 3 study; public health relevance; rare variant; targeted sequencing; tool; urinary

 DESCRIPTION (provided by applicant): The overall objective of the proposed study is to identify novel genes and functional variants associated with diabetic nephropathy (DN) by conducting whole-exome sequencing, follow-up targeted sequencing, and replication studies among DN cases and controls of African and European ancestry. We will use next-generation technology to sequence the whole-exomes (including protein coding regions, exon flanking sequences, and small non-coding RNAs) of 300 African-American (AA) and 300 European-American (EA) Chronic Renal Insufficiency Cohort (CRIC) study participants. The 600 CRIC DN cases will include those with a history of T2D, reduced glomerular filtration rate, and elevated 24-hour urinary albumin excretion at the CRIC baseline examination, along with rapid progression of kidney function decline in up to 10-years follow-up. Controls will include 15,487 DN free ARIC study participants (4,199 AA and 11,288 EA) with existing whole- exome sequencing data (generated by the same sequencing platform, exome-capture, and protocol used for sequencing CRIC DN cases). State-of-the-art statistical methods will be used to test the association between genetic variants and DN in AA and EA participants, separately, and adjust for important confounding factors. We will conduct targeted sequencing of the 200 most significant genes with novel rare variants from aggregate analyses and genotype the 3,000 most significant novel low-frequency and common variants from single- marker analyses among the remaining 772 CRIC DN cases (398 AA and 374 EA). The associations between the novel variants and DN will be validated in verification study of all 1,372 CRIC DN cases (772 from targeted sequencing/genotyping + 600 from whole-exome sequencing) and 15,487 ARIC non-DN controls, stratified by race. The large sample of controls will allow us to conduct secondary analyses comparing DN cases to controls with T2D and no nephropathy to identify genes and variants related to the development of DN among T2D patients, controls with neither T2D nor nephropathy to identify genes and variants that may initiate T2D and promote kidney injury in healthy individuals, and controls with nephropathy but no T2D to identify genes and variants specific for DN. We will replicate the top 20 genes with novel rare variants and 100 novel low- frequency and common variants from the verification study among approximately 1,763 DN cases (1,195 AA and 568 EA) and 3,159 non-DN controls (1,614 AA and 1,545 EA) in race-stratified analyses. Replication samples will include CRIC Phase III study participants as well as participants with existing phenotype and whole-exome sequencing data from the T2D Genetic Exploration by Next-generation sequencing in multi- Ethnic Samples consortium, the Cohorts for Health and Aging Research in Genomic Epidemiology consortium, and the Women's Health Initiative Sequencing Project. The proposed work is timely, powerful, and cost- effective with great potential to pinpoint novel genomic mechanisms and functional variants related to DN.

 描述(由申请人提供)：拟议研究的总体目标是通过在非洲和欧洲血统的糖尿病肾病患者和对照中进行完整外显子组测序、后续靶向测序和复制研究，确定与糖尿病肾病相关的新基因和功能变异。我们将使用下一代技术对300名非洲裔美国人(AA)和300名欧洲-美国人(EA)慢性肾功能不全队列(CRIC)研究参与者的整个外显子(包括蛋白质编码区、外显子侧翼序列和小的非编码RNA)进行测序。600例CRIC肾病患者将包括那些在CRIC基线检查中有T2D病史、肾小球滤过率降低、24小时尿白蛋白排泄率升高，并在长达10年的随访期内肾功能迅速恶化的患者。对照将包括15,487名无糖尿病肾病的ARIC研究参与者(4,199名AA和11,288名EA)，他们具有现有的完整外显子组测序数据(由相同的测序平台、外显子组捕获和用于对CRIC糖尿病肾病病例进行测序的方案生成)。将使用最先进的统计方法分别测试AA和EA参与者中遗传变异与糖尿病肾病之间的关联，并对重要的混杂因素进行调整。我们将对来自聚合分析的200个具有新的罕见变异的最重要的基因进行有针对性的测序，并在剩余的772例CRIC糖尿病肾病病例(398个AA和374个EA)中，对来自单标记分析的3,000个最重要的新的低频和常见的变异进行基因分型。在对所有1372例CRIC糖尿病肾病病例(772例来自靶向测序/基因分型+600例来自全外显子组测序)和15487例ARIC非糖尿病肾病对照(按种族分层)的验证研究中，将验证新变种与糖尿病肾病之间的相关性。大量对照样本将使我们能够进行二次分析，将糖尿病肾病患者与有T2D和无肾病的对照组进行比较，以确定T2D患者中与糖尿病肾病的发展相关的基因和变异，以确定可能引发T2D并促进健康个体肾脏损伤的基因和变异，以及有肾病但没有T2D的对照，以确定糖尿病肾病特有的基因和变异。在种族分层分析中，我们将复制来自大约1,763例糖尿病肾病患者(1,195例AA和568例EA)和3,159例非糖尿病对照(1,614例AA和1,545例EA)的验证性研究中的前20个具有新的罕见变异和100个新的低频和常见变异的基因。复制样本将包括CRIC第三阶段研究参与者以及拥有现有表型和全外显子组测序数据的参与者，这些数据来自多种族样本中的下一代测序T2D基因探索联合体、基因组流行病学健康和老龄化研究队列联盟以及妇女健康倡议测序项目。拟议的工作是及时的，强大的，具有成本效益的，具有确定与糖尿病肾病相关的新的基因组机制和功能变体的巨大潜力。