Immunoglobulin A Nephropathy (IgAN) is a major cause of kidney disease worldwide and the leading cause of end stage renal disease (ESRD) among Asians. The affected individuals develop IgA1-containing antibody complexes that deposit in the kidney producing tissue injury. An increased serum level of galactose- deficient IgA1 (Gd-IgA1) has emerged as a useful biomarker of IgAN. Gd-IgA1 promotes formation and kidney deposition of IgA1-containing immune complexes, but the reason why IgAN patients have high Gd-IgA1 is not well understood. We have formed a multidisciplinary team of experienced investigators in order to accelerate the discovery of pathogenic mechanisms in IgAN. Through our collaborative efforts, we have already made significant contributions to the field, including the identification of the first Mendelian mutation that affects production of Gd-IgA1 and causes familial IgAN. We also completed a large genome-wide association study of IgAN involving 20,574 individuals and identified 15 common susceptibility alleles associated with disease risk. We observed that the worldwide distribution of common alleles closely parallels the disease epidemiology and that a burden of inherited risk alleles correlates with the age of disease onset. Our findings identify intestinal immunity as the key pathway involved in the disease pathogenesis. In this proposal, we hypothesize that both common and rare genetic variants contribute to the pathogenesis of IgAN and that these variants induce discrete lesions in innate and adaptive immunity, which inexorably lead to the development of kidney injury. We will leverage a large, well-characterized cohort of patients to define the biological and clinical impact of known risk variants and apply exome sequencing to define new genes underlying IgAN. The first part of this proposal will relate the newly discovered genetic factors to immunologic disease features, specific kidney biopsy findings, and clinical parameters of disease severity and progression. These studies are expected to refine the pathogenesis model and will be critical in enhancing the diagnosis and classification of IgAN. The second part of the proposal aims to define additional rare mutations with large effect underlying familial IgAN. Our innovative gene mapping strategy combines family screening for elevated serum Gd-IgA1 levels with exome sequencing to efficiently identify segregating pathogenic variants. We will perform functional analysis of candidate genes using knockdown and overexpression in IgA1-producing cell lines. Finally, we will aim to identify independent pathogenic mutations by sequencing of sporadic individuals with extreme values of Gd-IgA1 levels.
Successful completion of the proposed studies will identify novel mutations underlying the disease, refine the pathogenesis model of IgAN, and provide the knowledge necessary to translate our new genetic discoveries into clinical applications.
|Reily, Colin; Rizk, Dana V; Julian, Bruce A et al. (2018) Assay for galactose-deficient IgA1 enables mechanistic studies with primary cells from IgA nephropathy patients. Biotechniques 65:71-77|
|Hastings, M Colleen; Bursac, Zoran; Julian, Bruce A et al. (2018) Life Expectancy for Patients From the Southeastern United States With IgA Nephropathy. Kidney Int Rep 3:99-104|
|Placzek, William J; Yanagawa, Hiroyuki; Makita, Yuko et al. (2018) Serum galactose-deficient-IgA1 and IgG autoantibodies correlate in patients with IgA nephropathy. PLoS One 13:e0190967|
|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|
|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|
|Sanders, John T; Hastings, M Colleen; Moldoveanu, Zina et al. (2017) Serial Galactose-Deficient IgA1 Levels in Children with IgA Nephropathy and Healthy Controls. Int J Nephrol 2017:8210641|
|Renfrow, Matthew B; Novak, Jan (2017) What insights can proteomics give us into IgA nephropathy (Berger's disease)? Expert Rev Proteomics 14:645-647|
|Maixnerova, Dita; Reily, Colin; Bian, Qi et al. (2016) Markers for the progression of IgA nephropathy. J Nephrol 29:535-41|
|Xie, Jingyuan; Kiryluk, Krzysztof; Li, Yifu et al. (2016) Fine Mapping Implicates a Deletion of CFHR1 and CFHR3 in Protection from IgA Nephropathy in Han Chinese. J Am Soc Nephrol 27:3187-3194|
|Neprasova, Michaela; Maixnerova, Dita; Novak, Jan et al. (2016) Toward Noninvasive Diagnosis of IgA Nephropathy: A Pilot Urinary Metabolomic and Proteomic Study. Dis Markers 2016:3650909|
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