IgA nephropathy (IgAN) is characterized by mesangial IgA1 immune deposits that originate from circulating immune complexes containing aberrantly-glycosylated IgA1, i.e., IgA1 with galactose-deficient O-glycans (Gd- IgA1). Several lines of evidence suggest a direct causal relationship between aberrant glycosylation, the formation of immune complexes containing aberrantly glycosylated IgA1, their deposition in the mesangium, and renal injury in IgAN. We have now localized the primary defect to IgA1-secreting cells from IgAN patients and our preliminary data indicate that serum Gd-IgA1 levels are a highly heritable biomarker of IgAN. Our initial genetic studies have identified two genomic regions that influence this trait in IgAN. Preliminary genome-wide expression profiling has demonstrated that 65% of the genes from these two chromosomal intervals are expressed in IgA1-producing cell lines with 19 of them being differentially expressed in cells that produce Gd-IgA1. We hypothesize that a high level of serum Gd-IgA1 defines an endophenotype that can be used to identify the genetic basis for this disease. We have established a standardized sensitive technique for high through-put analysis of Gd-IgA1 in the serum;IgA1-secreting cell lines from patients with IgAN and healthy controls that permit confirmation of genetic defects with molecular effects in vitro;and extensive collaborations that provide access to well-characterized IgAN patients and disease controls. We therefore propose to further establish the sensitivity and specificity of the serum Gd-IgA1 test in multiple existing independent cohorts, and, using genetic and biochemical studies, determine the contribution of the identified loci to the sporadic and familial forms of IgAN. We will then prioritize genes within these two linkage intervals by gene expression analysis and functional studies in our IgA1-producing cell lines. Finally, we will stratify cases and controls by Gd-IgA1 levels and perform genetic association studies to identify IgAN susceptibility alleles. Relevance: IgAN is the most common primary glomerulonephritis and leads to loss of renal function in 20% to 40% of patients. Our current inability to describe the pathogenesis of IgAN at the molecular level is a major barrier to the development of IgAN-specific treatments. The proposed studies will provide the foundation for the future development and testing of disease-specific interventions and advance the quality of care for IgAN patients.

Public Health Relevance

IgAN is the most common primary glomerulonephritis. It has been established that the production of aberrantly glycosylated IgA1 is a pivotal pathogenic feature. The proposed genetic and biochemical studies of the mechanisms that result in the production of this aberrantly glycosylated IgA1 will identify the factors that result in the development of IgAN and, thus, lay the basis for the development of effective therapies.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Special Emphasis Panel (ZRG1-RUS-C (03))
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Moxey-Mims, Marva M
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University of Alabama Birmingham
Schools of Medicine
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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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