Genome-wide association study of clinically defined Gout identifies multiple risk loci and its association with clinical subtypes

Hirotaka Matsuo, Ken Yamamoto, Hirofumi Nakaoka, Akiyoshi Nakayama, Masayuki Sakiyama, Toshinori Chiba, Atsushi Takahashi, Takahiro Nakamura, Hiroshi Nakashima, Yuzo Takada, Inaho Danjoh, Seiko Shimizu, Junko Abe, Yusuke Kawamura, Sho Terashige, Hiraku Ogata, Seishiro Tatsukawa, Guang Yin, Rieko Okada, Emi MoritaMariko Naito, Atsumi Tokumasu, Hiroyuki Onoue, Keiichi Iwaya, Toshimitsu Ito, Tappei Takada, Katsuhisa Inoue, Yukio Kato, Yukio Nakamura, Yutaka Sakurai, Hiroshi Suzuki, Yoshikatsu Kanai, Tatsuo Hosoya, Nobuyuki Hamajima, Ituro Inoue, Michiaki Kubo, Kimiyoshi Ichida, Hiroshi Ooyama, Toru Shimizu, Nariyoshi Shinomiya

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

Objective: Gout, caused by hyperuricaemia, is a multifactorial disease. Although genome-wide association studies (GWASs) of gout have been reported, they included self-reported gout cases in which clinical information was insufficient. Therefore, the relationship between genetic variation and clinical subtypes of gout remains unclear. Here, we first performed a GWAS of clinically defined gout cases only. Methods: A GWAS was conducted with 945 patients with clinically defined gout and 1213 controls in a Japanese male population, followed by replication study of 1048 clinically defined cases and 1334 controls. Results: Five gout susceptibility loci were identified at the genome-wide significance level (p<5.0×10-8), which contained well-known urate transporter genes (ABCG2 and SLC2A9) and additional genes: rs1260326 (p=1.9×10-12; OR=1.36) of GCKR (a gene for glucose and lipid metabolism), rs2188380 (p=1.6×10-23; OR=1.75) of MYL2-CUX2 (genes associated with cholesterol and diabetes mellitus) and rs4073582 (p=6.4×10-9; OR=1.66) of CNIH-2 (a gene for regulation of glutamate signalling). The latter two are identified as novel gout loci. Furthermore, among the identified single-nucleotide polymorphisms (SNPs), we demonstrated that the SNPs of ABCG2 and SLC2A9 were differentially associated with types of gout and clinical parameters underlying specific subtypes (renal underexcretion type and renal overload type). The effect of the risk allele of each SNP on clinical parameters showed significant linear relationships with the ratio of the case-control ORs for two distinct types of gout (r=0.96 [p=4.8×10-4] for urate clearance and r=0.96 [p=5.0×10-4] for urinary urate excretion). Conclusions Our findings provide clues to better understand the pathogenesis of gout and will be useful for development of companion diagnostics.

Original languageEnglish
Pages (from-to)652-659
Number of pages8
JournalAnnals of the Rheumatic Diseases
Volume75
Issue number4
DOIs
Publication statusPublished - 04-2016

Fingerprint

Gout
Genome-Wide Association Study
Genes
Polymorphism
Nucleotides
Single Nucleotide Polymorphism
Uric Acid
Kidney
Medical problems
Glutamic Acid
Lipid Metabolism
Cholesterol
Diabetes Mellitus
Glucose
Alleles
Genome

