A Genome-Wide Association Analysis of 2,622,830 Individuals Reveals New Pathogenic Pathways in Gout

Tony Merriman¹, Hirotaka Matsuo², Riku Takei³, Megan Leask³, Ruth Topless¹, Yuya Shirai⁴, Zhiqiang Li⁵, Murray Cadzow¹, Richard Reynolds³, kenneth saag³, Tayaza Fadason⁶, Justin O'Sullivan⁶, Nicola Dalbeth⁶, Lisa Stamp⁷, Abhishek Abhishek⁸, Michael Doherty⁸, Edward Roddy⁹, Lennart Jacobsson¹⁰, Meliha Kapetanovic¹¹, Mariano Andrès¹², Fernando Perez-Ruiz¹³, Rosa Torres Jimenez¹⁴, Timothy Radstake¹⁵, Timothy Jansen¹⁶, Matthijs Janssen¹⁷, Leo Joosten¹⁸, Tania Octavia Crisan¹⁹, Tom Huizinga²⁰, Frederic LIOTE²¹, Pascal Richette²², Thomas Bardin²³, Tristan Pascart²⁴, Geraldine McCarthy²⁵, Blanka Stiburkova²⁶, Anne Tausche²⁷, Till Uhlig²⁸, Veronique Vitart²⁹, Philip Riches²⁹, Stuart Ralston²⁹, Thomas MacDonald³⁰, Akiyoshi Nakayama², Masahiro Nakatochi³¹, Kimiyoshi Ichida³², Tappei Takada³³, Chaeyoung Lee³⁴, Matthew Brown³⁵, Philip Robinson³⁶, Catherine Hill³⁷, Hyon Choi³⁸, Nicholas Sumpter³, Marilyn Merriman³, Amanda Phipps-Green¹, Wenhua Wei¹, Sally McCormick¹, Olle Melander³⁹, René Toes²⁰, Hang-Korng Ea²¹, Fina Kurreeman²⁰, Laura Helbert²⁵, Thibaud Boutin²⁹, Nariyoshi Shinomiya², Linda Bradbury⁴⁰, Russell Buchanan⁴¹, Susan Lester³⁷, Malcolm Smith⁴², Maureen Rischmueller⁴³, On behalf of Japan Gout Genomics Consortium (J-Gout)⁴⁴, On behalf of Japan Multi-Instl Collab Cohort Study (J-MICC)⁴⁵, Eli Stahl⁴⁶, Jeff Miner⁴⁷, Daniel Solomon⁴⁸, Jing Cui⁴⁸, Kathleen Giacomini⁴⁹, Deanna Brackman⁴⁹, Eric Jorgenson⁵⁰, On behalf of 23andMe Research Team⁵¹, Suyash Shringapure⁵¹, Alexander So⁵², Yukinori Okada⁴, Changgui Li⁵, Yongyong Shi⁵³ and Tanya Major¹, ¹University of Otago, Dunedin, New Zealand, ²National Defense Medical College, Saitama, Japan, ³University of Alabama at Birmingham, Birmingham, AL, ⁴Osaka University, Suita, Osaka, Japan, ⁵The Affiliated Hospital of Qingdao University, Qingdao, China, ⁶University of Auckland, Auckland, New Zealand, ⁷University of Otago, Christchurch, New Zealand, ⁸University of Nottingham, Nottingham, United Kingdom, ⁹Keele University, Keele, United Kingdom, ¹⁰Department of Rheumatology and Inflammation Research, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden, ¹¹Lund University, Department for clinical sciences Lund, section of rheumatology and Lund University Hospital Lund and Malmö, Lund, Sweden, ¹²Dr Balmis Alicante General University Hospital-ISABIAL, Alicante, Spain, ¹³University of the Basque Country, Barakaldo, Spain, ¹⁴La Paz University Hospital, Madrid, Spain, ¹⁵University Medical College Uthrecht, Utrecht, Netherlands, ¹⁶VieCuri Medical Centre, Venlo, Netherlands, ¹⁷Rijnstate Hospital, Bennekom, Netherlands, ¹⁸Radboudumc, Nijmegen, Netherlands, ¹⁹University of Medicine and Pharmacy "Iuliu Hatieganu" Cluj-Napoca, Cluj-Napoca, Romania, ²⁰Leiden University Medical Center, Leiden, Netherlands, ²¹University of Paris, Paris, France, ²²Department of Rheumatology, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris, Paris, France, ²³Hôpital Lariboisiere, Paris, France, ²⁴Lille Catholic University, Lille, France, ²⁵Mater Misericordiae University Hospital, Dublin, Ireland, ²⁶Institute of Rheumatology, Prague, Czech Republic, ²⁷University Clinic 'Carl Gustav Carus' at the Technical University, Dresden, Germany, ²⁸Diakonhjemmet Hospital, Oslo, Norway, ²⁹University of Edinburgh, Edinburgh, Scotland, United Kingdom, ³⁰University of Dundee, Dundee, United Kingdom, ³¹Nagoya University Hospital, Nagoya, Japan, ³²Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan, ³³University of Tokyo Hospital, Tokyo, Japan, ³⁴Soongsil University, Seoul, Republic of Korea, ³⁵Genomics England, London, United Kingdom, ³⁶University of Queensland, Brisbane, Australia, ³⁷The Queen Elizabeth Hospital, Adelaide, Australia, ³⁸Massachusetts General Hospital, Lexington, MA, ³⁹Lund University, Malmö, Sweden, ⁴⁰Gold Coast University Hospital, Brisbane, Australia, ⁴¹Austin Health, Heidelberg, Australia, ⁴²Flinders Medical Centre, Adelaide, Australia, ⁴³RheumatologySA, Adelaide, Australia, ⁴⁴Japan Gout Genomics Consortium (J-Gout), Saitama, Japan, ⁴⁵Japan Multi-Institutional Collaborative Cohort Study (J-MICC), Nagoya, Japan, ⁴⁶Regeneron, New York, NY, ⁴⁷ViscientBio, San Diego, CA, ⁴⁸Brigham and Women's Hospital, Boston, MA, ⁴⁹University of California San Francisco, San Francisco, CA, ⁵⁰Kaiser Permanente, San Francisco, CA, ⁵¹23andMe, Inc., Sunnyvale, CA, ⁵²University of Lausanne, Lausanne, Switzerland, ⁵³Shanghai Jiao Tong University, Shanghai, China

