Genome-wide association analyses define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy

Kiryluk, Krzysztof; Sánchez, Elena; Zhou, Xu‐Jie; Zanoni, Francesca; Liu, Lili; Mladkova, Nikol; Khan, Atlas; Marasà, Maddalena; Zhang, Junying; Balderes, Olivia; Sanna‐Cherchi, Simone; Bomback, Andrew S.; Canetta, Pietro A.; Appel, Gerald B.; Radhakrishnan, Jai; Trimarchi, Hernán; Sprangers, Ben; Cattran, Daniel C.; Reich, Heather N.; Pei, York; Ravani, Pietro; Gales̃ić, Kres̆imir; Maixnerová, Dita; Tesař, Vladimı́r; Stengel, Bénédicte; Metzger, Marie; Canaud, Guillaume; Maillard, Nicolas; Berthoux, F; Berthelot, Laureline; Pillebout, Évangéline; Monteiro, Renato C.; Nelson, Raoul D.; Wyatt, Robert; Smoyer, William E.; Mahan, John D.; Samhar, Al-Akash; Hidalgo, Guillermo; Quiroga, Alejandro; Weng, Patricia L.; Sreedharan, Raji; Selewski, David T.; Davis, Keefe; Kallash, Mahmoud; Vasylyeva, Tetyana L.; Rheault, Michelle N.; Chishti, Aftab S.; Ranch, Daniel; Wenderfer, Scott E.; Samsonov, Dmitry; Claes, Donna; Akchurin, Oleh; Goumenos, Dimitrios; Stangou, Maria; Nagy, Judit; Kovács, Tibor; Fiaccadori, Enrico; Amoroso, Antonio; Barlassina, Cristina; Cusi, Daniele; Vecchio, Lucia Del; Battaglia, Giovanni Giorgio; Bodria, Monica; Boer, Emanuela; Bono, Luisa; Boscutti, Giuliano; Caridi, Gianluca; Lugani, Francesca; Ghiggeri, Gian Marco; Coppo, Rosanna; Peruzzi, Licia; Esposito, Vittoria; Esposito, Ciro; Feriozzi, Sandro; Polci, Rosaria; Frascà, Giovanni M.; Galliani, Marco; Garozzo, Maurizio; Mitrotti, Adele; Gesualdo, Loreto; Granata, Simona; Zaza, Gianluigi; Lotti, Francesco; Magistroni, Riccardo; Pisani, Isabella; Magnano, Andrea; Marcantoni, Carmelita; Messa, Piergiorgio; Mignani, Renzo; Pani, Antonello; Ponticelli, Claudio; Roccatello, Dario; Salvadori, Maurizio; Salvi, Erica; Santoro, Domenico; Gembillo, Guido; Savoldi, Silvana; Spotti, D.; Zamboli, Pasquale; Izzi, Claudia; Alberici, Federico; Delbarba, Elisa; Florczak, Michał; Krata, Natalia; Mucha, Krzysztof; Pączek, Leszek; Niemczyk, Stanisław; Moszczuk, Barbara; Pańczyk-Tomaszewska, Małgorzata; Mizerska-Wasiak, Małgorzata; Perkowska‐Ptasińska, Agnieszka; Bączkowska, Teresa; Durlik, Magdalena; Pawlaczyk, Krzysztof; Sikora, Przemysław; Zaniew, Marcin; Kamińska, Dorota; Krajewska, Magdalena; Kuźmiuk-Glembin, Izabella; Heleniak, Zbigniew; Bułło‐Piontecka, Barbara; Liberek, Tomasz; Dębska‐Ślizień, Alicja; Hryszko, Tomasz; Materna‐Kiryluk, Anna; Miklaszewska, Monika; Szczepański, Tomasz; Dyga, Katarzyna; Machura, Edyta; Siniewicz‐Luzeńczyk, Katarzyna; Pawlak-Bratkowska, Monika; Tkaczyk, Marcin; Runowski, Dariusz; Kwella, Norbert; Drożdż, Dorota; Habura, Ireneusz; Kronenberg, Florian; Prikhodina, Larisa; Heel, David A. van; Fontaine, Bertrand; Cotsapas, Chris; Wijmenga, Cisca; Franke, André; Annese, Vito; Gregersen, Peter K.; Parameswaran, Sreeja; Weirauch, Matthew T.; Kottyan, Leah C.; Harley, John B.; Suzuki, Hitoshi; Narita, Ichiei; Goto, Shin; Lee, Hajeong; Kim, Yon Su; Park, Jin-Ho; Cho, Belong; Choi, Murim; Wijk, Ans Van; Huerta, Ana; Ars, Elisabet; Ballarín, J.; Lundberg, Sigrid; Vogt, Bruno; Mani, Laila-Yasmin; Çalışkan, Yaşar; Barratt, Jonathan; Abeygunaratne, Thilini; Kalra, Philip A.; Gale, Daniel P.; Panzer, Ulf; Rauen, Thomas; Floege, Jürgen; Schlosser, Pascal; Ekici, Arif B.; Eckardt, Kai Uwe; Chen, Nan; Xie, Jingyuan; Lifton, Richard P.; Loos, Ruth J.F.; Kenny, Eimear E.; Ionita‐Laza, Iuliana; Köttgen, Anna; Julian, Bruce A.; Novák, Jan; Scolari, Francesco; Zhang, Hong; Gharavi, Ali G.

