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（通过应用程序证明）：支撑研究的总体目标是通过进行全异位测序，对非洲和欧洲血统的靶向测序来确定与Betic肾病（DN）相关的新型基因和功能差异为300名非裔美国人（AA）和300名欧美（EA）慢性肾脏肾功能不全队列（CRIC）研究参与者，对整个外观和小型非编码RNA进行序列的下一代。 T2D痕量率和在CRIC基线检查中升高24小时尿白蛋白的排泄，以及肾功能的快速进展下降了10年的随访（由同一测序产生用于测序CRIC DN病例的平台，外部捕获和协议（分别为NDE EA参与者，并针对重要的共同因素进行调整。我们将进行有针对性的测序，以200个最重要的基因进行测序，并具有稀有变体的一致性分析和基因型的稀有变体。在其余772个Cric DN病例中，来自单标记分析的3000个最重要的新型低颤音和mon变体（398 aa和374 EA）在所有1,372例CRIC DN的验证研究中均具有新型变体和DN的关联。通过种族分层的靶向测序 + 600和15,487个ARIC非DN对照。 T2D患者的DN发育，T2D和肾病的对照识别可能启动T2D并促进健康个体的肾脏损伤的基因和变异，并且具有肾病的对照，但不能识别特定于DN的基因和变体。在大约1,763例DN病例中，有20种带有NOVEL的基因和100种新型低频和常见的变异除了在多种族样本中进行表型和全面测序的参与者，他的女性健康计划测序项目是及时的，有力的，具有更大的可能性与DN相关的变体。