All Science Journal Classification (ASJC) codes

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

Cite this

Matsuo, Hirotaka ; Yamamoto, Ken ; Nakaoka, Hirofumi ; Nakayama, Akiyoshi ; Sakiyama, Masayuki ; Chiba, Toshinori ; Takahashi, Atsushi ; Nakamura, Takahiro ; Nakashima, Hiroshi ; Takada, Yuzo ; Danjoh, Inaho ; Shimizu, Seiko ; Abe, Junko ; Kawamura, Yusuke ; Terashige, Sho ; Ogata, Hiraku ; Tatsukawa, Seishiro ; Yin, Guang ; Okada, Rieko ; Morita, Emi ; Naito, Mariko ; Tokumasu, Atsumi ; Onoue, Hiroyuki ; Iwaya, Keiichi ; Ito, Toshimitsu ; Takada, Tappei ; Inoue, Katsuhisa ; Kato, Yukio ; Nakamura, Yukio ; Sakurai, Yutaka ; Suzuki, Hiroshi ; Kanai, Yoshikatsu ; Hosoya, Tatsuo ; Hamajima, Nobuyuki ; Inoue, Ituro ; Kubo, Michiaki ; Ichida, Kimiyoshi ; Ooyama, Hiroshi ; Shimizu, Toru ; Shinomiya, Nariyoshi. / Genome-wide association study of clinically defined Gout identifies multiple risk loci and its association with clinical subtypes. In: Annals of the Rheumatic Diseases. 2016 ; Vol. 75, No. 4. pp. 652-659.
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title = "Genome-wide association study of clinically defined Gout identifies multiple risk loci and its association with clinical subtypes",
abstract = "Objective: Gout, caused by hyperuricaemia, is a multifactorial disease. Although genome-wide association studies (GWASs) of gout have been reported, they included self-reported gout cases in which clinical information was insufficient. Therefore, the relationship between genetic variation and clinical subtypes of gout remains unclear. Here, we first performed a GWAS of clinically defined gout cases only. Methods: A GWAS was conducted with 945 patients with clinically defined gout and 1213 controls in a Japanese male population, followed by replication study of 1048 clinically defined cases and 1334 controls. Results: Five gout susceptibility loci were identified at the genome-wide significance level (p<5.0×10-8), which contained well-known urate transporter genes (ABCG2 and SLC2A9) and additional genes: rs1260326 (p=1.9×10-12; OR=1.36) of GCKR (a gene for glucose and lipid metabolism), rs2188380 (p=1.6×10-23; OR=1.75) of MYL2-CUX2 (genes associated with cholesterol and diabetes mellitus) and rs4073582 (p=6.4×10-9; OR=1.66) of CNIH-2 (a gene for regulation of glutamate signalling). The latter two are identified as novel gout loci. Furthermore, among the identified single-nucleotide polymorphisms (SNPs), we demonstrated that the SNPs of ABCG2 and SLC2A9 were differentially associated with types of gout and clinical parameters underlying specific subtypes (renal underexcretion type and renal overload type). The effect of the risk allele of each SNP on clinical parameters showed significant linear relationships with the ratio of the case-control ORs for two distinct types of gout (r=0.96 [p=4.8×10-4] for urate clearance and r=0.96 [p=5.0×10-4] for urinary urate excretion). Conclusions Our findings provide clues to better understand the pathogenesis of gout and will be useful for development of companion diagnostics.",
author = "Hirotaka Matsuo and Ken Yamamoto and Hirofumi Nakaoka and Akiyoshi Nakayama and Masayuki Sakiyama and Toshinori Chiba and Atsushi Takahashi and Takahiro Nakamura and Hiroshi Nakashima and Yuzo Takada and Inaho Danjoh and Seiko Shimizu and Junko Abe and Yusuke Kawamura and Sho Terashige and Hiraku Ogata and Seishiro Tatsukawa and Guang Yin and Rieko Okada and Emi Morita and Mariko Naito and Atsumi Tokumasu and Hiroyuki Onoue and Keiichi Iwaya and Toshimitsu Ito and Tappei Takada and Katsuhisa Inoue and Yukio Kato and Yukio Nakamura and Yutaka Sakurai and Hiroshi Suzuki and Yoshikatsu Kanai and Tatsuo Hosoya and Nobuyuki Hamajima and Ituro Inoue and Michiaki Kubo and Kimiyoshi Ichida and Hiroshi Ooyama and Toru Shimizu and Nariyoshi Shinomiya",
year = "2016",
month = "4",
doi = "10.1136/annrheumdis-2014-206191",
language = "English",
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pages = "652--659",
journal = "Annals of the Rheumatic Diseases",
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Matsuo, H, Yamamoto, K, Nakaoka, H, Nakayama, A, Sakiyama, M, Chiba, T, Takahashi, A, Nakamura, T, Nakashima, H, Takada, Y, Danjoh, I, Shimizu, S, Abe, J, Kawamura, Y, Terashige, S, Ogata, H, Tatsukawa, S, Yin, G, Okada, R, Morita, E, Naito, M, Tokumasu, A, Onoue, H, Iwaya, K, Ito, T, Takada, T, Inoue, K, Kato, Y, Nakamura, Y, Sakurai, Y, Suzuki, H, Kanai, Y, Hosoya, T, Hamajima, N, Inoue, I, Kubo, M, Ichida, K, Ooyama, H, Shimizu, T & Shinomiya, N 2016, 'Genome-wide association study of clinically defined Gout identifies multiple risk loci and its association with clinical subtypes', Annals of the Rheumatic Diseases, vol. 75, no. 4, pp. 652-659. https://doi.org/10.1136/annrheumdis-2014-206191

