ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 1278

Evaluating a Causal Role of Mitochondrial Variation in the Development of Gout

Amara Shaukat1, Anna Gosling1, Matthew Bixley1, Amanda Phipps-Green1, Tanya J. Major1, Murray Cadzow1, Nicola Dalbeth2, Lisa K. Stamp3, Elizabeth Matisoo-Smith1, Jennie Harre Hindmarsh4, Leo .A.B. Joosten5, Tim Jansen6, Matthijs Janssen6, Anne-Kathrin Tausche7, Philip Riches8, Alexander So9, Mariano Andres10, Geraldine M. McCarthy11, Fernando Perez-Ruiz12, Michael Doherty13, Rosa Torres14, Tom W.J. Huizinga15, Rachel Knevel16, Fina Kurreeman17 and Tony R. Merriman1, 1University of Otago, Dunedin, New Zealand, 2University of Auckland, Auckland, New Zealand, 3University of Otago, Christchurch, New Zealand, 4Ngati Porou Hauora Charitable Trust, Te Puia Springs, New Zealand, 5Radboud University Medical Center, Nijmegen, Netherlands, 6VieCuri Medical Center, Venlo, Netherlands, 7Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Dresden, Germany, 8University of Edinburgh, Edinburgh, United Kingdom, 9University of Lausanne, Lausanne, Switzerland, 10Hospital General Universitario de Alicante-ISABIAL, Alicante, Spain, 11Mater Misericordiae University Hospital, Dublin, Ireland, 12BioCruces Health Research Institute, Barakaldo, Spain, 13The University of Nottingham, Nottingham, United Kingdom, 14La Paz University Hospital, Madrid, Spain, 15Department of Rheumatology, LUMC, Leiden, Netherlands, 16Brigham and Women's Hospital, Boston, MA, 17Leiden University Medical Centre, Leiden, Netherlands

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: , ,

Session Information

Date: Monday, October 22, 2018

Title: Metabolic and Crystal Arthropathies – Basic and Clinical Science Poster I

Session Type: ACR Poster Session B

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

Background/Purpose: Mitochondria execute roles in diverse cellular pathways. As a danger signal, damaged mitochondria can induce inflammation in response to stress through NLRP3 inflammasome activation, which is central to gout. We recently reported association of reduced mitochondrial DNA (mtDNA) copy number with prevalent gout in New Zealand Māori and Pacific (Polynesian) people1. However the cause-effect relationship is unknown. This could be evaluated by testing nuclear genetic variants that associate with mtDNA copy number for association with gout. Here the aims were: 1) Perform a genome wide association study (GWAS) to identify nuclear variants associated with mtDNA copy number; 2) test these identified variants for association with gout.

Methods: The mtDNA copy number GWAS comprised 1,340 Eastern Polynesian, 816 Western Polynesian and 4,579 European individuals (New Zealand, Europe) genotyped on the Illumina CoreExome v24 array. The median of the absolute differences in X and Y probe intensities was used as a measure of mtDNA copy number. This measure was associated with genome-wide genotype calls, adjusted by age, sex and by principal component vectors calculated from the probe intensities of an additional 10,000 randomly selected autosomal SNPs. Nuclear variants identified as being associated with mtDNA copy number were then tested for association with gout, adjusting by age, sex and the first 10 principle component vectors generated from genotype calls for 3,000 independent autosomal SNPs.

Results:

As previously reported mtDNA copy number negatively associated with gout in the Polynesian sample sets (ß=-2.81, P=2.9×10-6 for East Polynesian and ß=-8.11, P=3.6×10-16 for West Polynesian). However there was no evidence for association in the European sample set (ß=-0.16, P=0.66). The nuclear variant MUC17 rs78010183 T-allele associated with increased mitochondrial CN at an experiment-wide level of significant (P<1×10-7) in people of Eastern Polynesian ancestry (ß=0.07, P=4.7×10-13). There were no other nuclear variants significantly associated with mtDNA copy number in the Western Polynesian or European sample sets. Association of the MUC17 rs78010183 variant with increased mtDNA copy number replicated in Europeans, with the T-allele increasing copy number (ß=0.06, P=1×10-4) but not in Western Polynesian (ß=0.09, P=0.15). Testing for association with gout, the rs78010183 T-allele was not significantly associated in Eastern Polynesian (OR=1.38, P=0.17) but was associated in European (OR=15.88, P=1×10-3) sample sets, with the mtDNA copy number-increasing allele associated with increased risk of gout.

Conclusion: Genetic variants associated with mtDNA copy number also associate with gout, providing evidence for a direct role of either mtDNA copy number, or another related factor such as mitochondrial dysfunction, in gout. However, the nuclear variant rs78010183 supports a direct relation of increased mtDNA copy number with gout, conflicting with our previous observational report of association of reduced mtDNA copy number with gout.

Disclosure: A. Shaukat, None; A. Gosling, None; M. Bixley, None; A. Phipps-Green, None; T. J. Major, None; M. Cadzow, None; N. Dalbeth, Horizon, 5,Kowa, 5,Amgen Inc., 2,AstraZeneca/Ironwood, 2,AbbVie Inc., 8,Pfizer, Inc., 8,Janssen, 8; L. K. Stamp, Amgen Inc., 8; E. Matisoo-Smith, None; J. Harre Hindmarsh, None; L. A. B. Joosten, None; T. Jansen, AbbVie Inc., 5, 8,AstraZeneca, 2,Celgene Corporation, 5,Grunenthal, 5, 8; M. Janssen, None; A. K. Tausche, None; P. Riches, None; A. So, Grunenthal, 8,Menarini, 8,SOBI pharma, 5; M. Andres, None; G. M. McCarthy, None; F. Perez-Ruiz, Amgen Inc., 5, 8,Grünenthal, 5, 8,Menarini, 5, 8,Asociación de Reumatólogos de Cruces, 2; M. Doherty, None; R. Torres, None; T. W. J. Huizinga, BMS, 2,EU, 2,Arthritis Foundation, 2,IMI, 2,LUMC, 3,Abblynx, 5,Merck & Co., 5,UCB, Inc., 5,BMS, 5,Biotest AG, 5,Janssen, 5,Pfizer, Inc., 5,Novartis, 5,Roche, 5,Sanofi-Aventis, 5,Abbott, 5,Consulting Bioscience, 5,Galapagos, 5,Nycomed, 5,Boeringher, 5,Takeda, 5,Zydus, 5,Epirus, 5,Eli Lilly and Co., 5; R. Knevel, None; F. Kurreeman, None; T. R. Merriman, None.

To cite this abstract in AMA style:

Shaukat A, Gosling A, Bixley M, Phipps-Green A, Major TJ, Cadzow M, Dalbeth N, Stamp LK, Matisoo-Smith E, Harre Hindmarsh J, Joosten LAB, Jansen T, Janssen M, Tausche AK, Riches P, So A, Andres M, McCarthy GM, Perez-Ruiz F, Doherty M, Torres R, Huizinga TWJ, Knevel R, Kurreeman F, Merriman TR. Evaluating a Causal Role of Mitochondrial Variation in the Development of Gout [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/evaluating-a-causal-role-of-mitochondrial-variation-in-the-development-of-gout/. Accessed .

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