GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes

Akiyoshi Nakayama, Hirofumi Nakaoka, Ken Yamamoto, Masayuki Sakiyama, Amara Shaukat, Yu Toyoda, Yukinori Okada, Yoichiro Kamatani, Takahiro Nakamura, Tappei Takada, Katsuhisa Inoue, Tomoya Yasujima, Hiroaki Yuasa, Yuko Shirahama, Hiroshi Nakashima, Seiko Shimizu, Toshihide Higashino, Yusuke Kawamura, Hiraku Ogata, Makoto KawaguchiYasuyuki Ohkawa, Inaho Danjoh, Atsumi Tokumasu, Keiko Ooyama, Toshimitsu Ito, Takaaki Kondo, Kenji Wakai, Blanka Stiburkova, Karel Pavelka, Lisa K. Stamp, Nicola Dalbeth, Yutaka Sakurai, Hiroshi Suzuki, Makoto Hosoyamada, Shin Fujimori, Takashi Yokoo, Tatsuo Hosoya, Ituro Inoue, Atsushi Takahashi, Michiaki Kubo, Hiroshi Ooyama, Toru Shimizu, Kimiyoshi Ichida, Nariyoshi Shinomiya, Tony R. Merriman, Hirotaka Matsuo

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Objective A genome-wide association study (GWAS) of gout and its subtypes was performed to identify novel gout loci, including those that are subtype-specific. Methods Putative causal association signals from a GWAS of 945 clinically defined gout cases and 1213 controls from Japanese males were replicated with 1396 cases and 1268 controls using a custom chip of 1961 single nucleotide polymorphisms (SNPs). We also first conducted GWASs of gout subtypes. Replication with Caucasian and New Zealand Polynesian samples was done to further validate the loci identified in this study. Results In addition to the five loci we reported previously, further susceptibility loci were identified at a genome-wide significance level (p<5.0×10-8): Urate transporter genes (SLC22A12 and SLC17A1) and HIST1H2BF-HIST1H4E for all gout cases, and NIPAL1 and FAM35A for the renal underexcretion gout subtype. While NIPAL1 encodes a magnesium transporter, functional analysis did not detect urate transport via NIPAL1, suggesting an indirect association with urate handling. Localisation analysis in the human kidney revealed expression of NIPAL1 and FAM35A mainly in the distal tubules, which suggests the involvement of the distal nephron in urate handling in humans. Clinically ascertained male patients with gout and controls of Caucasian and Polynesian ancestries were also genotyped, and FAM35A was associated with gout in all cases. A meta-analysis of the three populations revealed FAM35A to be associated with gout at a genome-wide level of significance (p meta =3.58×10-8). Conclusions Our findings including novel gout risk loci provide further understanding of the molecular pathogenesis of gout and lead to a novel concept for the therapeutic target of gout/hyperuricaemia.

Original languageEnglish
Pages (from-to)869-877
Number of pages9
JournalAnnals of the Rheumatic Diseases
Volume76
Issue number5
DOIs
Publication statusPublished - May 1 2017

Fingerprint

Gout
Genome-Wide Association Study
Genes
Uric Acid
Functional analysis
Polymorphism
Magnesium
Nucleotides
urate transporter
Genome
Kidney
Nephrons
New Zealand
Single Nucleotide Polymorphism
Meta-Analysis

