IgA Nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide and the leading cause of renal failure in East Asia. The affected individuals develop characteristic IgA1-containing antibody complexes that deposit in the kidney, producing progressive renal injury. The disease is associated with a specific pathogenic defect in the O-glycosylation of IgA1 that promotes formation of immune complexes. Similar to other immune-mediated disorders, IgAN has a complex genetic architecture. In a recent GWAS involving 20,574 individuals, we identified 15 genome-wide significant susceptibility loci for IgAN. Our new loci implicated both adaptive and innate immunity in the disease pathogenesis and defined the Network of Intestinal IgA Production as the key pathogenic disease pathway. Based on our results, we developed an original multi-hit pathogenesis model that describes sequential steps and molecular candidates involved in the development of the disease. In this application, we propose to further refine this model by defining additional genetic hits involved in the defective regulation of mucosal IgA response. We specifically aim to discover additional IgAN susceptibility loci by a quantitative GWAS for serum levels for IgA and galactose-deficient IgA1 (Gd-IgA1). The GWAS discovery phase will include a well-powered multi-ethnic population-based cohort of 9,707 individuals. New genome-wide significant loci will be replicated independently and annotated using existing datasets and public resources. Next, through integrative network-based analyses, we will dissect precise pathogenic mechanisms behind each of the GWAS risk alleles. We will use a systems genetics approach that integrates RNA-seq and SNP microarray data to reconstruct gene regulatory networks in IgA1 secreting cells. Based on our network analyses, we will define master regulators and key drivers of the disease process. Our network predictions will be validated using experimental, computational, and genetic approaches. These studies are expected to refine the disease pathogenesis model and will be critical in defining potential targets for novel therapeutic interventions in IgAN.

Public Health Relevance

Genetics of IgA nephropathy by integrative network-based association studies Narrative: IgA nephropathy is the most common form of primary glomerulonephritis worldwide and a major contributor to the global burden of end stage kidney disease. This project aims to discover new susceptibility genes for IgA nephropathy using a systems biology approach. The proposal integrates genome-wide association studies of intermediate phenotypes, network-based transcriptomic analysis of IgA1-secreting cells, and focused cell culture-based validation experiments. The proposed studies will provide new insights into the genetic regulation of IgA production and identify potential targets for therapeutc interventions in IgA nephropathy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK105124-01
Application #
8863093
Study Section
Kidney, Nutrition, Obesity and Diabetes (KNOD)
Program Officer
Rasooly, Rebekah S
Project Start
2015-06-17
Project End
2020-03-31
Budget Start
2015-06-17
Budget End
2016-03-31
Support Year
1
Fiscal Year
2015
Total Cost
$437,668
Indirect Cost
$134,858
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Polubriaginof, Fernanda C G; Vanguri, Rami; Quinnies, Kayla et al. (2018) Disease Heritability Inferred from Familial Relationships Reported in Medical Records. Cell 173:1692-1704.e11
Backenroth, Daniel; He, Zihuai; Kiryluk, Krzysztof et al. (2018) FUN-LDA: A Latent Dirichlet Allocation Model for Predicting Tissue-Specific Functional Effects of Noncoding Variation: Methods and Applications. Am J Hum Genet 102:920-942
Son, Jung Hoon; Xie, Gangcai; Yuan, Chi et al. (2018) Deep Phenotyping on Electronic Health Records Facilitates Genetic Diagnosis by Clinical Exomes. Am J Hum Genet 103:58-73
Kiryluk, Krzysztof; Bomback, Andrew S; Cheng, Yim-Ling et al. (2018) Precision Medicine for Acute Kidney Injury (AKI): Redefining AKI by Agnostic Kidney Tissue Interrogation and Genetics. Semin Nephrol 38:40-51
Liu, Lili; Kiryluk, Krzysztof (2018) Insights into CKD from Metabolite GWAS. J Am Soc Nephrol 29:1349-1351
Sanna-Cherchi, Simone; Khan, Kamal; Westland, Rik et al. (2017) Exome-wide Association Study Identifies GREB1L Mutations in Congenital Kidney Malformations. Am J Hum Genet 101:789-802
Lopez-Rivera, Esther; Liu, Yangfan P; Verbitsky, Miguel et al. (2017) Genetic Drivers of Kidney Defects in the DiGeorge Syndrome. N Engl J Med 376:742-754
Kiryluk, Krzysztof; Li, Yifu; Moldoveanu, Zina et al. (2017) GWAS for serum galactose-deficient IgA1 implicates critical genes of the O-glycosylation pathway. PLoS Genet 13:e1006609
Mladkova, Nikol; Kiryluk, Krzysztof (2017) Genetic Complexities of the HLA Region and Idiopathic Membranous Nephropathy. J Am Soc Nephrol 28:1331-1334
Yamada, Koshi; Huang, Zhi-Qiang; Raska, Milan et al. (2017) Inhibition of STAT3 Signaling Reduces IgA1 Autoantigen Production in IgA Nephropathy. Kidney Int Rep 2:1194-1207

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