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THU0464 A genome-wide association study of gout in people of european ancestry
  1. TR Merriman1,
  2. M Cadzow1,
  3. M Merriman1,
  4. A Phipps-Green1,
  5. R Topless1,
  6. A Abhishek2,
  7. M Andres3,
  8. L Bradbury4,
  9. R Buchanan5,
  10. K Cremin6,
  11. E de Guzman4,
  12. J de Zoysa7,
  13. M Doherty2,
  14. C Hill8,
  15. T Huizinga9,
  16. T Jansen10,
  17. M Janssen11,
  18. L Joosten12,
  19. F Kurreeman9,
  20. S Lester8,
  21. F Liote13,
  22. D Macartney-Coxson14,
  23. H Matsuo15,
  24. G McCarthy16,
  25. S McCormick1,
  26. R Murphy7,
  27. K Pavelka17,
  28. F Perez-Ruiz18,
  29. J Puig19,
  30. T Radstake20,
  31. P Riches21,
  32. M Rischmueller8,
  33. E Roddy22,
  34. M Smith23,
  35. E Stahl24,
  36. B Stiburkova17,
  37. R Stubbs25,
  38. A-K Tausche26,
  39. R Torres19,
  40. R Walker1,
  41. K Yamamoto27,
  42. M Brown4,
  43. H Choi28,
  44. N Dalbeth7,
  45. A So29,
  46. L Stamp1,
  47. T Flynn1
  1. 1University of Otago, Dunedin, New Zealand
  2. 2University of Nottingham, Nottingham, United Kingdom
  3. 3Universidad Miguel Hernández, Alicante, Spain
  4. 4Queensland University of Technology, Brisbane
  5. 5University of Melbourne, Melbourne
  6. 6University of Queensland, Brisbane, Australia
  7. 7University of Auckland, Auckland, New Zealand
  8. 8Queen Elizabeth Hospital, Adelaide, Australia
  9. 9Leiden University Medical Center, Leiden
  10. 10VieCuri Medical Centre, Venlo
  11. 11Rijnstate Hospital, Arnhem
  12. 12Radboud University Medical Center, Nijmegen, Netherlands
  13. 13Hospital Lariboisière, Paris, France
  14. 14Environmental and Scientific Research, Wellington, New Zealand
  15. 15National Defense Medical College, Saitama, Japan
  16. 16University College Dublin, Dublin, Ireland
  17. 17institute of Rheumatology, Prague, Czech Republic
  18. 18Hospital de Cruces, Vizcaya
  19. 19Hospital Universitario la Paz, Madrid, Spain
  20. 20University Medical Centre Utrecht, Utrecht, Netherlands
  21. 21University of Edinburgh, Edinburgh
  22. 22Keele University, Newcastle, United Kingdom
  23. 23Flinders Medical Centre and Repatriation Hospita, Adelaide, Australia
  24. 24Mt Sinai School of Medicine, New York, United States
  25. 25P3 Research Ltd, Wellington, New Zealand
  26. 26University of Dresden, Dresden, Germany
  27. 27Kurume University, Kurume, Japan
  28. 28Harvard Medical School, Boston, United States
  29. 29University of Lausanne, Lausanne, Switzerland

Abstract

Background Gout progresses through three stages: hyperuricemia, deposition of monosodium urate (MSU) crystals, and innate immune system response to MSU crystals. Genome wide association studies (GWAS) have provided insight into the molecular control of progression to hyperuricemia. However, less is known about the progression from hyperuricemia to gout.

Objectives To conduct a GWAS for gout (where an immune response to MSU crystals has occurred) using 5,835 cases - the largest GWAS of gout to date.

Methods The GWAS comprised 3 data sets: NZ/Eurogout (2,365 clinically-ascertained cases; 1,485 controls), the Health Professionals Follow-Up (HPFS) and Nurses' Health Studies (NHS) (1,038 cases, self-ascertained using ACR criteria; 1,095 controls), and UK Biobank (2,432 cases, ascertained by self-report of gout, hospital records, and/or use of urate-lowering therapy; 102,989 controls). The NZ/Eurogout samples were genotyped using the Illumina CoreExome v24 bead chip array (547,644 markers), the HPFS/NHS samples using the Illumina OmniExpress v12 bead chip array (730,525 markers), and the UK Biobank samples using an Affymetrix Axiom array (820,967 markers). UK Biobank genotypes had been imputed to ∼73.3M SNPs. Neither the NZ/Eurogout nor NHS/HPFS genotype sets were imputed. Markers common to all three data sets (279,939) were associated with gout (adjusted for sex, age) within each data set separately using PLINK 1.9. An inverse-variance weighted meta-analysis was done with meta v4.4 in R.

Results There were seven loci with genome-wide significant (P<5x10-8) evidence for association with gout: SLC2A9 (OR=1.67), ABCG2(OR=1.72), GCKR (OR=1.24), SLC17A1-A4 (OR=1.20), SLC22A12 (OR=1.21), PDZK1 (OR=1.14), TRIM46 (OR=1.18).

Conclusions All seven loci have been previously associated with serum urate levels in GWAS. Our data emphasise the relative importance of genetic control of serum urate, compared to the genetic control of MSU crystal formation or the innate immune response, in determining gout.

Disclosure of Interest None declared

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