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Original article
Multiple common and rare variants of ABCG2 cause gout
  1. Toshihide Higashino1,
  2. Tappei Takada2,
  3. Hirofumi Nakaoka3,
  4. Yu Toyoda2,
  5. Blanka Stiburkova4,5,
  6. Hiroshi Miyata2,
  7. Yuki Ikebuchi2,
  8. Hiroshi Nakashima6,
  9. Seiko Shimizu1,
  10. Makoto Kawaguchi1,
  11. Masayuki Sakiyama1,
  12. Akiyoshi Nakayama1,
  13. Airi Akashi1,
  14. Yuki Tanahashi1,
  15. Yusuke Kawamura1,
  16. Takahiro Nakamura7,
  17. Kenji Wakai8,
  18. Rieko Okada8,
  19. Ken Yamamoto9,
  20. Kazuyoshi Hosomichi3,10,
  21. Tatsuo Hosoya11,12,
  22. Kimiyoshi Ichida11,13,
  23. Hiroshi Ooyama14,
  24. Hiroshi Suzuki2,
  25. Ituro Inoue3,
  26. Tony R Merriman15,
  27. Nariyoshi Shinomiya1 and
  28. Hirotaka Matsuo1
  1. 1 Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Japan
  2. 2 Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
  3. 3 Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Mishima, Japan
  4. 4 First Faculty of Medicine, Charles University and General University Hospital in Prague, Institute of Inherited Metabolic Disorders, Prague, Czech Republic
  5. 5 Institute of Rheumatology, Prague, Czech Republic
  6. 6 Department of Preventive Medicine and Public Health, National Defense Medical College, Tokorozawa, Japan
  7. 7 Laboratory for Mathematics, National Defense Medical College, Tokorozawa, Japan
  8. 8 Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
  9. 9 Department of Medical Chemistry, Kurume University School of Medicine, Kurume, Japan
  10. 10 Department of Bioinformatics and Genomics, Graduate School of Medical Sciences, Kanazawa University, Ishikawa, Japan
  11. 11 Division of Kidney and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
  12. 12 Department of Pathophysiology and Therapy in Chronic Kidney Disease, Jikei University School of Medicine, Tokyo, Japan
  13. 13 Department of Pathophysiology, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
  14. 14 Ryougoku East Gate Clinic, Tokyo, Japan
  15. 15 Department of Biochemistry, University of Otago, Dunedin, New Zealand
  1. Correspondence to Dr Hirotaka Matsuo; hmatsuo{at}ndmc.ac.jp

Abstract

Objective Previous studies have suggested an association between gout susceptibility and common dysfunctional variants in ATP-binding cassette transporter subfamily G member 2/breast cancer resistance protein (ABCG2/BCRP), including rs72552713 (Q126X) and rs2231142 (Q141K). However, the association of rare ABCG2 variants with gout is unknown. Therefore, we investigated the effects of rare ABCG2 variants on gout susceptibility in this study.

Methods We sequenced the exons of ABCG2 in 480 patients with gout and 480 healthy controls (Japanese males). We also performed functional analyses of non-synonymous variants of ABCG2 and analysed the correlation between urate transport function and scores from the protein prediction algorithms (Sorting Intolerant from Tolerant (SIFT) and Polymorphism Phenotyping v2 (PolyPhen-2)). Stratified association analyses and multivariate logistic regression analysis were performed to evaluate the effects of rare and common ABCG2 variants on gout susceptibility.

Results We identified 3 common and 19 rare non-synonymous variants of ABCG2. SIFT scores were significantly correlated with the urate transport function, although some ABCG2 variants showed inconsistent scores. When the effects of common variants were removed by stratified association analysis, the rare variants of ABCG2 were associated with a significantly increased risk of gout (OR=3.2, p=6.4×10−3). Multivariate logistic regression analysis revealed that the size effect of these rare ABCG2 variants (OR=2.7, p=3.0×10−3) was similar to that of the common variants, Q126X (OR=3.4, p=3.2×10−6) and Q141K (OR=2.3, p=2.7×10−16).

Conclusions This study revealed that multiple common and rare variants of ABCG2 are independently associated with gout. These results could support both the ‘Common Disease, Common Variant’ and ‘Common Disease, Multiple Rare Variant’ hypotheses for the association between ABCG2 and gout susceptibility.

  • gout
  • gene polymorphism
  • epidemiology
  • arthritis

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Footnotes

  • Contributor THigashino, TT, HNakaoka and YToyoda contributed equally.

  • Contributors THi, TT, HNakao, KH, NS and HMa conceived and designed this study. BS and KY assisted with research design. KW, RO and HO collected samples and analysed clinical data. THi, HNakao, SS, MS, MK, AN, AA, YTa, YK, KY, KH, II, NS and HMa performed genetic analysis. TT, YTo, HMi and YI performed functional analysis. THi, HNakao, HNakas, TN and HMa performed statistical analyses. BS, KY, KH, THo, KI, HS, TRM and NS provided intellectual input and assisted with the preparation of the manuscript. THi, TT, HNakao, YTo and HMa wrote the manuscript. All authors have read and approved the final version of 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 JSPS KAKENHI Grants (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 NZ.

  • Competing interests TT, TN, KI, HS, NS and HMa have a patent pending based on the work reported in this paper.

  • Patient consent Obtained.

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

  • Data sharing statement No additional data are available.

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