doi:10.1038/s41588-023-01422-x

Cited by 44 publications

(26 citation statements)

References 93 publications

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“… 35 Interestingly, LIF was shown as a drug target gene with a high score by the GWAS additional functional criteria evaluation. 17 In this study, we examined the signaling in the LIF/JAK/STAT system related to elevated Gd-IgA1 production.…”

Section: Discussionmentioning

confidence: 99%

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LIF/JAK2/STAT1 Signaling Enhances Production of Galactose-Deficient IgA1 by IgA1-Producing Cell Lines Derived From Tonsils of Patients With IgA Nephropathy

Yamada,

Huang,

Reily

et al. 2024

Kidney International Reports

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Section: Discussionmentioning

confidence: 99%

“…The Chr.22q12 locus with HORMAD2/LIF/OSM genes was identified in several studies, and is associated with the regulation of IgA production in the mucosa and serum IgA levels. 15 , 16 , 17 Furthermore, another GWAS study revealed that the same locus was associated with acute tonsilitis and chronic inflammation of tonsils leading to tonsillectomy. 18 …”

mentioning

confidence: 99%

LIF/JAK2/STAT1 Signaling Enhances Production of Galactose-Deficient IgA1 by IgA1-Producing Cell Lines Derived From Tonsils of Patients With IgA Nephropathy

Yamada,

Huang,

Reily

et al. 2024

Kidney International Reports

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“…In the VALIGA cohort, patients from Northern Europe had significantly worse kidney outcomes ( p < 0.001) than patients from Southern Europe despite similarities in clinical baseline data [ 32 ]. The most relevant risk factor was the significantly higher corticosteroid use in patients from Southern Europe [ 32 ], although the differences could also be due to environmental or genetic factors [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Use of corticosteroids in Norwegian patients with immunoglobulin a nephropathy progressing to end-stage kidney disease: a retrospective cohort study

