A Genome-Wide Association Study of Gout in People of European Ancestry

Tony R. Merriman¹, Murray Cadzow¹, Marilyn E. Merriman¹, Amanda Phipps-Green¹, Ruth Topless¹, Abhishek Abhishek², Mariano Andrés³, Linda A. Bradbury⁴, Russell Buchanan⁵, Katie Cremin⁶, Erika De Guzman⁶, Janak de Zoysa⁷, Michael Doherty⁸, Catherine Hill⁹, Tom W.J. Huizinga¹⁰, Tim Jansen¹¹, M. Janssen¹², Leo .A.B. Joosten¹³, Fina Kurreeman¹⁴, Susan Lester¹⁵, Frederic Liote¹⁶, Donia Macartney-Coxson¹⁷, Hirotaka Matsuo¹⁸, Geraldine M. McCarthy¹⁹, Sally McCormick²⁰, Rinki Murphy²¹, Karel Pavelka²², Fernando Perez-Ruiz²³, Juan Puig²⁴, Timothy RDJ Radstake²⁵, Philip Riches²⁶, Maureen Rischmueller²⁷, Edward Roddy²⁸, Malcolm Smith²⁹, Eli A. Stahl³⁰, Blanka Stiburkova³¹, Richard Stubbs³², Anne-Kathrin Tausche³³, Rosa Torres³⁴, Rob Walker¹, Ken Yamamoto³⁵, Matthew A. Brown⁶, Hyon K. Choi³⁶, Nicola Dalbeth²¹, Jeffrey N. Miner³⁷, Alexander So³⁸, Lisa K. Stamp³⁹ and Tanya Major⁴⁰, ¹University of Otago, Dunedin, New Zealand, ²Devision of Rheumatology, University of Nottingham, NG5 1PB, England, ³Reumatología, Hospital General Universitario Alicante, Alicante, Spain, ⁴Queensland University of Technology, Brisbane, Australia, ⁵University of Melbourne, Melbourne, Australia, ⁶Translational Genomics Group, Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Brisbane, Australia, Brisbane, Australia, ⁷Waitemata District Health Board, Auckland, New Zealand, ⁸Academic Rheumatology, University of Nottingham, Nottingham, Great Britain, ⁹Medicine, The University of Adelaide, Adelaide, Australia, ¹⁰Rheumatology, Leiden University Medical Center, Leiden, Netherlands, ¹¹VieCuri Medical Center, Venlo, Netherlands, ¹²Department of Rheumatology, Rijnstate Hospital Arnhem, Arnhem, Netherlands, ¹³Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands, ¹⁴Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands, Leiden, Netherlands, ¹⁵Rheumatology, Queen Elizabeth Hospital, Woodville South, Australia, ¹⁶University Paris Diderot, Paris, France, ¹⁷Institute if Environmental and Scientific Reseacrh, Wellington, New Zealand, ¹⁸Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Japan, ¹⁹Div of Rheumatology, Mater Misericordiae University Hospital, Dublin, Ireland, ²⁰Department of Biochemistry, University of Otago, Dunedin, New Zealand, ²¹University of Auckland, Auckland, New Zealand, ²²Institute of Rheumatology, Prague, Czech Republic, ²³BioCruces Health Research Institute, Barakaldo, Spain, ²⁴Hospital Universitario La Paz, Madrid, Spain, ²⁵Rheumatic Diseases, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands, ²⁶University of Edinburgh, Edinburgh, United Kingdom, ²⁷Rheumatology, The Queen Elizabeth Hospital, South Australia, Adelaide, Australia, ²⁸Research Institute for Primary Care and Health Sciences, Keele University, Keele, United Kingdom, ²⁹Flinders Medical Centre and Repatriation Hospital, Adelaide, Australia, ³⁰Divisions of Rheumatology and Genetics, Brigham and Women's Hospital, Boston, MA, ³¹Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University, Prague, Czech Republic, ³²P3 Research Limited, Wellington, New Zealand, ³³Medizinische Klinik und Poliklinik III, Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Dresden, Germany, ³⁴La Paz University Hospital, Madrid, Spain, ³⁵Department of Medical Chemistry, Kurume University School of Medicine, Kurume, Japan, ³⁶Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, ³⁷Discovery Biology, Ardea Biosciences, Inc., San Diego, CA, ³⁸Rheumatology, CHUV, Univ of Lausanne, Lausanne, Switzerland, ³⁹University of Otago, Christchurch, New Zealand, ⁴⁰Biochemistry, University of Otago, Dunedin, New Zealand

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: genetics, genome and gout

Session Information

Date: Monday, November 6, 2017

Title: Metabolic and Crystal Arthropathies Poster I

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

A genome-wide association study of gout in people of European ancestry

Background/Purpose: Genome wide association studies (GWAS) have provided considerable insight into the molecular control of urate levels. However, less is known about the progression from asymptomatic hyperuricemia to gout. Our aim was to conduct a GWAS for gout in people of European ancestry using the largest number of cases of gout to date.