All Science Journal Classification (ASJC) codes

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

Cite this

GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes. / Nakayama, Akiyoshi; Nakaoka, Hirofumi; Yamamoto, Ken; Sakiyama, Masayuki; Shaukat, Amara; Toyoda, Yu; Okada, Yukinori; Kamatani, Yoichiro; Nakamura, Takahiro; Takada, Tappei; Inoue, Katsuhisa; Yasujima, Tomoya; Yuasa, Hiroaki; Shirahama, Yuko; Nakashima, Hiroshi; Shimizu, Seiko; Higashino, Toshihide; Kawamura, Yusuke; Ogata, Hiraku; Kawaguchi, Makoto; Ohkawa, Yasuyuki; Danjoh, Inaho; Tokumasu, Atsumi; Ooyama, Keiko; Ito, Toshimitsu; Kondo, Takaaki; Wakai, Kenji; Stiburkova, Blanka; Pavelka, Karel; Stamp, Lisa K.; Dalbeth, Nicola; Sakurai, Yutaka; Suzuki, Hiroshi; Hosoyamada, Makoto; Fujimori, Shin; Yokoo, Takashi; Hosoya, Tatsuo; Inoue, Ituro; Takahashi, Atsushi; Kubo, Michiaki; Ooyama, Hiroshi; Shimizu, Toru; Ichida, Kimiyoshi; Shinomiya, Nariyoshi; Merriman, Tony R.; Matsuo, Hirotaka.

In: Annals of the Rheumatic Diseases, Vol. 76, No. 5, 01.05.2017, p. 869-877.

Research output: Contribution to journalArticle

Nakayama, A, Nakaoka, H, Yamamoto, K, Sakiyama, M, Shaukat, A, Toyoda, Y, Okada, Y, Kamatani, Y, Nakamura, T, Takada, T, Inoue, K, Yasujima, T, Yuasa, H, Shirahama, Y, Nakashima, H, Shimizu, S, Higashino, T, Kawamura, Y, Ogata, H, Kawaguchi, M, Ohkawa, Y, Danjoh, I, Tokumasu, A, Ooyama, K, Ito, T, Kondo, T, Wakai, K, Stiburkova, B, Pavelka, K, Stamp, LK, Dalbeth, N, Sakurai, Y, Suzuki, H, Hosoyamada, M, Fujimori, S, Yokoo, T, Hosoya, T, Inoue, I, Takahashi, A, Kubo, M, Ooyama, H, Shimizu, T, Ichida, K, Shinomiya, N, Merriman, TR & Matsuo, H 2017, 'GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes', Annals of the Rheumatic Diseases, vol. 76, no. 5, pp. 869-877. https://doi.org/10.1136/annrheumdis-2016-209632
Nakayama, Akiyoshi ; Nakaoka, Hirofumi ; Yamamoto, Ken ; Sakiyama, Masayuki ; Shaukat, Amara ; Toyoda, Yu ; Okada, Yukinori ; Kamatani, Yoichiro ; Nakamura, Takahiro ; Takada, Tappei ; Inoue, Katsuhisa ; Yasujima, Tomoya ; Yuasa, Hiroaki ; Shirahama, Yuko ; Nakashima, Hiroshi ; Shimizu, Seiko ; Higashino, Toshihide ; Kawamura, Yusuke ; Ogata, Hiraku ; Kawaguchi, Makoto ; Ohkawa, Yasuyuki ; Danjoh, Inaho ; Tokumasu, Atsumi ; Ooyama, Keiko ; Ito, Toshimitsu ; Kondo, Takaaki ; Wakai, Kenji ; Stiburkova, Blanka ; Pavelka, Karel ; Stamp, Lisa K. ; Dalbeth, Nicola ; Sakurai, Yutaka ; Suzuki, Hiroshi ; Hosoyamada, Makoto ; Fujimori, Shin ; Yokoo, Takashi ; Hosoya, Tatsuo ; Inoue, Ituro ; Takahashi, Atsushi ; Kubo, Michiaki ; Ooyama, Hiroshi ; Shimizu, Toru ; Ichida, Kimiyoshi ; Shinomiya, Nariyoshi ; Merriman, Tony R. ; Matsuo, Hirotaka. / GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes. In: Annals of the Rheumatic Diseases. 2017 ; Vol. 76, No. 5. pp. 869-877.
