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.
authors: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors: Hirotaka
authors: H
authors: Matsuo
authors: Department of Medical Chemistry, Kurume University School of Medicine, Kurume, Fukuoka, Japan.
authors: Ken
authors: K
authors: Yamamoto
authors: Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Mishima, Shizuoka, Japan.
authors: Hirofumi
authors: H
authors: Nakaoka
authors: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan Medical Group, Headquarters, Iwo-to Air Base Group, Japan Air Self-Defense Force, Tokyo, Japan.
authors: Akiyoshi
authors: A
authors: Nakayama
authors: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan Department of Dermatology, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors: Masayuki
authors: M
authors: Sakiyama
authors: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors: Toshinori
authors: T
authors: Chiba
authors: Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN, Yokohama, Kanagawa, Japan.
authors: Atsushi
authors: A
authors: Takahashi
authors: Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN, Yokohama, Kanagawa, Japan Laboratory for Mathematics, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors: Takahiro
authors: T
authors: Nakamura
authors: Department of Preventive Medicine and Public Health, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors: Hiroshi
authors: H
authors: Nakashima
authors: The Central Research Institute, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors: Yuzo
authors: Y
authors: Takada
authors: Cell Engineering Division, RIKEN BioResource Center, Tsukuba, Ibaraki, Japan Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Miyagi, Japan.
authors: Inaho
authors: I
authors: Danjoh
authors: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors: Seiko
authors: S
authors: Shimizu
authors: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors: Junko
authors: J
authors: Abe
authors: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors: Yusuke
authors: Y
authors: Kawamura
authors: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors: Sho
authors: S
authors: Terashige
authors: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors: Hiraku
authors: H
authors: Ogata
authors: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors: Seishiro
authors: S
authors: Tatsukawa
authors: Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan Department of Nutritional Sciences, Faculty of Health and Welfare, Seinan Jo Gakuin University, Fukuoka, Japan.
authors: Guang
authors: G
authors: Yin
authors: Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors: Rieko
authors: R
authors: Okada
authors: Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors: Emi
authors: E
authors: Morita
authors: Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors: Mariko
authors: M
authors: Naito
authors: Ryougoku East Gate Clinic, Tokyo, Japan.
authors: Atsumi
authors: A
authors: Tokumasu
authors: Department of Internal Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors: Hiroyuki
authors: H
authors: Onoue
authors: Department of Pathology, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors: Keiichi
authors: K
authors: Iwaya
authors: Department of Internal Medicine, Self-Defense Forces Central Hospital, Tokyo, Japan.
authors: Toshimitsu
authors: T
authors: Ito
authors: Department of Pharmacy, The University of Tokyo Hospital, Tokyo, Japan.
authors: Tappei
authors: T
authors: Takada
authors: Department of Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
authors: Katsuhisa
authors: K
authors: Inoue
authors: Faculty of Pharmacy, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors: Yukio
authors: Y
authors: Kato
authors: Cell Engineering Division, RIKEN BioResource Center, Tsukuba, Ibaraki, Japan.
authors: Yukio
authors: Y
authors: Nakamura
authors: Department of Preventive Medicine and Public Health, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors: Yutaka
authors: Y
authors: Sakurai
authors: Department of Pharmacy, The University of Tokyo Hospital, Tokyo, Japan.
authors: Hiroshi
authors: H
authors: Suzuki
authors: Division of Bio-system Pharmacology, Department of Pharmacology, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors: Yoshikatsu
authors: Y
authors: Kanai
authors: Division of Kidney and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan Department of Pathophysiology and Therapy in Chronic Kidney Disease, Jikei University School of Medicine, Tokyo, Japan.
authors: Tatsuo
authors: T
authors: Hosoya
authors: Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Nobuyuki
authors: N
authors: Hamajima
authors: Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Mishima, Shizuoka, Japan.
authors: Ituro
authors: I
authors: Inoue
authors: Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama, Kanagawa, Japan.
authors: Michiaki
authors: M
authors: Kubo
authors: Division of Kidney and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan Department of Pathophysiology, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
authors: Kimiyoshi
authors: K
authors: Ichida
authors: Ryougoku East Gate Clinic, Tokyo, Japan.
authors: Hiroshi
authors: H
authors: Ooyama
authors: Midorigaoka Hospital, Osaka, Japan.
authors: Toru
authors: T
authors: Shimizu
authors: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors: Nariyoshi
authors: N
authors: Shinomiya
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics; D024722:Cardiac Myosins / Q000235:genetics; D016022:Case-Control Studies; D004527:Egg Proteins / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D051246:Glucose Transport Proteins, Facilitative / Q000235:genetics; D006073:Gout / Q000209:etiology / Q000235:genetics* / Q000652:urine; D006801:Humans; D033461:Hyperuricemia / Q000150:complications / Q000235:genetics* / Q000652:urine; D007564:Japan; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D018994:Myosin Light Chains / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D014527:Uric Acid / Q000652:urine
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D048868:Adaptor Proteins, Signal Transducing; C118276:CNIH1 protein, human; D004527:Egg Proteins; C485100:GCKR protein, human; D051246:Glucose Transport Proteins, Facilitative; D008565:Membrane Proteins; D018994:Myosin Light Chains; D009363:Neoplasm Proteins; C411811:SLC2A9 protein, human; C107184:myosin light chain 2; D014527:Uric Acid; D024722:Cardiac Myosins
keywords: Arthritis; Gene Polymorphism; Gout
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