Date: Monday, October 22, 2018
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.
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.
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 10). https://acrabstracts.org/abstract/evaluating-a-causal-role-of-mitochondrial-variation-in-the-development-of-gout/. Accessed September 28, 2021.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/evaluating-a-causal-role-of-mitochondrial-variation-in-the-development-of-gout/