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

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Clinical and epidemiological research
Extended report
GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes
  1. Akiyoshi Nakayama1,
  2. Hirofumi Nakaoka2,
  3. Ken Yamamoto3,
  4. Masayuki Sakiyama1,4,
  5. Amara Shaukat5,
  6. Yu Toyoda6,
  7. Yukinori Okada7,8,9,
  8. Yoichiro Kamatani8,
  9. Takahiro Nakamura10,
  10. Tappei Takada6,
  11. Katsuhisa Inoue11,
  12. Tomoya Yasujima12,
  13. Hiroaki Yuasa12,
  14. Yuko Shirahama3,
  15. Hiroshi Nakashima13,
  16. Seiko Shimizu1,
  17. Toshihide Higashino1,
  18. Yusuke Kawamura1,
  19. Hiraku Ogata1,
  20. Makoto Kawaguchi1,
  21. Yasuyuki Ohkawa14,
  22. Inaho Danjoh15,
  23. Atsumi Tokumasu16,
  24. Keiko Ooyama16,
  25. Toshimitsu Ito17,
  26. Takaaki Kondo18,
  27. Kenji Wakai19,
  28. Blanka Stiburkova20,21,
  29. Karel Pavelka21,
  30. Lisa K Stamp22,
  31. Nicola Dalbeth23,
  32. Eurogout Consortium,
  33. Yutaka Sakurai13,
  34. Hiroshi Suzuki6,
  35. Makoto Hosoyamada24,
  36. Shin Fujimori25,
  37. Takashi Yokoo26,
  38. Tatsuo Hosoya26,27,
  39. Ituro Inoue2,
  40. Atsushi Takahashi8,28,
  41. Michiaki Kubo29,
  42. Hiroshi Ooyama16,
  43. Toru Shimizu30,31,
  44. Kimiyoshi Ichida27,32,
  45. Nariyoshi Shinomiya1,
  46. Tony R Merriman5,
  47. Hirotaka Matsuo1
    1. 1Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan
    2. 2Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Mishima, Shizuoka, Japan
    3. 3Department of Medical Chemistry, Kurume University School of Medicine, Kurume, Fukuoka, Japan
    4. 4Department of Dermatology, National Defense Medical College, Tokorozawa, Saitama, Japan
    5. 5Department of Biochemisty, University of Otago, Dunedin, New Zealand
    6. 6Department of Pharmacy, The University of Tokyo Hospital, Tokyo, Japan
    7. 7Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
    8. 8Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan
    9. 9Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan
    10. 10Laboratory for Mathematics, National Defense Medical College, Tokorozawa, Saitama, Japan
    11. 11Department of Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
    12. 12Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi, Japan
    13. 13Department of Preventive Medicine and Public Health, National Defense Medical College, Tokorozawa, Saitama, Japan
    14. 14Division of Transcriptomics, Research Center for Transomics Medicine, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
    15. 15Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Miyagi, Japan
    16. 16Ryougoku East Gate Clinic, Tokyo, Japan
    17. 17Department of Internal Medicine, Self-Defense Forces Central Hospital, Tokyo, Japan
    18. 18Program in Radiological and Medical Laboratory Sciences, Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
    19. 19Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
    20. 20First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Institute of Inherited Metabolic Disorders, Prague, Czech Republic
    21. 21Institute of Rheumatology, Prague, Czech Republic
    22. 22Department of Medicine, University of Otago, Christchurch, New Zealand
    23. 23Department of Medicine, University of Auckland, Grafton, Auckland, New Zealand
    24. 24Department of Human Physiology and Pathology, Faculty of Pharma-Sciences, Teikyo University, Tokyo, Japan
    25. 25Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
    26. 26Division of Kidney and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
    27. 27Department of Pathophysiology and Therapy in Chronic Kidney Disease, Jikei University School of Medicine, Tokyo, Japan
    28. 28Omics Research Center, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan
    29. 29Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama, Kanagawa, Japan
    30. 30Midorigaoka Hospital, Takatsuki, Osaka, Japan
    31. 31Kyoto Industrial Health Association, Kyoto, Japan
    32. 32Department of Pathophysiology, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
    1. Correspondence to Dr Hirotaka Matsuo, Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan; hmatsuo{at}ndmc.ac.jp

    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 (pmeta=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.

