Genome-wide association study revealed novel loci which aggravate asymptomatic hyperuricaemia into gout

Yusuke Kawamura; Hirofumi Nakaoka; Akiyoshi Nakayama; Yukinori Okada; Ken Yamamoto; Toshihide Higashino; Masayuki Sakiyama; Toru Shimizu; Hiroshi Ooyama; Keiko Ooyama; Mitsuo Nagase; Yuji Hidaka; Yuko Shirahama; Kazuyoshi Hosomichi; Yuichiro Nishida; Ippei Shimoshikiryo; Asahi Hishida; Sakurako Katsuura-Kamano; Seiko Shimizu; Makoto Kawaguchi; Hirokazu Uemura; Rie Ibusuki; Megumi Hara; Mariko Naito; Mikiya Takao; Mayuko Nakajima; Satoko Iwasawa; Hiroshi Nakashima; Keizo Ohnaka; Takahiro Nakamura; Blanka Stiburkova; Tony R. Merriman; Masahiro Nakatochi; Sahoko Ichihara; Mitsuhiro Yokota; Tappei Takada; Tatsuya Saitoh; Yoichiro Kamatani; Atsushi Takahashi; Kokichi Arisawa; Toshiro Takezaki; Keitaro Tanaka; Kenji Wakai; Michiaki Kubo; Tatsuo Hosoya; Kimiyoshi Ichida; Ituro Inoue; Nariyoshi Shinomiya; Hirotaka Matsuo

doi:10.1136/annrheumdis-2019-215521

Genome-wide association study revealed novel loci which aggravate asymptomatic hyperuricaemia into gout

Yusuke Kawamura, Hirofumi Nakaoka, Akiyoshi Nakayama, Yukinori Okada, Ken Yamamoto, Toshihide Higashino, Masayuki Sakiyama, Toru Shimizu, Hiroshi Ooyama, Keiko Ooyama, Mitsuo Nagase, Yuji Hidaka, Yuko Shirahama, Kazuyoshi Hosomichi, Yuichiro Nishida, Ippei Shimoshikiryo, Asahi Hishida, Sakurako Katsuura-Kamano, Seiko Shimizu, Makoto KawaguchiHirokazu Uemura, Rie Ibusuki, Megumi Hara, Mariko Naito, Mikiya Takao, Mayuko Nakajima, Satoko Iwasawa, Hiroshi Nakashima, Keizo Ohnaka, Takahiro Nakamura, Blanka Stiburkova, Tony R. Merriman, Masahiro Nakatochi, Sahoko Ichihara, Mitsuhiro Yokota, Tappei Takada, Tatsuya Saitoh, Yoichiro Kamatani, Atsushi Takahashi, Kokichi Arisawa, Toshiro Takezaki, Keitaro Tanaka, Kenji Wakai, Michiaki Kubo, Tatsuo Hosoya, Kimiyoshi Ichida, Ituro Inoue, Nariyoshi Shinomiya, Hirotaka Matsuo

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Abstract

Objective The first ever genome-wide association study (GWAS) of clinically defined gout cases and asymptomatic hyperuricaemia (AHUA) controls was performed to identify novel gout loci that aggravate AHUA into gout. Methods We carried out a GWAS of 945 clinically defined gout cases and 1003 AHUA controls followed by 2 replication studies. In total, 2860 gout cases and 3149 AHUA controls (all Japanese men) were analysed. We also compared the ORs for each locus in the present GWAS (gout vs AHUA) with those in the previous GWAS (gout vs normouricaemia). Results This new approach enabled us to identify two novel gout loci (rs7927466 of CNTN5 and rs9952962 of MIR302F) and one suggestive locus (rs12980365 of ZNF724) at the genome-wide significance level (p<5.0×10-8). The present study also identified the loci of ABCG2, ALDH2 and SLC2A9. One of them, rs671 of ALDH2, was identified as a gout locus by GWAS for the first time. Comparing ORs for each locus in the present versus the previous GWAS revealed three â € gout vs AHUA GWAS'-specific loci (CNTN5, MIR302F and ZNF724) to be clearly associated with mechanisms of gout development which distinctly differ from the known gout risk loci that basically elevate serum uric acid level. Conclusions This meta-analysis is the first to reveal the loci associated with crystal-induced inflammation, the last step in gout development that aggravates AHUA into gout. Our findings should help to elucidate the molecular mechanisms of gout development and assist the prevention of gout attacks in high-risk AHUA individuals.

