A genome-wide association analysis reveals new pathogenic pathways in gout.
Major Tanya J, Takei Riku, Matsuo Hirotaka, Leask Megan P, Sumpter Nicholas A, Topless Ruth K, Shirai Yuya, Wang Wei, Cadzow Murray J, Phipps-Green Amanda J, Li Zhiqiang, Ji Aichang, Merriman Marilyn E, Morice Emily, Kelley Eric E, Wei Wen-Hua, McCormick Sally P A, Bixley Matthew J, Reynolds Richard J, Saag Kenneth G, Fadason Tayaza, Golovina Evgenia, O'Sullivan Justin M, Stamp Lisa K, Dalbeth Nicola, Abhishek Abhishek, Doherty Michael, Roddy Edward, Jacobsson Lennart T H, Kapetanovic Meliha C, Melander Olle, Andrés Mariano, Pérez-Ruiz Fernando, Torres Rosa J, Radstake Timothy, Jansen Timothy L, Janssen Matthijs, Joosten Leo A B, Liu Ruiqi, Gaal Orsolya I, Crişan Tania O, Rednic Simona, Kurreeman Fina, Huizinga Tom W J, Toes René, Lioté Frédéric, Richette Pascal, Bardin Thomas, Ea Hang Korng, Pascart Tristan, McCarthy Geraldine M, Helbert Laura, Stibůrková Blanka, Tausche Anne-K, Uhlig Till, Vitart Véronique, Boutin Thibaud S, Hayward Caroline, Riches Philip L, Ralston Stuart H, Campbell Archie, MacDonald Thomas M, FAST Study Group, Nakayama Akiyoshi, Takada Tappei, Nakatochi Masahiro, Shimizu Seiko, Kawamura Yusuke, Toyoda Yu, Nakaoka Hirofumi, Yamamoto Ken, Matsuo Keitaro, Shinomiya Nariyoshi, Ichida Kimiyoshi, Japan Gout Genomics Consortium, Lee Chaeyoung, Asia Pacific Gout Consortium, Bradbury Linda A, Brown Matthew A, Robinson Philip C, Buchanan Russell R C, Hill Catherine L, Lester Susan, Smith Malcolm D, Rischmueller Maureen, Choi Hyon K, Stahl Eli A, Miner Jeff N, Solomon Daniel H, Cui Jing, Giacomini Kathleen M, Brackman Deanna J, Jorgenson Eric M, GlobalGout Genetics Consortium, Liu Hongbo, Susztak Katalin, 23andMe Research Team, Shringarpure Suyash, So Alexander, Okada Yukinori, Li Changgui, Shi Yongyong, Merriman Tony R
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Аннотация
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.
Для цитирования: Major Tanya J, Takei Riku, Matsuo Hirotaka, Leask Megan P, Sumpter Nicholas A, Topless Ruth K, Shirai Yuya, Wang Wei, Cadzow Murray J, Phipps-Green Amanda J, Li Zhiqiang, Ji Aichang, Merriman Marilyn E, Morice Emily, Kelley Eric E, Wei Wen-Hua, McCormick Sally P A, Bixley Matthew J, Reynolds Richard J, Saag Kenneth G, Fadason Tayaza, Golovina Evgenia, O'Sullivan Justin M, Stamp Lisa K, Dalbeth Nicola, Abhishek Abhishek, Doherty Michael, Roddy Edward, Jacobsson Lennart T H, Kapetanovic Meliha C, Melander Olle, Andrés Mariano, Pérez-Ruiz Fernando, Torres Rosa J, Radstake Timothy, Jansen Timothy L, Janssen Matthijs, Joosten Leo A B, Liu Ruiqi, Gaal Orsolya I, Crişan Tania O, Rednic Simona, Kurreeman Fina, Huizinga Tom W J, Toes René, Lioté Frédéric, Richette Pascal, Bardin Thomas, Ea Hang Korng, Pascart Tristan, McCarthy Geraldine M, Helbert Laura, Stibůrková Blanka, Tausche Anne-K, Uhlig Till, Vitart Véronique, Boutin Thibaud S, Hayward Caroline, Riches Philip L, Ralston Stuart H, Campbell Archie, MacDonald Thomas M, FAST Study Group, Nakayama Akiyoshi, Takada Tappei, Nakatochi Masahiro, Shimizu Seiko, Kawamura Yusuke, Toyoda Yu, Nakaoka Hirofumi, Yamamoto Ken, Matsuo Keitaro, Shinomiya Nariyoshi, Ichida Kimiyoshi, Japan Gout Genomics Consortium, Lee Chaeyoung, Asia Pacific Gout Consortium, Bradbury Linda A, Brown Matthew A, Robinson Philip C, Buchanan Russell R C, Hill Catherine L, Lester Susan, Smith Malcolm D, Rischmueller Maureen, Choi Hyon K, Stahl Eli A, Miner Jeff N, Solomon Daniel H, Cui Jing, Giacomini Kathleen M, Brackman Deanna J, Jorgenson Eric M, GlobalGout Genetics Consortium, Liu Hongbo, Susztak Katalin, 23andMe Research Team, Shringarpure Suyash, So Alexander, Okada Yukinori, Li Changgui, Shi Yongyong, Merriman Tony R. A genome-wide association analysis reveals new pathogenic pathways in gout.. Nature genetics. 2024. DOI: 10.1038/s41588-024-01921-5.
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