Genome-wide association study of clinically defined Gout identifies multiple risk loci and its association with clinical subtypes. / Matsuo, Hirotaka; Yamamoto, Ken; Nakaoka, Hirofumi; Nakayama, Akiyoshi; Sakiyama, Masayuki; Chiba, Toshinori; Takahashi, Atsushi; Nakamura, Takahiro; Nakashima, Hiroshi; Takada, Yuzo; Danjoh, Inaho; Shimizu, Seiko; Abe, Junko; Kawamura, Yusuke; Terashige, Sho; Ogata, Hiraku; Tatsukawa, Seishiro; Yin, Guang; Okada, Rieko; Morita, Emi; Naito, Mariko; Tokumasu, Atsumi; Onoue, Hiroyuki; Iwaya, Keiichi; Ito, Toshimitsu; Takada, Tappei; Inoue, Katsuhisa; Kato, Yukio; Nakamura, Yukio; Sakurai, Yutaka; Suzuki, Hiroshi; Kanai, Yoshikatsu; Hosoya, Tatsuo; Hamajima, Nobuyuki; Inoue, Ituro; Kubo, Michiaki; Ichida, Kimiyoshi; Ooyama, Hiroshi; Shimizu, Toru; Shinomiya, Nariyoshi.

In: Annals of the Rheumatic Diseases, Vol. 75, No. 4, 04.2016, p. 652-659.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genome-wide association study of clinically defined Gout identifies multiple risk loci and its association with clinical subtypes

