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（由适用提供）：拟议研究的总体目标是通过进行全异位测序，随访的靶向测序以及非洲和欧洲祖先的DN病例中的整个外观测序，进行随访的靶向测序以及重复研究，以确定与糖尿病肾病（DN）相关的新型基因和功能变异。我们将使用下一代技术来对300名非裔美国人（AA）和300名欧美（EA）（EA）慢性肾脏不足智度队列（cric）研究参与者进行300名非裔美国人（AA）和300名欧美（EA）欧美（AA）和300名欧美（EA）的整个外观（包括蛋白质编码区域，外显侧侧翼序列和小型非编码RNA）。 600例CRIC DN病例将包括具有T2D病史的病例，肾小球过滤率降低以及在CRIC基线检查中升高的24小时尿白蛋白排泄，以及最多10年的肾脏功能下降的快速进展。对照组将包括15,487个免费ARIC研究参与者（4,199 AA和11,288 EA），其中包括现有的全外观测序数据（由同一测序平台生成，外来组捕获量，以及用于测序CRIC DN病例的协议）。最先进的统计方法将用于测试AA和EA参与者中遗传变异和DN之间的关联，并针对重要的混杂因素进行调整。我们将对200个最重要的基因进行有针对性的测序，这些基因通过骨料分析和基因型的新型稀有变体进行了3,000个最重要的新型低频和共同变体，而其余772个CRIC DN病例（398 AA和374 EA）中的单标记分析中的共同变体。在所有1,372例CRIC DN病例的验证研究中，新型变体与DN之间的关联将得到验证（来自全异位测序的靶向测序/基因分型 + 600的772例）和15,487 ARIC非DN对照组，通过种族分层。大量的对照样本将使我们能够进行次要分析，将DN病例与T2D和无肾病的对照进行比较，以识别与T2D患者之间与DN的发展相关的基因和变异，T2D和肾病的对照既不是识别T2D和NO note no ne ne ne ne ne ney ney ney ney ne ney ne ney的基因和变体，否则肾脏既不识别T2D的基因和变体，但特异性DN。我们将在大约1,763例DN病例（1,195 AA和568 EA）中复制具有新颖的稀有变体和100种新型低频和100种新型低频和共同变异的基因。复制样本将包括CRIC III期研究参与者以及与T2D遗传探索的现有表型和全外活体测序数据的参与者，该数据是通过下一代测序在多民族样本联盟中进行的，是针对健康和衰老研究的同类，用于基因组流行病学体会中的健康和衰老研究。拟议的工作是及时，有力且具有成本效益的，具有很大的潜力，可以确定与DN相关的新型基因组机制和功能变体。