Genetic Variants in Membranous Nephropathy

Salant, David J.

doi:10.1681/asn.2013020166

Cited by 37 publications

(30 citation statements)

References 19 publications

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“…Interestingly, the disease-associated genotype of PLA2R1 (rs4664308) is the common genotype, which was previously reported (14,30). These associations with relatively common variants, although IMN is a rare disease, raised the hypothesis that the confluence of relatively common polymorphisms in these genes may result in a rare haplotype that confers susceptibility to IMN (29,31). In this study, we assessed, for the first time, the putative association between FCGR3A and FCGR3B CNVs and IMN.…”

Section: Discussionmentioning

confidence: 72%

HLA-DQA1 and PLA2R1 Polymorphisms and Risk of Idiopathic Membranous Nephropathy

Bullich

Ballarín

Oliver³

et al. 2014

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Single nucleotide polymorphisms (SNPs) within HLA complex class II HLA-DQ a-chain 1 (HLA-DQA1) and M-type phospholipase A2 receptor (PLA2R1) genes were identified as strong risk factors for idiopathic membranous nephropathy (IMN) development in a recent genome-wide association study. Copy number variants (CNVs) within the Fc gamma receptor III (FCGR3) locus have been associated with several autoimmune diseases, but their role in IMN has not been studied. This study aimed to validate the association of HLA-DQA1 and PLA2R1 risk alleles with IMN in a Spanish cohort, test the putative association of FCGR3A and FCGR3B CNVs with IMN, and assess the use of these genetic factors to predict the clinical outcome of the disease.Design, settings, participants, & measurements A Spanish cohort of 89 IMN patients and 286 matched controls without nephropathy was recruited between October of 2009 and July of 2012. Case-control studies for SNPs within HLA-DQA1 (rs2187668) and PLA2R1 (rs4664308) genes and CNVs for FCGR3A and FCGR3B genes were performed. The contribution of these polymorphisms to predict clinical outcome and renal function decline was analyzed.Results This study validated the association of these HLA-DQA1 and PLA2R1 SNPs with IMN in a Spanish cohort and its increased risk when combining both risk genotypes. No significant association was found between FCGR3 CNVs and IMN. These results revealed that HLA-DQA1 and PLA2R1 genotype combination adjusted for baseline proteinuria strongly predicted response to immunosuppressive therapy. HLA-DQA1 genotype adjusted for proteinuria was also linked with renal function decline. ConclusionThis study confirms that HLA-DQA1 and PLA2R1 genotypes are risk factors for IMN, whereas no association was identified for FCGR3 CNVs. This study provides, for the first time, evidence of the contribution of these HLA-DQA1 and PLA2R1 polymorphisms in predicting IMN response to immunosuppressors and disease progression. Future studies are needed to validate and identify prognostic markers.

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Section: Discussionmentioning

confidence: 72%

HLA-DQA1 and PLA2R1 Polymorphisms and Risk of Idiopathic Membranous Nephropathy

Bullich

Ballarín

Oliver³

et al. 2014

Clinical Journal of the American Society of Nephrology

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“…Our data support the previous genetic findings that the potential conformational change on the surface of PLA 2 R may not be fully responsible for the generation of autoantibody in patients. 25,29 Our findings have important clinical applications. We have shown that, compared with the full-length PLA 2 R, the 1-3 construct can be obtained at a high level in the HEK 293 cell culture medium and that it is equally efficient to the full-length PLA 2 R for large-scale patient sample screening for autoantibodies.…”

Section: Discussionmentioning

confidence: 73%

Identification of the Immunodominant Epitope Region in Phospholipase A2 Receptor-Mediating Autoantibody Binding in Idiopathic Membranous Nephropathy

Kao

Lam

Waldman

et al. 2015

Journal of the American Society of Nephrology

128

109

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Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults. Recent clinical studies established that .70% of patients with idiopathic (also called primary) MN (IMN) possess circulating autoantibodies targeting the M-type phospholipase A 2 receptor-1 (PLA 2 R) on the surface of glomerular visceral epithelial cells (podocytes). In situ, these autoantibodies trigger the formation of immune complexes, which are hypothesized to cause enhanced glomerular permeability to plasma proteins. Indeed, the level of autoantibody in circulation correlates with the severity of proteinuria in patients. The autoantibody only recognizes the nonreduced form of PLA 2 R, suggesting that disulfide bonds determine the antigenic epitope conformation. Here, we identified the immunodominant epitope region in PLA 2 R by probing isolated truncated PLA 2 R extracellular domains with sera from patients with IMN that contain anti-PLA 2 R autoantibodies. Patient sera specifically recognized a protein complex consisting of the cysteinerich (CysR), fibronectin-like type II (FnII), and C-type lectin-like domain 1 (CTLD1) domains of PLA 2 R only under nonreducing conditions. Moreover, absence of either the CysR or CTLD1 domain prevented autoantibody recognition of the remaining domains. Additional analysis suggested that this three-domain complex contains at least one disulfide bond required for conformational configuration and autoantibody binding. Notably, the three-domain complex completely blocked the reactivity of autoantibodies from patient sera with the full-length PLA 2 R, and the reactivity of patient sera with the three-domain complex on immunoblots equaled the reactivity with full-length PLA 2 R. These results indicate that the immunodominant epitope in PLA 2 R is exclusively located in the CysR-FnII-CTLD1 region.

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“…18,19 Recently, after the identification of membranous nephropathy (MN) -associated common variants in PLA2R1 by the GWAS, Coenen et al 20 convincingly excluded the possibility that rare variants in PLA2R1 are involved in MN pathogenesis. 21 However, for IgAN, although the GWAS identified several diseaseassociated loci and common variants, 7,17,22,23 few studies have focused on rare variants in candidate genes. Here, after screening for variants in the exons, intronic flanking regions, and UTRs of CFHR5, we applied a popular rare variant association test, SKAT, to evaluate the association between variants in CFHR5 and IgAN.…”

Section: Discussionmentioning

confidence: 99%

Rare Variants in the Complement Factor H–Related Protein 5 Gene Contribute to Genetic Susceptibility to IgA Nephropathy

Zhai

Meng

Zhu

et al. 2016

JASN

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A recent genome-wide association study of IgA nephropathy (IgAN) identified 1q32, which contains multiple complement regulatory genes, including the complement factor H (CFH) gene and the complement factor H-related (CFHRs) genes, as an IgAN susceptibility locus. Abnormal complement activation caused by a mutation in CFHR5 was shown to cause CFHR5 nephropathy, which shares many characteristics with IgAN. To explore the genetic effect of variants in CFHR5 on IgAN susceptibility, we recruited 500 patients with IgAN and 576 healthy controls for genetic analysis. We sequenced all exons and their intronic flanking regions as well as the untranslated regions of CFHR5 and compared the frequencies of identified variants using the sequence kernel association test. We identified 32 variants in CFHR5, including 28 rare and four common variants.

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Genetic Variants in Membranous Nephropathy

Cited by 37 publications

References 19 publications

HLA-DQA1 and PLA2R1 Polymorphisms and Risk of Idiopathic Membranous Nephropathy

HLA-DQA1 and PLA2R1 Polymorphisms and Risk of Idiopathic Membranous Nephropathy

Identification of the Immunodominant Epitope Region in Phospholipase A2 Receptor-Mediating Autoantibody Binding in Idiopathic Membranous Nephropathy

Rare Variants in the Complement Factor H–Related Protein 5 Gene Contribute to Genetic Susceptibility to IgA Nephropathy

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