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Extended report
Genome-wide association study of clinically defined gout identifies multiple risk loci and its association with clinical subtypes
  1. Hirotaka Matsuo1,
  2. Ken Yamamoto2,
  3. Hirofumi Nakaoka3,
  4. Akiyoshi Nakayama1,4,
  5. Masayuki Sakiyama1,5,
  6. Toshinori Chiba1,
  7. Atsushi Takahashi6,
  8. Takahiro Nakamura6,7,
  9. Hiroshi Nakashima8,
  10. Yuzo Takada9,
  11. Inaho Danjoh10,11,
  12. Seiko Shimizu1,
  13. Junko Abe1,
  14. Yusuke Kawamura1,
  15. Sho Terashige1,
  16. Hiraku Ogata1,
  17. Seishiro Tatsukawa1,
  18. Guang Yin12,13,
  19. Rieko Okada12,
  20. Emi Morita12,
  21. Mariko Naito12,
  22. Atsumi Tokumasu14,
  23. Hiroyuki Onoue15,
  24. Keiichi Iwaya16,
  25. Toshimitsu Ito17,
  26. Tappei Takada18,
  27. Katsuhisa Inoue19,
  28. Yukio Kato20,
  29. Yukio Nakamura10,
  30. Yutaka Sakurai8,
  31. Hiroshi Suzuki18,
  32. Yoshikatsu Kanai21,
  33. Tatsuo Hosoya22,23,
  34. Nobuyuki Hamajima24,
  35. Ituro Inoue3,
  36. Michiaki Kubo25,
  37. Kimiyoshi Ichida22,26,
  38. Hiroshi Ooyama14,
  39. Toru Shimizu27,
  40. Nariyoshi Shinomiya1
  1. 1Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan
  2. 2Department of Medical Chemistry, Kurume University School of Medicine, Kurume, Fukuoka, Japan
  3. 3Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Mishima, Shizuoka, Japan
  4. 4Medical Group, Headquarters, Iwo-to Air Base Group, Japan Air Self-Defense Force, Tokyo, Japan
  5. 5Department of Dermatology, National Defense Medical College, Tokorozawa, Saitama, Japan
  6. 6Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN, Yokohama, Kanagawa, Japan
  7. 7Laboratory for Mathematics, National Defense Medical College, Tokorozawa, Saitama, Japan
  8. 8Department of Preventive Medicine and Public Health, National Defense Medical College, Tokorozawa, Saitama, Japan
  9. 9The Central Research Institute, National Defense Medical College, Tokorozawa, Saitama, Japan
  10. 10Cell Engineering Division, RIKEN BioResource Center, Tsukuba, Ibaraki, Japan
  11. 11Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Miyagi, Japan
  12. 12Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
  13. 13Department of Nutritional Sciences, Faculty of Health and Welfare, Seinan Jo Gakuin University, Fukuoka, Japan
  14. 14Ryougoku East Gate Clinic, Tokyo, Japan
  15. 15Department of Internal Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan
  16. 16Department of Pathology, National Defense Medical College, Tokorozawa, Saitama, Japan
  17. 17Department of Internal Medicine, Self-Defense Forces Central Hospital, Tokyo, Japan
  18. 18Department of Pharmacy, The University of Tokyo Hospital, Tokyo, Japan
  19. 19Department of Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
  20. 20Faculty of Pharmacy, Kanazawa University, Kanazawa, Ishikawa, Japan
  21. 21Division of Bio-system Pharmacology, Department of Pharmacology, Graduate School of Medicine, Osaka University, Osaka, Japan
  22. 22Division of Kidney and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
  23. 23Department of Pathophysiology and Therapy in Chronic Kidney Disease, Jikei University School of Medicine, Tokyo, Japan
  24. 24Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Japan
  25. 25Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama, Kanagawa, Japan
  26. 26Department of Pathophysiology, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
  27. 27Midorigaoka Hospital, Osaka, 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 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.

  • Gout
  • Arthritis
  • Gene Polymorphism

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/

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