Methods: This GWAS (7,431 cases and 105,631 controls) was comprised of three data sets: a mixed New Zealand (NZ), Eurogout, and Ardea Biosciences group (3,961 cases; 1,547 controls; genotyped using the Illumina CoreExome v24 array, 547,644 markers), a composite set from the Health Professionals Follow-Up (HPFS) and NursesÕ Health Studies (NHS) (1,038 cases; 1,095 controls; genotyped using the Illumina OmniExpress v12 array, 730,525 markers), and UK Biobank (2,432 cases; 102,989 controls; genotyped using an Affymetrix Axiom array, 820,967 markers). The UK Biobank genotypes were imputed to ~73.3M SNPs. Neither the NZ/Eurogout/Ardea nor NHS/HPFS genotype sets were imputed. Markers found within all three data sets (234,062) were identified and associated with gout (adjusted for sex and age), within each data set separately, using PLINK v1.9. An inverse-variance weighted meta-analysis of the results was then performed using the meta v4.4 package within R v3.2.3. The overall genome inflation factor was 0.90.

Results: There were nine loci with experiment-wide significance (0.05/234,062; P < 2×10^-7) for association with gout: ABCG2 (OR=1.77), SLC2A9 (OR=1.69), GCKR (OR=1.24), MLXIPL (OR=1.18), SLC17A1-A4 (OR=1.22), SLC16A9 (OR=1.18), SLC22A12 (OR=1.16), PDZK1 (OR=1.16), TRIM46 (OR=1.15). All nine of these loci have been previously associated with serum urate levels in genome-wide studies with the urate-increasing alleles also associated with increased risk of gout in this study.

Conclusion: Our data emphasize the central importance of genetic involvement in serum urate levels, compared to the genetic involvement in MSU crystal formation, or the innate immune response, in determining gout.

Disclosure: T. R. Merriman, Ardea Biosciences, 2; M. Cadzow, None; M. E. Merriman, Ardea Biosciences, Inc, 2; A. Phipps-Green, None; R. Topless, None; A. Abhishek, AstraZeneca, 7; M. Andrés, None; L. A. Bradbury, None; R. Buchanan, None; K. Cremin, None; E. D. Guzman, None; J. de Zoysa, None; M. Doherty, None; C. Hill, None; T. W. J. Huizinga, Reasearch grants from Arthritis Foundation, ZonMW and European Union, 2,Tom WJ Huizinga/the department of rheumatology LUMC has received lecture fees/consultancy fees from Bristol Myers Squibb, Janssen, Pfizer, Roche, Sanofi-Aventis, Crescendo Bioscience,, Boeringher, Epirus and Eli Lilly, 5; T. Jansen, None; M. Janssen, None; L. A. B. Joosten, None; F. Kurreeman, None; S. Lester, None; F. Liote, None; D. Macartney-Coxson, None; H. Matsuo, None; G. M. McCarthy, None; S. McCormick, None; R. Murphy, None; K. Pavelka, None; F. Perez-Ruiz, Asociacion de reumatologos de Cruces, 2,Grünenthal, 5,Grünenthal, 8,Menarini, 5,Menarini, 8; J. Puig, None; T. R. Radstake, None; P. Riches, None; M. Rischmueller, None; E. Roddy, None; M. Smith, None; E. A. Stahl, None; B. Stiburkova, None; R. Stubbs, None; A. K. Tausche, None; R. Torres, None; R. Walker, None; K. Yamamoto, None; M. A. Brown, None; H. K. Choi, None; N. Dalbeth, Takeda, AstraZeneca, Abbvie, 9; J. N. Miner, Ardea biosciences, 3; A. So, None; L. K. Stamp, Amgen, 8; T. Major, None.

To cite this abstract in AMA style:

Merriman TR, Cadzow M, Merriman ME, Phipps-Green A, Topless R, Abhishek A, Andrés M, Bradbury LA, Buchanan R, Cremin K, Guzman ED, de Zoysa J, Doherty M, Hill C, Huizinga TWJ, Jansen T, Janssen M, Joosten LAB, Kurreeman F, Lester S, Liote F, Macartney-Coxson D, Matsuo H, McCarthy GM, McCormick S, Murphy R, Pavelka K, Perez-Ruiz F, Puig J, Radstake TR, Riches P, Rischmueller M, Roddy E, Smith M, Stahl EA, Stiburkova B, Stubbs R, Tausche AK, Torres R, Walker R, Yamamoto K, Brown MA, Choi HK, Dalbeth N, Miner JN, So A, Stamp LK, Major T. A Genome-Wide Association Study of Gout in People of European Ancestry [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/a-genome-wide-association-study-of-gout-in-people-of-european-ancestry/. Accessed .

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