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An Integrative Systems Genetics Approach to Nephrotic Syndrome

肾病综合征的综合系统遗传学方法

基本信息

批准号：
8737893
负责人：
MATTHEW Gordon SAMPSON
金额：
$ 15.34万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-19 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8737893
关键词：
Adverse effects Affect African American Age Age of Onset Alleles American Biochemical Bioinformatics Biological Markers Biology Biopsy Blood Caring Characteristics Child Classification Clinic Clinical Clinical Data Data Set Databases Development Disease Disease Progression Disease remission Elements Excretory function Focal Segmental Glomerulosclerosis Functional RNA Functional disorder Gene Expression Gene Expression Profile Gene Frequency Genes Genetic Genome Genomics Genotype Goals Haplotypes Hereditary Disease Heritability Histologic Immunosuppression Individual Infection Kidney Kidney Diseases Knowledge Learning Mentors Methods Michigan Minor Molecular Morbidity - disease rate Natural History Nephrotic Syndrome Nucleic Acid Regulatory Sequences Other Genetics Outcome Pathogenesis Pathway interactions Patient observation Patients Permeability Pharmaceutical Preparations Phenotype Population Population Genetics Predisposition Prevalence Proteins Proteinuria Quantitative Trait Loci Recruitment Activity Renal function Research Research Personnel Research Project Grants Resources Risk Role Specimen Steroid Resistance Steroids Syndrome System Systems Biology Technology Testing Therapeutic Thromboembolism Time Tissues Training Activity Universities Urine Variant Venous Work base biobank career development clinical Diagnosis clinical care clinical decision-making clinical effect clinical phenotype cohort comparative genomics cost design endophenotype experience functional genomics gene discovery genetic risk factor genetic variant genome wide association study genome-wide improved insight meetings mortality novel programs prospective public health relevance rare variant response therapeutic development therapeutic target trait urinary

项目摘要

DESCRIPTION (provided by applicant): Nephrotic syndrome (NS) is a clinical syndrome of massive proteinuria caused by abnormal glomerular permeability. This proteinuria is accompanied by increased risk of infection, venous thromboembolism, and progressive loss of renal function. Morbidity also results from side effects of nonspecific immunosuppression medications used to treat this disease. The major histologic classifications of primary NS affecting children are minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). It is challenging to provide targeted, individualized care for people at increased risk of, or currently affected by, NS. One strategy to meet this challenge is to more fully understand the genomic underpinnings of NS. This research team is studying a subset of 450 patients of all ages with incident NS recruited into two prospective observational cohorts at the time of renal biopsy. The investigators will first determine the prevalence of variants across the allele frequency spectrum for 20 genes known to cause monogenic forms of steroid-resistant NS (SRNS) and for which genotype-phenotype correlations have been observed previously. The association with clinical outcomes such as age of onset, remission of proteinuria, and decline of renal function will be determined for patients with rare variants in these genes (minor allele frequency <0.5%). The impact on SRNS outcomes from heterozygous rare variants in recessive SRNS genes or rare variants of unknown significance will also be studied, as well as possible contributions from less rare variants (0.5-1%). In addition to characterizing the clinical impact o variants in known SRNS genes, the discovery of novel genes or non-coding, regulatory genomic elements associated with NS will also be sought using an expression quantitative trait loci (eQTL) study. As opposed to a traditional genome-wide association study, the outcome for this eQTL study will be gene expression from the kidney biopsies of NS subjects. Using gene expression as an intermediate endophenotype improves power to detect significant associations and will also directly illuminate biologic pathways that would not have been detected otherwise. Finally, the investigator will continue to work with his collaborators in computational genetics to develop novel, genome-wide methods to identify genes under strong negative selection and to predict the functional impact of variants discovered in sequencing or integrative genomics studies of NS. This will be achieved by integrating genomic and functional characteristics from diverse high quality comparative genomics, population genetics, and disease specific datasets. Throughout this project, the applicant will acquire expertise in conducting integrative genomics research through these analyses and via formal coursework in bioinformatics programming, systems biology, and advanced statistical genetics. Altogether, integrating genomic variants with prospectively collected gene expression, histologic, biochemical, and clinical data will maximize ability to derive mechanistic insight about NS pathogenesis, identify novel biomarkers of risk, therapeutic response, or disease progression, and guide targeted therapeutic development strategies.

描述（由申请人提供）：肾病综合征（Nephrotic syndrome， NS）是由肾小球渗透性异常引起的大量蛋白尿的临床综合征。这种蛋白尿伴随着感染、静脉血栓栓塞和肾功能进行性丧失的风险增加。用于治疗这种疾病的非特异性免疫抑制药物的副作用也会导致发病率。影响儿童的原发性NS的主要组织学分类是微小改变病（MCD）和局灶节段性肾小球硬化（FSGS）。为风险增加的人群提供有针对性的个性化护理是一项挑战，