title: GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes.
abstract: A genome-wide association study (GWAS) of gout and its subtypes was performed to identify novel gout loci, including those that are subtype-specific.
  
  
  
  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.
  
  
  
  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 (SLC22A12andSLC17A1) andHIST1H2BF-HIST1H4Efor all gout cases, andNIPAL1andFAM35Afor the renal underexcretion gout subtype. WhileNIPAL1encodes 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, andFAM35Awas associated with gout in all cases. A meta-analysis of the three populations revealedFAM35Ato be associated with gout at a genome-wide level of significance (pmeta=3.58×10-8).
  
  
  
  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.
authors.affiliation: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Nakayama
authors.affiliation: Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Mishima, Shizuoka, Japan.
authors.forename: Hirofumi
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authors.lastname: Nakaoka
authors.affiliation: Department of Medical Chemistry, Kurume University School of Medicine, Kurume, Fukuoka, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: 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.forename: Masayuki
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authors.lastname: Sakiyama
authors.affiliation: Department of Biochemisty, University of Otago, Dunedin, New Zealand.
authors.forename: Amara
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authors.lastname: Shaukat
authors.affiliation: Department of Pharmacy, The University of Tokyo Hospital, Tokyo, Japan.
authors.forename: Yu
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authors.lastname: Toyoda
authors.affiliation: Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.|Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.|Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.
authors.forename: Yoichiro
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authors.lastname: Kamatani
authors.affiliation: Laboratory for Mathematics, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Takahiro
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authors.lastname: Nakamura
authors.affiliation: Department of Pharmacy, The University of Tokyo Hospital, Tokyo, Japan.
authors.forename: Tappei
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authors.lastname: Takada
authors.affiliation: Department of Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
authors.forename: Katsuhisa
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authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi, Japan.
authors.forename: Tomoya
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authors.lastname: Yasujima
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi, Japan.
authors.forename: Hiroaki
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authors.lastname: Yuasa
authors.affiliation: Department of Medical Chemistry, Kurume University School of Medicine, Kurume, Fukuoka, Japan.
authors.forename: Yuko
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authors.lastname: Shirahama
authors.affiliation: Department of Preventive Medicine and Public Health, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Hiroshi
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authors.lastname: Nakashima
authors.affiliation: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Seiko
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authors.affiliation: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
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authors.affiliation: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Yusuke
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authors.lastname: Kawamura
authors.affiliation: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Hiraku
authors.initials: H
authors.lastname: Ogata
authors.affiliation: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Makoto
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authors.lastname: Kawaguchi
authors.affiliation: Division of Transcriptomics, Research Center for Transomics Medicine, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: Yasuyuki
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authors.affiliation: Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Miyagi, Japan.
authors.forename: Inaho
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authors.lastname: Danjoh
authors.affiliation: Ryougoku East Gate Clinic, Tokyo, Japan.
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authors.affiliation: Ryougoku East Gate Clinic, Tokyo, Japan.
authors.forename: Keiko
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authors.lastname: Ooyama
authors.affiliation: Department of Internal Medicine, Self-Defense Forces Central Hospital, Tokyo, Japan.
authors.forename: Toshimitsu
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authors.affiliation: Program in Radiological and Medical Laboratory Sciences, Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors.forename: Takaaki
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authors.affiliation: Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
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authors.affiliation: First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Institute of Inherited Metabolic Disorders, Prague, Czech Republic.|Institute of Rheumatology, Prague, Czech Republic.
authors.forename: Blanka
authors.initials: B
authors.lastname: Stiburkova
authors.affiliation: Institute of Rheumatology, Prague, Czech Republic.
authors.forename: Karel
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authors.lastname: Pavelka
authors.affiliation: Department of Medicine, University of Otago, Christchurch, New Zealand.
authors.forename: Lisa K
authors.initials: LK
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authors.affiliation: Department of Medicine, University of Auckland, Grafton, Auckland, New Zealand.
authors.forename: Nicola
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authors.lastname: Dalbeth
authors.affiliation: Department of Preventive Medicine and Public Health, National Defense Medical College, Tokorozawa, Saitama, Japan.
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authors.initials: Y
authors.lastname: Sakurai
authors.affiliation: Department of Pharmacy, The University of Tokyo Hospital, Tokyo, Japan.
authors.forename: Hiroshi
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authors.affiliation: Department of Human Physiology and Pathology, Faculty of Pharma-Sciences, Teikyo University, Tokyo, Japan.
authors.forename: Makoto
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authors.affiliation: Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.
authors.forename: Shin
authors.initials: S
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authors.affiliation: Division of Kidney and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Takashi
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authors.affiliation: 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.forename: Tatsuo
authors.initials: T
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authors.affiliation: Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Mishima, Shizuoka, Japan.
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authors.initials: I
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authors.affiliation: Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.|Omics Research Center, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
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authors.affiliation: Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama, Kanagawa, Japan.
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authors.affiliation: Midorigaoka Hospital, Takatsuki, Osaka, Japan.|Kyoto Industrial Health Association, Kyoto, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Department of Pathophysiology and Therapy in Chronic Kidney Disease, Jikei University School of Medicine, Tokyo, Japan.|Department of Pathophysiology, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
authors.forename: Kimiyoshi
authors.initials: K
authors.lastname: Ichida
authors.affiliation: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Nariyoshi
authors.initials: N
authors.lastname: Shinomiya
authors.affiliation: Department of Biochemisty, University of Otago, Dunedin, New Zealand.
authors.forename: Tony R
authors.initials: TR
authors.lastname: Merriman
authors.affiliation: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Hirotaka
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authors.lastname: Matsuo
mesh_terms: D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D027682:Cation Transport Proteins / Q000235:genetics; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006073:Gout / Q000145:classification / Q000235:genetics*; D006657:Histones / Q000235:genetics; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics; D027701:Organic Cation Transport Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics; D050609:Sodium-Phosphate Cotransporter Proteins, Type I / Q000235:genetics; D044465:White People / Q000235:genetics
chemical_list: D027682:Cation Transport Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D006657:Histones; C000620301:NIPAL1 protein, human; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; D011506:Proteins; C000620302:SHLD2 protein, human; C493546:SLC17A1 protein, human; C491241:SLC22A12 protein, human; D050609:Sodium-Phosphate Cotransporter Proteins, Type I
keywords: Arthritis; Gene Polymorphism; Gout