Original language	English
Pages (from-to)	1430-1437
Number of pages	8
Journal	Annals of the Rheumatic Diseases
Volume	78
Issue number	10
DOIs	https://doi.org/10.1136/annrheumdis-2019-215521
Publication status	Published - Oct 1 2019

All Science Journal Classification (ASJC) codes

Rheumatology
Immunology and Allergy
Immunology
Biochemistry, Genetics and Molecular Biology(all)

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10.1136/annrheumdis-2019-215521

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Kawamura, Y., Nakaoka, H., Nakayama, A., Okada, Y., Yamamoto, K., Higashino, T., Sakiyama, M., Shimizu, T., Ooyama, H., Ooyama, K., Nagase, M., Hidaka, Y., Shirahama, Y., Hosomichi, K., Nishida, Y., Shimoshikiryo, I., Hishida, A., Katsuura-Kamano, S., Shimizu, S., ... Matsuo, H. (2019). Genome-wide association study revealed novel loci which aggravate asymptomatic hyperuricaemia into gout. Annals of the Rheumatic Diseases, 78(10), 1430-1437. https://doi.org/10.1136/annrheumdis-2019-215521

Kawamura, Y, Nakaoka, H, Nakayama, A, Okada, Y, Yamamoto, K, Higashino, T, Sakiyama, M, Shimizu, T, Ooyama, H, Ooyama, K, Nagase, M, Hidaka, Y, Shirahama, Y, Hosomichi, K, Nishida, Y, Shimoshikiryo, I, Hishida, A, Katsuura-Kamano, S, Shimizu, S, Kawaguchi, M, Uemura, H, Ibusuki, R, Hara, M, Naito, M, Takao, M, Nakajima, M, Iwasawa, S, Nakashima, H, Ohnaka, K, Nakamura, T, Stiburkova, B, Merriman, TR, Nakatochi, M, Ichihara, S, Yokota, M, Takada, T, Saitoh, T, Kamatani, Y, Takahashi, A, Arisawa, K, Takezaki, T, Tanaka, K, Wakai, K, Kubo, M, Hosoya, T, Ichida, K, Inoue, I, Shinomiya, N & Matsuo, H 2019, 'Genome-wide association study revealed novel loci which aggravate asymptomatic hyperuricaemia into gout', Annals of the Rheumatic Diseases, vol. 78, no. 10, pp. 1430-1437. https://doi.org/10.1136/annrheumdis-2019-215521

@article{4eaa210a71ac489f8396dd303d7b975f,

title = "Genome-wide association study revealed novel loci which aggravate asymptomatic hyperuricaemia into gout",

abstract = "Objective The first ever genome-wide association study (GWAS) of clinically defined gout cases and asymptomatic hyperuricaemia (AHUA) controls was performed to identify novel gout loci that aggravate AHUA into gout. Methods We carried out a GWAS of 945 clinically defined gout cases and 1003 AHUA controls followed by 2 replication studies. In total, 2860 gout cases and 3149 AHUA controls (all Japanese men) were analysed. We also compared the ORs for each locus in the present GWAS (gout vs AHUA) with those in the previous GWAS (gout vs normouricaemia). Results This new approach enabled us to identify two novel gout loci (rs7927466 of CNTN5 and rs9952962 of MIR302F) and one suggestive locus (rs12980365 of ZNF724) at the genome-wide significance level (p<5.0×10-8). The present study also identified the loci of ABCG2, ALDH2 and SLC2A9. One of them, rs671 of ALDH2, was identified as a gout locus by GWAS for the first time. Comparing ORs for each locus in the present versus the previous GWAS revealed three {\^a} € gout vs AHUA GWAS'-specific loci (CNTN5, MIR302F and ZNF724) to be clearly associated with mechanisms of gout development which distinctly differ from the known gout risk loci that basically elevate serum uric acid level. Conclusions This meta-analysis is the first to reveal the loci associated with crystal-induced inflammation, the last step in gout development that aggravates AHUA into gout. Our findings should help to elucidate the molecular mechanisms of gout development and assist the prevention of gout attacks in high-risk AHUA individuals.",