    • Gout
    • Gene Polymorphism
    • Arthritis

    This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

    https://doi.org/10.1136/annrheumdis-2016-209632

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      Footnotes

      • Handling editor Tore K Kvien

      • AN, HNakaoka, KY, MS, AS and YT contributed equally.

      • Collaborators Members of the Eurogout Consortium are: Mariano Andres (Sección de Reumatología, Hospital General Universitario de Alicante, Alicante), Leo A Joosten (Department of Internal Medicine and Radboud Institute of Molecular Life Science, Radboud University Medical Center, The Netherlands), Matthijs Janssen (Department of Rheumatology, Rijnstate Hospital, The Netherlands), Tim L Jansen (Department of IQ HealthCare, VieCuri Medical Centre, The Netherlands), Frederic Lioté (INSERM, UMR-S 1132, Hospital Lariboisière, Paris, University Paris Diderot (UFR de Médecine), Sorbonne Paris Cité, Paris), Timothy R Radstake (Department of Rheumatology and Clinical Immunology, Laboratory of Translational Immunology, University Medical Centre Utrecht, The Netherlands, and Department of Immunology, University Medical Centre Utrecht, The Netherlands), Philip L Riches (Rheumatic Diseases Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh), Alexander So (DAL, Service of Rheumatology, Laboratory of Rheumatology, University of Lausanne, CHUV, Nestlé), Anne-Kathrin Tausche (Department of Rheumatology, University Clinic ‘Carl-Gustav-Carus’, Dresden).

      • Contributors AN, HNakaoka, KY, MS, AS, YT, TT, NS, TRM and HM conceived and designed this study. YSakurai, HS, II, ATakahashi and MKubo assisted with research design. AN, HNakaoka, MS, YOkada, YKamatani, THigashino, YKawamura, ATokumasu, KO, TK, KW, BS, KP, ATakahashi, MKubo, HOoyama, TS, KIchida and HM collected and analyzed clinical data of Japanese participants. AS, LKS, ND, Eurogout Consortium and TRM collected and analyzed clinical data of replication participants. AN, KY, MS, AS, YShirahama, SS, THigashino, YKawamura, HOgata, MKawaguchi, ID, NS, TRM and HM performed genetic analysis. AN, HNakaoka, MS, AS, YOkada, YKamatani, TN, HNakashima, ATakahashi, TRM and HM performed statistical analysis. AN, YT, TT, KInoue, TYasujima, HY, HS and HM performed functional analysis and localization analysis. AN, HNakaoka, KY, MS, AS, YT, YOkada, YKamatani, TN, TT, KInoue, TYasujima, HY, YOhkawa, NS, TRM and HM analyzed data. ID, TI, MH, SF, TYokoo, THosoya, KIchida provided intellectual input and assisted with the preparation of the manuscript. AN, HNakaoka, KY, MS, AS, YT, NS, TRM and HM wrote the manuscript.

      • Funding This study was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, including MEXT KAKENHI (Nos. 25293145 and 15K15227), Grants-in-Aid for Scientific Research on Priority Areas (No. 17015018) and Innovative Areas (Nos. 221S0001 and 221S0002) and a JSPS KAKENHI Grant (Nos. 16H06277 and 16H06279), the Ministry of Health, Labour and Welfare of Japan, the Ministry of Defense of Japan, the Japan Society for the Promotion of Science, the Kawano Masanori Memorial Foundation for Promotion of Pediatrics, the Gout Research Foundation of Japan and the Health Research Council of New Zealand. The BioBank Japan Project was supported by MEXT of Japan.

      • Competing interests TT, KIchida, NS and HM have a patent pending based on the work reported in this paper.

      • Patient consent Obtained.

      • Ethics approval This study was approved by the institutional ethical committees, and written consent was obtained from all of its participants. All involved procedures were performed in accordance with the Declaration of Helsinki.

      • Provenance and peer review Not commissioned; externally peer reviewed.