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abstract = "Objective A genome-wide association study (GWAS) of gout and its subtypes was performed to identify novel gout loci, including those that are subtype-specific. Methods Putative causal association signals from a GWAS of 945 clinically defined gout cases and 1213 controls from Japanese males were replicated with 1396 cases and 1268 controls using a custom chip of 1961 single nucleotide polymorphisms (SNPs). We also first conducted GWASs of gout subtypes. Replication with Caucasian and New Zealand Polynesian samples was done to further validate the loci identified in this study. Results In addition to the five loci we reported previously, further susceptibility loci were identified at a genome-wide significance level (p<5.0×10-8): Urate transporter genes (SLC22A12 and SLC17A1) and HIST1H2BF-HIST1H4E for all gout cases, and NIPAL1 and FAM35A for the renal underexcretion gout subtype. While NIPAL1 encodes a magnesium transporter, functional analysis did not detect urate transport via NIPAL1, suggesting an indirect association with urate handling. Localisation analysis in the human kidney revealed expression of NIPAL1 and FAM35A mainly in the distal tubules, which suggests the involvement of the distal nephron in urate handling in humans. Clinically ascertained male patients with gout and controls of Caucasian and Polynesian ancestries were also genotyped, and FAM35A was associated with gout in all cases. A meta-analysis of the three populations revealed FAM35A to be associated with gout at a genome-wide level of significance (p meta =3.58×10-8). Conclusions Our findings including novel gout risk loci provide further understanding of the molecular pathogenesis of gout and lead to a novel concept for the therapeutic target of gout/hyperuricaemia.",
author = "Akiyoshi Nakayama and Hirofumi Nakaoka and Ken Yamamoto and Masayuki Sakiyama and Amara Shaukat and Yu Toyoda and Yukinori Okada and Yoichiro Kamatani and Takahiro Nakamura and Tappei Takada and Katsuhisa Inoue and Tomoya Yasujima and Hiroaki Yuasa and Yuko Shirahama and Hiroshi Nakashima and Seiko Shimizu and Toshihide Higashino and Yusuke Kawamura and Hiraku Ogata and Makoto Kawaguchi and Yasuyuki Ohkawa and Inaho Danjoh and Atsumi Tokumasu and Keiko Ooyama and Toshimitsu Ito and Takaaki Kondo and Kenji Wakai and Blanka Stiburkova and Karel Pavelka and Stamp, {Lisa K.} and Nicola Dalbeth and Yutaka Sakurai and Hiroshi Suzuki and Makoto Hosoyamada and Shin Fujimori and Takashi Yokoo and Tatsuo Hosoya and Ituro Inoue and Atsushi Takahashi and Michiaki Kubo and Hiroshi Ooyama and Toru Shimizu and Kimiyoshi Ichida and Nariyoshi Shinomiya and Merriman, {Tony R.} and Hirotaka Matsuo",
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TY - JOUR

