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.

Public Health Relevance

Primary nephrotic syndrome (NS) is a rare kidney disease caused by abnormal urinary excretion of protein that causes morbidity and mortality due to the disease itself as well as the non-specific, immunomodulatory medications used to try to treat it. This proposal aims to identify the clinical effects for individuals who have known genetic causes of NS while also discovering new genetic risk factors for NS. The ultimate goal of this work is to use increased knowledge of the genetic influences of NS to learn about the abnormal biology that causes NS to occur or progress, identify novel biomarkers to help direct clinical care, and identify genes and pathways for the development of targeted therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08DK100662-01
Application #
8616906
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2013-09-19
Project End
2016-06-30
Budget Start
2013-09-19
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$153,360
Indirect Cost
$11,360
Name
University of Michigan Ann Arbor
Department
Pediatrics
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Ng, Derek K; Robertson, Catherine C; Woroniecki, Robert P et al. (2017) APOL1-associated glomerular disease among African-American children: a collaboration of the Chronic Kidney Disease in Children (CKiD) and Nephrotic Syndrome Study Network (NEPTUNE) cohorts. Nephrol Dial Transplant 32:983-990
Crawford, Brendan D; Gillies, Christopher E; Robertson, Catherine C et al. (2017) Evaluating Mendelian nephrotic syndrome genes for evidence for risk alleles or oligogenicity that explain heritability. Pediatr Nephrol 32:467-476
Robertson, Catherine C; Gillies, Christopher E; Putler, Rosemary K B et al. (2017) An investigation of APOL1 risk genotypes and preterm birth in African American population cohorts. Nephrol Dial Transplant 32:2051-2058
Sampson, Matthew G (2016) Actualizing the Benefits of Genomic Discovery in Pediatric Nephrology. J Pediatr Genet 5:69-75
Sampson, Matthew G; Robertson, Catherine C; Martini, Sebastian et al. (2016) Integrative Genomics Identifies Novel Associations with APOL1 Risk Genotypes in Black NEPTUNE Subjects. J Am Soc Nephrol 27:814-23
Gillies, Christopher E; Otto, Edgar A; Vega-Warner, Virginia et al. (2016) tarSVM: Improving the accuracy of variant calls derived from microfluidic PCR-based targeted next generation sequencing using a support vector machine. BMC Bioinformatics 17:233
Sampson, Matthew G; Gillies, Christopher E; Robertson, Catherine C et al. (2016) Using Population Genetics to Interrogate the Monogenic Nephrotic Syndrome Diagnosis in a Case Cohort. J Am Soc Nephrol 27:1970-83
Gillies, Christopher E; Robertson, Catherine C; Sampson, Matthew G et al. (2015) GeneVetter: a web tool for quantitative monogenic assessment of rare diseases. Bioinformatics 31:3682-4
Spinale, Joann M; Mariani, Laura H; Kapoor, Shiv et al. (2015) A reassessment of soluble urokinase-type plasminogen activator receptor in glomerular disease. Kidney Int 87:564-74
Sampson, Matthew G; Hodgin, Jeffrey B; Kretzler, Matthias (2015) Defining nephrotic syndrome from an integrative genomics perspective. Pediatr Nephrol 30:51-63; quiz 59

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