TY - JOUR
T1 - Genome-wide meta-analysis identifies multiple novel loci associated with serum uric acid levels in Japanese individuals
AU - Nakatochi, Masahiro
AU - Kanai, Masahiro
AU - Nakayama, Akiyoshi
AU - Hishida, Asahi
AU - Kawamura, Yusuke
AU - Ichihara, Sahoko
AU - Akiyama, Masato
AU - Ikezaki, Hiroaki
AU - Furusyo, Norihiro
AU - Shimizu, Seiko
AU - Yamamoto, Ken
AU - Hirata, Makoto
AU - Okada, Rieko
AU - Kawai, Sayo
AU - Kawaguchi, Makoto
AU - Nishida, Yuichiro
AU - Shimanoe, Chisato
AU - Ibusuki, Rie
AU - Takezaki, Toshiro
AU - Nakajima, Mayuko
AU - Takao, Mikiya
AU - Ozaki, Etsuko
AU - Matsui, Daisuke
AU - Nishiyama, Takeshi
AU - Suzuki, Sadao
AU - Takashima, Naoyuki
AU - Kita, Yoshikuni
AU - Endoh, Kaori
AU - Kuriki, Kiyonori
AU - Uemura, Hirokazu
AU - Arisawa, Kokichi
AU - Oze, Isao
AU - Matsuo, Keitaro
AU - Nakamura, Yohko
AU - Mikami, Haruo
AU - Tamura, Takashi
AU - Nakashima, Hiroshi
AU - Nakamura, Takahiro
AU - Kato, Norihiro
AU - Matsuda, Koichi
AU - Murakami, Yoshinori
AU - Matsubara, Tatsuaki
AU - Naito, Mariko
AU - Kubo, Michiaki
AU - Kamatani, Yoichiro
AU - Shinomiya, Nariyoshi
AU - Yokota, Mitsuhiro
AU - Wakai, Kenji
AU - Okada, Yukinori
AU - Matsuo, Hirotaka
N1 - Funding Information:
We thank all subjects for their involvement in the study; staff of the institutions participating in the J-MICC Study, BBJ Project, and KING Study for their assistance in collection of samples and clinical information; Y. Mitsuda and K. Shibata (Department of Preventive Medicine, Nagoya University Graduate School of Medicine) for technical assistance; K. Gotanda, M. Miyazawa, and R. Sugiyama (National Defense Medical College) for discussion; and N. Hamajima (Nagoya University Graduate School of Medicine) for sample collection. We thank A.P. Morris for providing us with the MANTRA software. The present study was supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan including KAKENHI grants (nos. 25293145 and 15K15227); the Ministry of Health, Labor, and Welfare of Japan; the Ministry of Defense of Japan; the Japan Society for the Promotion of Science (JSPS); the Kawano Masanori Memorial Foundation for Promotion of Pediatrics; and the Gout Research Foundation of Japan. The KING Study was supported in part by Grants-in-Aid from MEXT (nos. 24390169, 16H05250, 25293144, 15K19242, 16H06277, and 18K06942) as well as by a grant from the Funding Program for Next-Generation World-Leading Researchers (NEXT Program, no. LS056). The J-MICC Study was supported by Grants-in-Aid for Scientific Research from MEXT, including those for Priority Areas of Cancer (no. 17015018) and Innovative Areas (no. 221S0001), as well as by a JSPS KAKENHI grant (no. 16H06277). This study was supported in part by funding from the BioBank Japan Project from the Japan Agency for Medical Research and Development, and the Ministry of Education, Culture, Sports, Science and Technology.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Gout is a common arthritis caused by elevated serum uric acid (SUA) levels. Here we investigated loci influencing SUA in a genome-wide meta-analysis with 121,745 Japanese subjects. We identified 8948 variants at 36 genomic loci (P<5 × 10–8) including eight novel loci. Of these, missense variants of SESN2 and PNPLA3 were predicted to be damaging to the function of these proteins; another five loci—TMEM18, TM4SF4, MXD3-LMAN2, PSORS1C1-PSORS1C2, and HNF4A—are related to cell metabolism, proliferation, or oxidative stress; and the remaining locus, LINC01578, is unknown. We also identified 132 correlated genes whose expression levels are associated with SUA-increasing alleles. These genes are enriched for the UniProt transport term, suggesting the importance of transport-related genes in SUA regulation. Furthermore, trans-ethnic meta-analysis across our own meta-analysis and the Global Urate Genetics Consortium has revealed 15 more novel loci associated with SUA. Our findings provide insight into the pathogenesis, treatment, and prevention of hyperuricemia/gout.
AB - Gout is a common arthritis caused by elevated serum uric acid (SUA) levels. Here we investigated loci influencing SUA in a genome-wide meta-analysis with 121,745 Japanese subjects. We identified 8948 variants at 36 genomic loci (P<5 × 10–8) including eight novel loci. Of these, missense variants of SESN2 and PNPLA3 were predicted to be damaging to the function of these proteins; another five loci—TMEM18, TM4SF4, MXD3-LMAN2, PSORS1C1-PSORS1C2, and HNF4A—are related to cell metabolism, proliferation, or oxidative stress; and the remaining locus, LINC01578, is unknown. We also identified 132 correlated genes whose expression levels are associated with SUA-increasing alleles. These genes are enriched for the UniProt transport term, suggesting the importance of transport-related genes in SUA regulation. Furthermore, trans-ethnic meta-analysis across our own meta-analysis and the Global Urate Genetics Consortium has revealed 15 more novel loci associated with SUA. Our findings provide insight into the pathogenesis, treatment, and prevention of hyperuricemia/gout.
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U2 - 10.1038/s42003-019-0339-0
DO - 10.1038/s42003-019-0339-0
M3 - Article
C2 - 31924945
AN - SCOPUS:85068744369
VL - 2
JO - Communications Biology
JF - Communications Biology
SN - 2399-3642
IS - 1
M1 - 115
ER -