Meeting: ACR Convergence 2022

Keywords: Genome Wide Association Studies, genomics, gout, Uric Acid, Urate

Session Information

Date: Monday, November 14, 2022

Title: Plenary III

Session Type: Plenary Session

Session Time: 11:30AM-1:00PM

Background/Purpose: Genome-wide association studies (GWAS) in gout have been relatively small (≤13,179 people with gout) and have provided little insight into the progression from hyperuricemia to gout. We present a gout GWAS that includes 120,282 people with gout.

Methods: Participants were from 13 cohorts and four ancestral groups (African 3,052 gout/77,891 non-gout; East Asian 10,729/82,807; European 100,661/2,106,003; Latina 5,840/235,847). Ancestry-specific GWAS summary statistics were meta-analysed to form the trans-ancestral GWAS. Candidate causal genes were identified by co-localization with expression quantitative trait loci (eQTL) using the Gene and Tissue Expression dataset and/or having a candidate missense causal variant and/or by MAGMA gene set analysis. IL-1β response QTL were identified using the 500FG cohort. Pathway analysis was done using KEGG and drug repositioning analysis was done using Genome for Repositioning Drugs.

Results: There were 339 gout-associated loci encompassing 515 independently-associated variants. 123 loci did not overlap with any previously reported in urate or gout. Co-localization of GWAS and eQTL signals identified 1,657 cis- and 267 trans-eQTLs for 252 of the 339 loci. Some co-localized eQTL genes regulate NLRP3 inflammasome activation and activity (e.g. TMEM176B, SCAP, INSIG2 SREBF-AS1, FADS2, NLRC3). Co-localized eQTLs also included TET2, EZH2, IDH2, and RUNX1, genes mutated in Clonal Hematopoiesis of Indeterminate Potential (CHIP). Enriched molecular pathways using candidate genes identified purine metabolism, amino acid metabolism and insulin signalling pathways (Figure 1). Genetic variants present in the 500FG dataset and not previously associated with urate (n=93, possibly involved in inflammation in gout) had amplification of signal that associated with IL-1b response to monosodium urate (MSU) crystal and LPS co-stimulation in peripheral blood mononuclear cells (Figure 2). However those associated with urate (n=317) did not exhibit amplified signal (Figure 2). The gout GWAS signal at the top-associated variant of the 93 variants not associated with urate (rs9973741) co-localized with genetic control of production of IL-1b upon stimulation (the gout risk allele associated with increased IL-1β level), and also co-localized with genetic control (eQTL) of IL1RN and IL-38 expression, implicating these genes as causal at this locus. An association signal at Xanthine Dehydrogenase was restricted to males and co-localized with XDH expression (eQTL) only in the prostate (Figure 3). Gout-associated loci represented drug repurposing possibilities from neoplasm, blood biochemistry, and metabolic disorder treatment categories.

Conclusion: We implicate multiple new causal genes and pathways in gout. In addition to genes that regulate urate, NLRP3 inflammasome activity and autophagy, this work has identified the CHIP pathway, that includes epigenome modification proteins, in gout pathogenesis. Other pathways identified involve insulin signalling and purine and glutamate metabolism. Uniquely regulated production of urate by the prostate potentially represents a novel risk factor for gout in men.

Figure 1. Molecular pathways causally implicated in gout pathogenesis.

Figure 2. Q-Q plots of association of non-urate-associated variants (n=93, left panel) and urate-associated variants (n=317, right panel) with IL_1b level after co-stimulation of PBMCs by MSU crystals and LPS.