Rivedal,

Haaskjold,

Eikrem

et al. 2024

BMC Nephrol

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Background Despite several clinical trials, the use of corticosteroid therapy for treating immunoglobulin A nephropathy (IgAN) remains controversial. We aimed to describe the use of corticosteroid therapy combined with supportive therapy in Norwegian patients with IgAN who had progressed to end-stage kidney disease. Methods We conducted a retrospective cohort study using data from the Norwegian Renal Registry. Overall, 143 patients with primary IgAN who progressed to end-stage kidney disease were divided into two groups: the corticosteroid group, who had been treated with corticosteroids and supportive therapy, and the non-corticosteroid group, which had underwent only supportive therapy. The kidney function, time to end-stage kidney disease, and adverse effects were described. The observation period lasted from the diagnostic kidney biopsy until the initiation of kidney replacement therapy. Results Of the 143 included patients, 103 underwent supportive therapy alone, and 40 were treated with corticosteroids. Most patients (94%) were treated with renin-angiotensin-system blockade, and all patients reached end-stage kidney disease after a median of 5 years (interquartile range; 2–9 years). Time from diagnosis until end-stage kidney disease was similar in the two study groups (p = 0.98). During 6 months of corticosteroid therapy, median eGFR declined from 21 (interquartile range; 13–46) mL/min/1.73 m2 to 20 (interquartile range; 12–40) mL/min/1.73 m2, and median proteinuria decreased from 5.5 g/24 h to 3.0 g/24 h. Most patients (87.5%) treated with corticosteroids reported adverse events. In our linear regression analysis investigating the time to ESKD, we found that age (β = -0.079, p = 0.008) and proteinuria at diagnosis (β = -0.50, p = 0.01) exhibited statistically significant associations with a delay in the progression to ESKD. Conclusions In this cohort of Norwegian patients with IgAN, corticosteroid therapy did not affect the time from diagnosis until end-stage kidney disease among a cohort of patients who all reached end-stage kidney disease. The treatment was also associated with adverse effects.

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“…Very recently, the up-to-date largest GWAS meta-analysis from 17 international case-control cohorts has identified 30 genome-wide significant risk loci of IgAN, including 16 novel loci in 10,146 IgAN patients and 28,751 healthy controls, which explained 11% of overall disease risk [ 51 ]. Using tissue- and cell-type-specific FUN-LDA scores, the researchers partitioned SNP-based heritability to map the most likely causal tissues and cell types.…”

Section: Genome-wide Association Studiesmentioning

confidence: 99%

An Update on the Genetics of IgA Nephropathy

Xu,

Zhou,

Zhang

2023

JCM

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Immunoglobulin A (IgA) nephropathy (IgAN), the most common form of glomerulonephritis, is one of the leading causes of end-stage kidney disease (ESKD). It is widely believed that genetic factors play a significant role in the development of IgAN. Previous studies of IgAN have provided important insights to unravel the genetic architecture of IgAN and its potential pathogenic mechanisms. The genome-wide association studies (GWASs) together have identified over 30 risk loci for IgAN, which emphasizes the importance of IgA production and regulation in the pathogenesis of IgAN. Follow-up fine-mapping studies help to elucidate the candidate causal variant and the potential pathogenic molecular pathway and provide new potential therapeutic targets. With the rapid development of next-generation sequencing technologies, linkage studies based on whole-genome sequencing (WGS)/whole-exome sequencing (WES) also identify rare variants associated with IgAN, accounting for some of the missing heritability. The complexity of pathogenesis and phenotypic variability may be better understood by integrating genetics, epigenetics, and environment. We have compiled a review summarizing the latest advancements in genetic studies on IgAN. We similarly summarized relevant studies examining the involvement of epigenetics in the pathogenesis of IgAN. Future directions and challenges in this field are also proposed.

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Genome-wide association analyses define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy

Cited by 44 publications

References 93 publications

LIF/JAK2/STAT1 Signaling Enhances Production of Galactose-Deficient IgA1 by IgA1-Producing Cell Lines Derived From Tonsils of Patients With IgA Nephropathy

LIF/JAK2/STAT1 Signaling Enhances Production of Galactose-Deficient IgA1 by IgA1-Producing Cell Lines Derived From Tonsils of Patients With IgA Nephropathy

Use of corticosteroids in Norwegian patients with immunoglobulin a nephropathy progressing to end-stage kidney disease: a retrospective cohort study

An Update on the Genetics of IgA Nephropathy

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