The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis

Xie, Jingyuan; Liu, Huan; Mladkova, Nikol; Li, Yifu; Ren, Hong; Wang, Weiming; Cui, Zhao; Li, Lin; Hu, Xiaofan; Yu, Xiaofeng; Xu, Jing; Liu, Gang; Çalışkan, Yaşar; Sidore, Carlo; Balderes, Olivia; Rosen, Raphael J.; Bodria, Monica; Zanoni, Francesca; Zhang, Jun Y.; Krithivasan, Priya; Mehl, Karla; Marasà, Maddalena; Khan, Atlas; Ozay, Fatih; Canetta, Pietro A.; Bomback, Andrew S.; Appel, Gerald B.; Sanna‐Cherchi, Simone; Sampson, Matthew G.; Mariani, Laura; Perkowska‐Ptasińska, Agnieszka; Durlik, Magdalena; Mucha, Krzysztof; Moszczuk, Barbara; Foroncewicz, Bartosz; Pączek, Leszek; Habura, Ireneusz; Ars, Elisabet; Ballarín, J.; Mani, Laila Yasmin; Vogt, Bruno; Öztürk, Savaş; Yıldız, Abdülmecit; Seyahi, Nurhan; Arıkan, Hakkı; Koç, Mehmet; Baştürk, Taner; Karahan, Gonca E.; Akgül, Sebahat; Sever, Mehmet Şükrü; Zhang, Dan; Santoro, Domenico; Bonomini, Mario; Lotti, Francesco; Gesualdo, Loreto; Reiterová, Jana; Tesař, Vladimı́r; Izzi, Claudia; Savoldi, Silvana; Spotti, D.; Marcantoni, Carmelita; Messa, Piergiorgio; Galliani, Marco; Roccatello, Dario; Granata, Simona; Zaza, Gianluigi; Lugani, Francesca; Ghiggeri, Gian Marco; Pisani, Isabella; Allegri, Landino; Sprangers, Ben; Park, Jin Ho; Cho, Belong; Kim, Yon Su; Suzuki, Hitoshi; Amoroso, Antonio; Cattran, Daniel C.; Fervenza, Fernando C.; Pani, Antonello; Hamilton, Patrick; Harris, S.D.; Gupta, Sanjana; Cheshire, Chris; Dufek, Stephanie; Issler, Naomi; Pepper, Ruth J.; Connolly, John; Powis, Stephen H.; Böckenhauer, Detlef; Stanescu, Horia; Ashman, Neil; Loos, Ruth J.F.; Kenny, Eimear E.; Wuttke, Matthias; Eckardt, Kai Uwe; Köttgen, Anna; Hofstra, Julia M.; Coenen, Marieke J. H.; Kiemeney, Lambertus A.; Akilesh, Shreeram; Kretzler, Matthias; Beck, Lawrence H.; Stengel, Bénédicte; Dębiec, Hanna; Ronco, Pierre; Wetzels, Jack F.M.; Żołędziewska, Magdalena; Cucca, Francesco; Ionita‐Laza, Iuliana; Lee, Hajeong; Hoxha, Elion; Stahl, Rolf A.K.; Brenchley, Paul; Scolari, Francesco; Zhao, Ming; Gharavi, Ali G.; Kleta, Robert; Chen, Nan; Kiryluk, Krzysztof

doi:10.1038/s41467-020-15383-w

Cited by 156 publications

(168 citation statements)

References 63 publications

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“…None of the risk allotypes remained significant after controlling for the 2 HLA-D lead SNPs (not shown). These results are consistent with the recent analysis of classical HLA-D allotypes showing that HLA-DQA1*05:01 was the most strongly associated risk allotypes in Europeans, followed by DRB1*03:01 that remained genome-wide significant after conditioning on HLA-DQA1*05:01 16 .…”

Section: J O U R N a L P R E -P R O O Fsupporting

confidence: 92%

“…These two lead SNPs are located in different haplotype blocks, separated by a recombination hotspot in intron 1. These results obtained by NGS of the PLA2R1 locus are suggestive of a second risk haplotype that has not been revealed by large GWAS studies 16 .…”

Section: Logistic Regression Analysis Revealed a Second Snp Rs130189mentioning

confidence: 62%

“…At the HLA-D locus, the SNP most significantly associated with disease was rs9271188 (P=8.1×10 -18 , odds ratio [OR], 3.45; 95% confidence interval [CI], 2.6-4.6), localized between HLA-DRB1 and HLA-DQA1 genes. This SNP is in low LD (r 2 = 0.33) with the lead SNP rs2187668 located in intron 1 of HLA-DQA1 previously identified as disease-associated in the first GWAS 14 , and in high LD (r 2 = 0.71) with the lead SNP rs9271541 located between HLA-DRB1 and HLA-DQA1 genes identified in Europeans by the latest GWAS 16 , (Table S1).…”

