Session Title: Metabolic and Crystal Arthropathies I: Mechanisms of Disease
Session Type: ACR Concurrent Abstract Session
Session Time: 4:30PM-6:00PM
Background/Purpose: Mitochondria play a central role in induction of an NLRP3 inflammatory response essential for gouty pathology. Mitochondria are in part self-encoding, possessing a 16.5 kb genome which encodes 36 genes. The objective of this study was to test whether mitochondrial genetic variation and copy number could contribute to susceptibility to gout in New Zealand Polynesians. The Māori and Pacific (Polynesian) populations of New Zealand exhibit a high prevalence of gout (6 and 8%, respectively).
Methods: To test for association of mitochondrial genetic variation with gout 439 whole mitochondrial genomes from Māori and Pacific men with Polynesian maternal grandmothers (327 cases, 112 controls) were generated using Illumina MiSeq technology. Association of mtDNA copy number variation with gout was investigated by a relative read depth approach using high throughput sequence data from two independent data sets (whole genome sequencing (n=73) and resequencing of urate loci (n=385)). Quantitative PCR was undertaken for mtDNA copy number replication in an independent sample set of 632 Polynesian male and female cases and 579 controls. Association analyses were done using R v3.3.0 adjusting by age and proportion of Polynesian ancestry.
Results: Within Polynesia, there is relatively little mitochondrial genetic diversity, with around 96% of those sequenced belonging to the B4a1a and derived sub-lineages. A lineage-specific heteroplasmy in hypervariable region I was found to associate with a higher risk of gout (e.g. heteroplasmy at position 16179: OR 3.28, P = 0.009; heteroplasmy at position 16181: 3.86, P = 9×10-5; heteroplasmy at position 16182: 3.43, P = 0.005). Relative to autosomal DNA an additional 10 mtDNA copies protected from gout in the whole genome sequence (OR=0.87, P=0.004) and resequence (OR=0.91, P=3.3×10-4) sample sets, including when using asymptomatic hyperuricemic (urate > 0.40 mmol/L) control individuals (OR=0.81, P=0.004 and OR=0.90, P=0.002, respectively) (Table). To replicate, quantitative PCR of mtDNA from the 1211 gout cases and controls showed that with each unit decrease in ΔCt (which reflects an increase in mtDNA content), there was also a decrease in gout risk using asymptomatic hyperuricemic controls (OR=0.76, P = 0.03). However there was no significant association of increased mtDNA copy number with gout risk using all controls (OR=0.92, P=0.32).
Conclusion: It is unclear whether the reduced mtDNA copy number in gout is a consequence of the gouty pathology or whether the reduced mtDNA copy number causally contributes to the risk of gout. The latter possibility is supported by the consistent protection towards gout of increased mtDNA copy number using hyperuricemic controls, consistent with a role for mitochondria in monosodium urate crystal formation and/or the immune response. Alongside research showing that mitochondria play a central role in induction of the NLRP3 inflammasome, these genetic observations support a role for mitochondria in the etiology of gout.
|Cases/Controls||OR [95% CI]||P|
|All controls||43/33||0.87 [0.79-0.95]||0.003|
|HU controls||43/18||0.81 [0.68-0.92]||0.004|
|All controls||162/249||0.91 [0.87-0.96]||0.00033|
|HU controls||162/53||0.90 [0.84-0.96]||0.002|
|All controls||632/579||0.92 [0.76-1.09]||0.32|
|HU controls||632/168||0.76 [0.58-0.98]||0.03|
To cite this abstract in AMA style:Merriman TR, Boocock J, Dalbeth N, Stamp LK, Stahl EA, Choi HK, Matisoo-Smith E, Gosling A. Mitochondrial Genetic Variation, Copy Number and Susceptibility to Gout in the New Zealand Polynesian Population [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/mitochondrial-genetic-variation-copy-number-and-susceptibility-to-gout-in-the-new-zealand-polynesian-population/. Accessed January 22, 2021.
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