author = "Yusuke Kawamura and Hirofumi Nakaoka and Akiyoshi Nakayama and Yukinori Okada and Ken Yamamoto and Toshihide Higashino and Masayuki Sakiyama and Toru Shimizu and Hiroshi Ooyama and Keiko Ooyama and Mitsuo Nagase and Yuji Hidaka and Yuko Shirahama and Kazuyoshi Hosomichi and Yuichiro Nishida and Ippei Shimoshikiryo and Asahi Hishida and Sakurako Katsuura-Kamano and Seiko Shimizu and Makoto Kawaguchi and Hirokazu Uemura and Rie Ibusuki and Megumi Hara and Mariko Naito and Mikiya Takao and Mayuko Nakajima and Satoko Iwasawa and Hiroshi Nakashima and Keizo Ohnaka and Takahiro Nakamura and Blanka Stiburkova and Merriman, {Tony R.} and Masahiro Nakatochi and Sahoko Ichihara and Mitsuhiro Yokota and Tappei Takada and Tatsuya Saitoh and Yoichiro Kamatani and Atsushi Takahashi and Kokichi Arisawa and Toshiro Takezaki and Keitaro Tanaka and Kenji Wakai and Michiaki Kubo and Tatsuo Hosoya and Kimiyoshi Ichida and Ituro Inoue and Nariyoshi Shinomiya and Hirotaka Matsuo",

note = "Funding Information: Funding 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, 221s0002, 16H06279 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 Japan multi-institutional collaborative cohort 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. Funding Information: 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, 221S0002, 16H06279 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 Japan Multi-Institutional Collaborative Cohort Study was supported by Grants-in-Aid for Scienti{\"i}¬ c 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: {\textcopyright} {\textcopyright} Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.",

year = "2019",

month = oct,

day = "1",

doi = "10.1136/annrheumdis-2019-215521",

language = "English",

volume = "78",

pages = "1430--1437",

journal = "Annals of the Rheumatic Diseases",

issn = "0003-4967",

publisher = "BMJ Publishing Group",

number = "10",

}

TY - JOUR

T1 - Genome-wide association study revealed novel loci which aggravate asymptomatic hyperuricaemia into gout

AU - Kawamura, Yusuke

AU - Nakaoka, Hirofumi

AU - Nakayama, Akiyoshi

AU - Okada, Yukinori

AU - Yamamoto, Ken

AU - Higashino, Toshihide

AU - Sakiyama, Masayuki

AU - Shimizu, Toru

AU - Ooyama, Hiroshi

AU - Ooyama, Keiko

AU - Nagase, Mitsuo

AU - Hidaka, Yuji

AU - Shirahama, Yuko

AU - Hosomichi, Kazuyoshi

AU - Nishida, Yuichiro

AU - Shimoshikiryo, Ippei

AU - Hishida, Asahi

AU - Katsuura-Kamano, Sakurako

AU - Shimizu, Seiko

AU - Kawaguchi, Makoto

AU - Uemura, Hirokazu

AU - Ibusuki, Rie

AU - Hara, Megumi

AU - Naito, Mariko

AU - Takao, Mikiya

AU - Nakajima, Mayuko

AU - Iwasawa, Satoko

AU - Nakashima, Hiroshi

AU - Ohnaka, Keizo

AU - Nakamura, Takahiro

AU - Stiburkova, Blanka

AU - Merriman, Tony R.