Figure 3. LocusZoom plots of gout association signal at the XDH locus in males (top left) and females (top right) from the European GWAS. Genetic control of XDH expression, specific to the prostate, is in the bottom plot. XDH is the fourth gene from the left in each plot. Individual genetic variants are represented as dots; genome position is on the x-axis and strength of evidence for association on the y-axis; genetic variants in strong linkage disequilibrium with the lead variant at the prostate-specific signal (rs7594591) are in red.

Disclosures: T. Merriman, None; H. Matsuo, None; R. Takei, None; M. Leask, None; R. Topless, None; Y. Shirai, None; Z. Li, None; M. Cadzow, None; R. Reynolds, None; k. saag, Horizon Therapeutics, SOBI, Shanton, AbbVie/Abbott; T. Fadason, None; J. O'Sullivan, None; N. Dalbeth, AstraZeneca, Dyve Biosciences, Horizon, Selecta, JW Pharmaceutical Corporation, PK Med, PTC Therapeutics, Protalix; L. Stamp, None; A. Abhishek, AstraZeneca, Pfizer, Oxford immunotec, Inflazome, NGMBiopharmaceuticals, Uptodate, Cadilla pharmaceuticals; M. Doherty, None; E. Roddy, None; L. Jacobsson, Novartis, Eli Lilly, Janssen; M. Kapetanovic, None; M. Andrès, Menarini, Grunenthal; F. Perez-Ruiz, None; R. Torres Jimenez, None; T. Radstake, None; T. Jansen, None; M. Janssen, None; L. Joosten, None; T. Crisan, None; T. Huizinga, None; F. LIOTE, None; P. Richette, AbbVie, Amgen, Biogen, Bristol Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, Roche, Sanofi-Aventis, UCB; T. Bardin, None; T. Pascart, None; G. McCarthy, None; B. Stiburkova, None; A. Tausche, None; T. Uhlig, None; V. Vitart, None; P. Riches, None; S. Ralston, None; T. MacDonald, Menarini; A. Nakayama, None; M. Nakatochi, None; K. Ichida, None; T. Takada, None; C. Lee, None; M. Brown, UCB Pharma, Pfizer, Clementia, Ipsen, Incyte, Regeneron, Grey Wolf Therapeutics, Xinthera, Novartis; P. Robinson, None; C. Hill, None; H. Choi, Horizon, Allena, LG, Protalix; N. Sumpter, None; M. Merriman, None; A. Phipps-Green, None; W. Wei, None; S. McCormick, None; O. Melander, None; R. Toes, None; H. Ea, None; F. Kurreeman, None; L. Helbert, None; T. Boutin, None; N. Shinomiya, None; L. Bradbury, Novartis; R. Buchanan, None; S. Lester, None; M. Smith, None; M. Rischmueller, None; O. Japan Gout Genomics Consortium (J-Gout), None; O. Japan Multi-Instl Collab Cohort Study (J-MICC), None; E. Stahl, None; J. Miner, None; D. Solomon, AbbVie/Abbott, Amgen, moderna, CorEvitas; J. Cui, None; K. Giacomini, None; D. Brackman, None; E. Jorgenson, None; O. 23andMe Research Team, 23andMe, Inc.; S. Shringapure, None; A. So, None; Y. Okada, None; C. Li, None; Y. Shi, None; T. Major, None.

To cite this abstract in AMA style:

Merriman T, Matsuo H, Takei R, Leask M, Topless R, Shirai Y, Li Z, Cadzow M, Reynolds R, saag k, Fadason T, O'Sullivan J, Dalbeth N, Stamp L, Abhishek A, Doherty M, Roddy E, Jacobsson L, Kapetanovic M, Andrès M, Perez-Ruiz F, Torres Jimenez R, Radstake T, Jansen T, Janssen M, Joosten L, Crisan T, Huizinga T, LIOTE F, Richette P, Bardin T, Pascart T, McCarthy G, Stiburkova B, Tausche A, Uhlig T, Vitart V, Riches P, Ralston S, MacDonald T, Nakayama A, Nakatochi M, Ichida K, Takada T, Lee C, Brown M, Robinson P, Hill C, Choi H, Sumpter N, Merriman M, Phipps-Green A, Wei W, McCormick S, Melander O, Toes R, Ea H, Kurreeman F, Helbert L, Boutin T, Shinomiya N, Bradbury L, Buchanan R, Lester S, Smith M, Rischmueller M, Japan Gout Genomics Consortium (J-Gout) O, Japan Multi-Instl Collab Cohort Study (J-MICC) O, Stahl E, Miner J, Solomon D, Cui J, Giacomini K, Brackman D, Jorgenson E, 23andMe Research Team O, Shringapure S, So A, Okada Y, Li C, Shi Y, Major T. A Genome-Wide Association Analysis of 2,622,830 Individuals Reveals New Pathogenic Pathways in Gout [abstract]. Arthritis Rheumatol. 2022; 74 (suppl 9). https://acrabstracts.org/abstract/a-genome-wide-association-analysis-of-2622830-individuals-reveals-new-pathogenic-pathways-in-gout/. Accessed .

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