Section: Identification Of Pmn-associated Snps and Hla-d Allotypesmentioning

confidence: 76%

“…At the PLA2R1 locus, the SNP most significantly associated with disease risk was rs6726925 (P=5.7×10 -11 , OR, 2.48; CI, 1.9-3.3), localized in intron 4. This lead SNP is in low LD (r 2 = 0.30) with the lead SNP rs4664308, located in intron 1, previously identified as diseaseassociated in the first GWAS 14 and with the lead SNP rs17831251, also located in intron 1 identified in both East Asian and European ethnicities by the latest GWAS 16 , (Table S2).…”

Section: Logistic Regression Analysis Revealed a Second Snp Rs927508mentioning

confidence: 84%

“…In addition to those mostly non-coding SNPs, classical HLA-D allotypes that code for histocompatibility class II molecules are at risk for pMN. A J o u r n a l P r e -p r o o f recent trans-ethnic GWAS meta-analysis of 3,782 cases of pMN and 9,038 controls reported ancestry-specific effects of three classical HLA alleles: DRB1*15:01 in East Asians, DQA1* 05:01 in Europeans, and DRB1*03:01 in both ethnicities 16 . Of note, PLA2R-Ab titers were correlated both with the lead SNPs of HLA-DQA1 17 and with the HLA-D allotypes DQA1* 05:01 and DQB1* 02:01 in Caucasians 9,18 , and DRB1*15:01 and DRB3*02:02 in Han Chinese 19 .…”

Section: J O U R N a L P R E -P R O O F Introductionmentioning

confidence: 99%

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HLA-D and PLA2R1 risk alleles associate with recurrent primary membranous nephropathy in kidney transplant recipients

Berchtold

Letouzé

Alexander

et al. 2021

Kidney International

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Section: J O U R N a L P R E -P R O O Fsupporting

confidence: 92%

Section: Logistic Regression Analysis Revealed a Second Snp Rs130189mentioning

confidence: 62%

Section: Identification Of Pmn-associated Snps and Hla-d Allotypesmentioning

confidence: 76%

Section: Logistic Regression Analysis Revealed a Second Snp Rs927508mentioning

confidence: 84%

Section: J O U R N a L P R E -P R O O F Introductionmentioning

confidence: 99%

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HLA-D and PLA2R1 risk alleles associate with recurrent primary membranous nephropathy in kidney transplant recipients

Berchtold

Letouzé

Alexander

et al. 2021

Kidney International

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Primary Membranous Nephropathy

Grover,

Valcour,

Naides

2024

Manual of Molecular and Clinical Laboratory Immunology

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Synovial Tissue Heterogeneity in Japanese Patients With Rheumatoid Arthritis Elucidated Using a Cell‐Type Deconvolution Approach

Nakajima

Tsuchiya

et al. 2023

Arthritis & Rheumatology

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ObjectiveRecent advances in single‐cell RNA sequencing technology have improved our understanding of the immunological landscape of rheumatoid arthritis (RA). We aimed to stratify the synovium from Japanese patients with RA by immune cell compositions and gain insight into the inflammatory drivers of each synovial phenotype.MethodsSynovial tissues were obtained from Japanese patients with RA (n = 41) undergoing articular surgery. The cellular composition was quantified by a deconvolution approach using a public single‐cell‐based reference. Inflammatory pathway activity was calculated by gene set variation analysis, and chromatin accessibility was evaluated using Assay of Transposase Accessible Chromatin (ATAC)‐sequencing.ResultsWe stratified RA synovium into three distinct subtypes based on the hierarchical clustering of cellular composition data. One subtype was characterized by abundant HLA‐DRAhigh synovial fibroblasts, autoimmune‐associated B cells (ABCs), GZMK+ GZMB+ CD8+ T cells, IL1‐β+ monocytes, and plasmablasts. In addition, TNF‐α, interferons, and IL‐6 signaling were highly activated in this subtype, and the expression of various chemokines was significantly enhanced. Moreover, we found an open chromatin region overlapping with RA risk locus rs9405192 near the IRF4 gene, suggesting the genetic background influences the development of this inflammatory synovial state. The other two subtypes were characterized by increased IFNs and IL‐6 signaling, and expression of molecules associated with degeneration, respectively.ConclusionThis study adds insights into the synovial heterogeneity in Japanese patients, and shows a promising link with predominant inflammatory signals. Evaluating the site of inflammation has the potential to lead to appropriate drug selection that matches the individual pathology.This article is protected by copyright. All rights reserved.

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The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis

Cited by 156 publications

References 63 publications

HLA-D and PLA2R1 risk alleles associate with recurrent primary membranous nephropathy in kidney transplant recipients

HLA-D and PLA2R1 risk alleles associate with recurrent primary membranous nephropathy in kidney transplant recipients

Primary Membranous Nephropathy

Synovial Tissue Heterogeneity in Japanese Patients With Rheumatoid Arthritis Elucidated Using a Cell‐Type Deconvolution Approach

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