AU - Matsuo, Hirotaka

AU - Yamamoto, Ken

AU - Nakaoka, Hirofumi

AU - Nakayama, Akiyoshi

AU - Sakiyama, Masayuki

AU - Chiba, Toshinori

AU - Takahashi, Atsushi

AU - Nakamura, Takahiro

AU - Nakashima, Hiroshi

AU - Takada, Yuzo

AU - Danjoh, Inaho

AU - Shimizu, Seiko

AU - Abe, Junko

AU - Kawamura, Yusuke

AU - Terashige, Sho

AU - Ogata, Hiraku

AU - Tatsukawa, Seishiro

AU - Yin, Guang

AU - Okada, Rieko

AU - Morita, Emi

AU - Naito, Mariko

AU - Tokumasu, Atsumi

AU - Onoue, Hiroyuki

AU - Iwaya, Keiichi

AU - Ito, Toshimitsu

AU - Takada, Tappei

AU - Inoue, Katsuhisa

AU - Kato, Yukio

AU - Nakamura, Yukio

AU - Sakurai, Yutaka

AU - Suzuki, Hiroshi

AU - Kanai, Yoshikatsu

AU - Hosoya, Tatsuo

AU - Hamajima, Nobuyuki

AU - Inoue, Ituro

AU - Kubo, Michiaki

AU - Ichida, Kimiyoshi

AU - Ooyama, Hiroshi

AU - Shimizu, Toru

AU - Shinomiya, Nariyoshi

PY - 2016/4

Y1 - 2016/4

N2 - Objective: Gout, caused by hyperuricaemia, is a multifactorial disease. Although genome-wide association studies (GWASs) of gout have been reported, they included self-reported gout cases in which clinical information was insufficient. Therefore, the relationship between genetic variation and clinical subtypes of gout remains unclear. Here, we first performed a GWAS of clinically defined gout cases only. Methods: A GWAS was conducted with 945 patients with clinically defined gout and 1213 controls in a Japanese male population, followed by replication study of 1048 clinically defined cases and 1334 controls. Results: Five gout susceptibility loci were identified at the genome-wide significance level (p<5.0×10-8), which contained well-known urate transporter genes (ABCG2 and SLC2A9) and additional genes: rs1260326 (p=1.9×10-12; OR=1.36) of GCKR (a gene for glucose and lipid metabolism), rs2188380 (p=1.6×10-23; OR=1.75) of MYL2-CUX2 (genes associated with cholesterol and diabetes mellitus) and rs4073582 (p=6.4×10-9; OR=1.66) of CNIH-2 (a gene for regulation of glutamate signalling). The latter two are identified as novel gout loci. Furthermore, among the identified single-nucleotide polymorphisms (SNPs), we demonstrated that the SNPs of ABCG2 and SLC2A9 were differentially associated with types of gout and clinical parameters underlying specific subtypes (renal underexcretion type and renal overload type). The effect of the risk allele of each SNP on clinical parameters showed significant linear relationships with the ratio of the case-control ORs for two distinct types of gout (r=0.96 [p=4.8×10-4] for urate clearance and r=0.96 [p=5.0×10-4] for urinary urate excretion). Conclusions Our findings provide clues to better understand the pathogenesis of gout and will be useful for development of companion diagnostics.

AB - Objective: Gout, caused by hyperuricaemia, is a multifactorial disease. Although genome-wide association studies (GWASs) of gout have been reported, they included self-reported gout cases in which clinical information was insufficient. Therefore, the relationship between genetic variation and clinical subtypes of gout remains unclear. Here, we first performed a GWAS of clinically defined gout cases only. Methods: A GWAS was conducted with 945 patients with clinically defined gout and 1213 controls in a Japanese male population, followed by replication study of 1048 clinically defined cases and 1334 controls. Results: Five gout susceptibility loci were identified at the genome-wide significance level (p<5.0×10-8), which contained well-known urate transporter genes (ABCG2 and SLC2A9) and additional genes: rs1260326 (p=1.9×10-12; OR=1.36) of GCKR (a gene for glucose and lipid metabolism), rs2188380 (p=1.6×10-23; OR=1.75) of MYL2-CUX2 (genes associated with cholesterol and diabetes mellitus) and rs4073582 (p=6.4×10-9; OR=1.66) of CNIH-2 (a gene for regulation of glutamate signalling). The latter two are identified as novel gout loci. Furthermore, among the identified single-nucleotide polymorphisms (SNPs), we demonstrated that the SNPs of ABCG2 and SLC2A9 were differentially associated with types of gout and clinical parameters underlying specific subtypes (renal underexcretion type and renal overload type). The effect of the risk allele of each SNP on clinical parameters showed significant linear relationships with the ratio of the case-control ORs for two distinct types of gout (r=0.96 [p=4.8×10-4] for urate clearance and r=0.96 [p=5.0×10-4] for urinary urate excretion). Conclusions Our findings provide clues to better understand the pathogenesis of gout and will be useful for development of companion diagnostics.

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