Interaction between PLA2R1 and HLA-DQA1 Variants Associates with Anti-PLA2R Antibodies and Membranous Nephropathy

Lv, Jicheng; Hou, Weimin; Zhou, Xu‐Jie; Liu, Gang; Zhou, Fu-de; Zhao, Na; Hou, Ping; Zhao, Ming‐Hui; Zhang, Hong

doi:10.1681/asn.2012080771

Cited by 135 publications

(166 citation statements)

References 20 publications

(23 reference statements)

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“…Our study provides additional support to the previously found associations between IMN and common coding and noncoding variants within PLA2R1 and HLA-DQA1 genes (14,18,19,29). 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).…”

Section: Discussionsupporting

confidence: 89%

“…Recently, Lv et al (30) found that 73% of individuals carrying these IMN susceptibility genotypes had anti-PLA2R antibodies, whereas these antibodies were absent in all carriers of the protective genotypes. In our cohort, immunosuppressive therapy was more effective in patients carrying the IMN susceptibility genotype combination, likely by decreasing anti-PLA2R levels.…”

Section: Discussionmentioning

confidence: 99%

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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: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

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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“…shown that, the antibody titres disappear with remission and reappear with disease relapses (8,13,14,17,18,(27)(28)(29)(30)(31)(32). Moreover, anti-PLA 2 R levels were in direct proportion to proteinuria and serum albumin levels.…”

Section: Discussionmentioning

confidence: 91%

Anti-phospholipase A2 receptor antibody in membranous nephropathy; an Indian experience

Yachha¹,

Sharma²,

Mehrotra³

et al. 2017

J Renal Inj Prev

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“…9 All three SNPs within PLA2R1 were highly associated with MN, and the strongest signal emerged from the same SNP (rs4664308) identified in the European GWAS. The HLA-DQA1 SNP (rs2187668) also showed association with MN, whereas two other HLA-located SNPs showed no such association with disease.…”

mentioning

confidence: 80%

Can Genetics Risk-Stratify Patients with Membranous Nephropathy?

Bomback

Gharavi

2013

Journal of the American Society of Nephrology

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Membranous nephropathy (MN) is the leading cause of primary nephrotic syndrome in white adults and a major cause of nephrotic syndrome across global populations. In MN, circulating antibodies permeate the glomerular basement membrane and, in the subepithelial space, form immune complexes with antigens on podocyte membranes. Recently, the M-type phospholipase A 2 receptor (PLA 2 R) was identified as the specific podocyte antigen responsible for eliciting immune complex formation with circulating antibodies. Anti-PLA 2 R antibodies are detected in 60%-75% of idiopathic MN cases across many ethnicities. 1,2 Additional podocyte autoantigens-mitochondrial SOD 2, aldose reductase, a-enolase, and neutral endopeptidase 3,4 -have likewise emerged as potential targets of MN-specific autoantibodies, potentially filling in the missing gaps in PLA 2 R antibody-negative disease. These breakthroughs have established MN as a disease of autoantibodies and, in many ways, challenge the continued use of the term idiopathic MN. 5 Nonetheless, we still do not know why, exactly, such autoantibodies develop in MN. The identified podocyte antigens are endogenously expressed; only the autoantibodies against such antigens are detected in patients with MN.Previous case reports of familial forms of MN have suggested a genetic predisposition to disease. 6 In a recent genomewide association study (GWAS) in three European populations (French, Dutch, and British), Stanescu et al. described associations of MN with the HLA locus on chromosome 6p21 and the PLA2R1 locus (encoding PLA 2 R) on chromosome 2q24. 7 The association with HLA was significant in all three patient samples, whereas the association with PLA2R1 was significant in the Dutch and British samples (as well as in joint analysis of all three populations). Strikingly, whereas the risk of disease was relatively modest in individuals with risk alleles at any one locus, the odds ratio for MN was an astronomical 78.5 (95% confidence interval [95% CI], 34.6 to 178.2) in individuals homozygous for risk alleles at both loci, indicative of strong genetic interaction. This GWAS was thus unusual because the effect sizes imparted by the combined risk alleles were very large, suggesting a potential role for genetics for noninvasive screening or risk stratification of MN. This study also provided an independent line of evidence implicating PLA2R1 in the pathogenesis of disease, suggesting that sequence variants within PLA2R1 may alter expression or function of PLA 2 R, potentially unmasking it as an autoantigen that, in conjunction with the right MHC haplotype, results in activation of T cells and stimulation of autoantibody production. Limitations of this GWAS included the relatively small sample size, which precluded precise localization of the risk alleles within each locus. Particularly, the origin of the signal within the MHC locus remained unclear, 8 because this region has a very complicated structure, and class I and class II response loci may each contain multiple independent haplotypes wi...

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Interaction between PLA2R1 and HLA-DQA1 Variants Associates with Anti-PLA2R Antibodies and Membranous Nephropathy

Cited by 135 publications

References 20 publications

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

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

Anti-phospholipase A2 receptor antibody in membranous nephropathy; an Indian experience

Can Genetics Risk-Stratify Patients with Membranous Nephropathy?

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