1. A genome-wide association analysis reveals new pathogenic pathways in gout.
- Author
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Major TJ, Takei R, Matsuo H, Leask MP, Sumpter NA, Topless RK, Shirai Y, Wang W, Cadzow MJ, Phipps-Green AJ, Li Z, Ji A, Merriman ME, Morice E, Kelley EE, Wei WH, McCormick SPA, Bixley MJ, Reynolds RJ, Saag KG, Fadason T, Golovina E, O'Sullivan JM, Stamp LK, Dalbeth N, Abhishek A, Doherty M, Roddy E, Jacobsson LTH, Kapetanovic MC, Melander O, Andrés M, Pérez-Ruiz F, Torres RJ, Radstake T, Jansen TL, Janssen M, Joosten LAB, Liu R, Gaal OI, Crişan TO, Rednic S, Kurreeman F, Huizinga TWJ, Toes R, Lioté F, Richette P, Bardin T, Ea HK, Pascart T, McCarthy GM, Helbert L, Stibůrková B, Tausche AK, Uhlig T, Vitart V, Boutin TS, Hayward C, Riches PL, Ralston SH, Campbell A, MacDonald TM, Nakayama A, Takada T, Nakatochi M, Shimizu S, Kawamura Y, Toyoda Y, Nakaoka H, Yamamoto K, Matsuo K, Shinomiya N, Ichida K, Lee C, Bradbury LA, Brown MA, Robinson PC, Buchanan RRC, Hill CL, Lester S, Smith MD, Rischmueller M, Choi HK, Stahl EA, Miner JN, Solomon DH, Cui J, Giacomini KM, Brackman DJ, Jorgenson EM, Liu H, Susztak K, Shringarpure S, So A, Okada Y, Li C, Shi Y, and Merriman TR
- Subjects
- Humans, Mendelian Randomization Analysis, NLR Family, Pyrin Domain-Containing 3 Protein genetics, Male, Hyperuricemia genetics, Gout genetics, Genome-Wide Association Study, Genetic Predisposition to Disease, Uric Acid, Polymorphism, Single Nucleotide
- Abstract
Gout is a chronic disease that is caused by an innate immune response to deposited monosodium urate crystals in the setting of hyperuricemia. Here, we provide insights into the molecular mechanism of the poorly understood inflammatory component of gout from a genome-wide association study (GWAS) of 2.6 million people, including 120,295 people with prevalent gout. We detected 377 loci and 410 genetically independent signals (149 previously unreported loci in urate and gout). An additional 65 loci with signals in urate (from a GWAS of 630,117 individuals) but not gout were identified. A prioritization scheme identified candidate genes in the inflammatory process of gout, including genes involved in epigenetic remodeling, cell osmolarity and regulation of NOD-like receptor protein 3 (NLRP3) inflammasome activity. Mendelian randomization analysis provided evidence for a causal role of clonal hematopoiesis of indeterminate potential in gout. Our study identifies candidate genes and molecular processes in the inflammatory pathogenesis of gout suitable for follow-up studies., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
- Published
- 2024
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