T1 - GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes

AU - Nakayama, Akiyoshi

AU - Nakaoka, Hirofumi

AU - Yamamoto, Ken

AU - Sakiyama, Masayuki

AU - Shaukat, Amara

AU - Toyoda, Yu

AU - Okada, Yukinori

AU - Kamatani, Yoichiro

AU - Nakamura, Takahiro

AU - Takada, Tappei

AU - Inoue, Katsuhisa

AU - Yasujima, Tomoya

AU - Yuasa, Hiroaki

AU - Shirahama, Yuko

AU - Nakashima, Hiroshi

AU - Shimizu, Seiko

AU - Higashino, Toshihide

AU - Kawamura, Yusuke

AU - Ogata, Hiraku

AU - Kawaguchi, Makoto

AU - Ohkawa, Yasuyuki

AU - Danjoh, Inaho

AU - Tokumasu, Atsumi

AU - Ooyama, Keiko

AU - Ito, Toshimitsu

AU - Kondo, Takaaki

AU - Wakai, Kenji

AU - Stiburkova, Blanka

AU - Pavelka, Karel

AU - Stamp, Lisa K.

AU - Dalbeth, Nicola

AU - Sakurai, Yutaka

AU - Suzuki, Hiroshi

AU - Hosoyamada, Makoto

AU - Fujimori, Shin

AU - Yokoo, Takashi

AU - Hosoya, Tatsuo

AU - Inoue, Ituro

AU - Takahashi, Atsushi

AU - Kubo, Michiaki

AU - Ooyama, Hiroshi

AU - Shimizu, Toru

AU - Ichida, Kimiyoshi

AU - Shinomiya, Nariyoshi

AU - Merriman, Tony R.

AU - Matsuo, Hirotaka

PY - 2017/5/1

Y1 - 2017/5/1

N2 - Objective A genome-wide association study (GWAS) of gout and its subtypes was performed to identify novel gout loci, including those that are subtype-specific. Methods Putative causal association signals from a GWAS of 945 clinically defined gout cases and 1213 controls from Japanese males were replicated with 1396 cases and 1268 controls using a custom chip of 1961 single nucleotide polymorphisms (SNPs). We also first conducted GWASs of gout subtypes. Replication with Caucasian and New Zealand Polynesian samples was done to further validate the loci identified in this study. Results In addition to the five loci we reported previously, further susceptibility loci were identified at a genome-wide significance level (p<5.0×10-8): Urate transporter genes (SLC22A12 and SLC17A1) and HIST1H2BF-HIST1H4E for all gout cases, and NIPAL1 and FAM35A for the renal underexcretion gout subtype. While NIPAL1 encodes a magnesium transporter, functional analysis did not detect urate transport via NIPAL1, suggesting an indirect association with urate handling. Localisation analysis in the human kidney revealed expression of NIPAL1 and FAM35A mainly in the distal tubules, which suggests the involvement of the distal nephron in urate handling in humans. Clinically ascertained male patients with gout and controls of Caucasian and Polynesian ancestries were also genotyped, and FAM35A was associated with gout in all cases. A meta-analysis of the three populations revealed FAM35A to be associated with gout at a genome-wide level of significance (p meta =3.58×10-8). Conclusions Our findings including novel gout risk loci provide further understanding of the molecular pathogenesis of gout and lead to a novel concept for the therapeutic target of gout/hyperuricaemia.

AB - Objective A genome-wide association study (GWAS) of gout and its subtypes was performed to identify novel gout loci, including those that are subtype-specific. Methods Putative causal association signals from a GWAS of 945 clinically defined gout cases and 1213 controls from Japanese males were replicated with 1396 cases and 1268 controls using a custom chip of 1961 single nucleotide polymorphisms (SNPs). We also first conducted GWASs of gout subtypes. Replication with Caucasian and New Zealand Polynesian samples was done to further validate the loci identified in this study. Results In addition to the five loci we reported previously, further susceptibility loci were identified at a genome-wide significance level (p<5.0×10-8): Urate transporter genes (SLC22A12 and SLC17A1) and HIST1H2BF-HIST1H4E for all gout cases, and NIPAL1 and FAM35A for the renal underexcretion gout subtype. While NIPAL1 encodes a magnesium transporter, functional analysis did not detect urate transport via NIPAL1, suggesting an indirect association with urate handling. Localisation analysis in the human kidney revealed expression of NIPAL1 and FAM35A mainly in the distal tubules, which suggests the involvement of the distal nephron in urate handling in humans. Clinically ascertained male patients with gout and controls of Caucasian and Polynesian ancestries were also genotyped, and FAM35A was associated with gout in all cases. A meta-analysis of the three populations revealed FAM35A to be associated with gout at a genome-wide level of significance (p meta =3.58×10-8). Conclusions Our findings including novel gout risk loci provide further understanding of the molecular pathogenesis of gout and lead to a novel concept for the therapeutic target of gout/hyperuricaemia.

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