AU - Nakatochi, Masahiro

AU - Ichihara, Sahoko

AU - Yokota, Mitsuhiro

AU - Takada, Tappei

AU - Saitoh, Tatsuya

AU - Kamatani, Yoichiro

AU - Takahashi, Atsushi

AU - Arisawa, Kokichi

AU - Takezaki, Toshiro

AU - Tanaka, Keitaro

AU - Wakai, Kenji

AU - Kubo, Michiaki

AU - Hosoya, Tatsuo

AU - Ichida, Kimiyoshi

AU - Inoue, Ituro

AU - Shinomiya, Nariyoshi

AU - Matsuo, Hirotaka

N1 - Funding Information: Funding 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, 221s0002, 16H06279 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 Japan multi-institutional collaborative cohort 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. Funding Information: 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, 221S0002, 16H06279 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 Japan Multi-Institutional Collaborative Cohort Study was supported by Grants-in-Aid for Scientiï¬ c 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: © © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.

PY - 2019/10/1

Y1 - 2019/10/1

N2 - Objective The first ever genome-wide association study (GWAS) of clinically defined gout cases and asymptomatic hyperuricaemia (AHUA) controls was performed to identify novel gout loci that aggravate AHUA into gout. Methods We carried out a GWAS of 945 clinically defined gout cases and 1003 AHUA controls followed by 2 replication studies. In total, 2860 gout cases and 3149 AHUA controls (all Japanese men) were analysed. We also compared the ORs for each locus in the present GWAS (gout vs AHUA) with those in the previous GWAS (gout vs normouricaemia). Results This new approach enabled us to identify two novel gout loci (rs7927466 of CNTN5 and rs9952962 of MIR302F) and one suggestive locus (rs12980365 of ZNF724) at the genome-wide significance level (p<5.0×10-8). The present study also identified the loci of ABCG2, ALDH2 and SLC2A9. One of them, rs671 of ALDH2, was identified as a gout locus by GWAS for the first time. Comparing ORs for each locus in the present versus the previous GWAS revealed three â € gout vs AHUA GWAS'-specific loci (CNTN5, MIR302F and ZNF724) to be clearly associated with mechanisms of gout development which distinctly differ from the known gout risk loci that basically elevate serum uric acid level. Conclusions This meta-analysis is the first to reveal the loci associated with crystal-induced inflammation, the last step in gout development that aggravates AHUA into gout. Our findings should help to elucidate the molecular mechanisms of gout development and assist the prevention of gout attacks in high-risk AHUA individuals.

AB - Objective The first ever genome-wide association study (GWAS) of clinically defined gout cases and asymptomatic hyperuricaemia (AHUA) controls was performed to identify novel gout loci that aggravate AHUA into gout. Methods We carried out a GWAS of 945 clinically defined gout cases and 1003 AHUA controls followed by 2 replication studies. In total, 2860 gout cases and 3149 AHUA controls (all Japanese men) were analysed. We also compared the ORs for each locus in the present GWAS (gout vs AHUA) with those in the previous GWAS (gout vs normouricaemia). Results This new approach enabled us to identify two novel gout loci (rs7927466 of CNTN5 and rs9952962 of MIR302F) and one suggestive locus (rs12980365 of ZNF724) at the genome-wide significance level (p<5.0×10-8). The present study also identified the loci of ABCG2, ALDH2 and SLC2A9. One of them, rs671 of ALDH2, was identified as a gout locus by GWAS for the first time. Comparing ORs for each locus in the present versus the previous GWAS revealed three â € gout vs AHUA GWAS'-specific loci (CNTN5, MIR302F and ZNF724) to be clearly associated with mechanisms of gout development which distinctly differ from the known gout risk loci that basically elevate serum uric acid level. Conclusions This meta-analysis is the first to reveal the loci associated with crystal-induced inflammation, the last step in gout development that aggravates AHUA into gout. Our findings should help to elucidate the molecular mechanisms of gout development and assist the prevention of gout attacks in high-risk AHUA individuals.

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UR - http://www.scopus.com/inward/citedby.url?scp=85068737607&partnerID=8YFLogxK

U2 - 10.1136/annrheumdis-2019-215521

DO - 10.1136/annrheumdis-2019-215521

M3 - Article

C2 - 31289104

AN - SCOPUS:85068737607

SN - 0003-4967

VL - 78

SP - 1430

EP - 1437

JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

IS - 10

ER -

Genome-wide association study revealed novel loci which aggravate asymptomatic hyperuricaemia into gout

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