Gosling A.L. 1,2, Boocock L.1, Dalbeth N.3, Stamp L.K.4, Stahl E.A.5, Choi H.K.6, Matisoo-Smith E.A.2, Merriman T.R.1
1Department of Biochemistry, University of Otago, Dunedin, NZ. 2 Department of Anatomy, University of Otago, Dunedin, NZ. 3Department of Medicine, University of Auckland, Auckland, NZ. 4 Department of Medicine, University of Otago Christchurch, NZ. 5 Department of Psychiatry, Mount Sinai School of Medicine, New York, US. 6 Section of Rheumatology and Clinical Epidemiology Unit, Boston University School of Medicine, Boston, US.
Mitochondria appear to play a central role in the induction of the NLRP3 inflammatory response, which is critical for the development of gout. Mitochondria are partly self-encoding, possessing a 16.5 kB genome with 36 genes. Thus mitochondrial genetic variation may contribute to susceptibility to gout. The Māori and Pacific (Polynesian) populations of New Zealand exhibit a high prevalence of gout (6 and 8%, respectively). The objective of this study was to test whether mitochondrial genetic variation and copy number among New Zealand Polynesians may contribute to susceptibility to gout.
Methods: 439 whole mitochondrial genomes of Māori and Pacific men from New Zealand (327 cases/112 controls) were sequenced. mtDNA copy number variation was also investigated by looking at relative read depth using Next Generation Sequencing data produced from whole genome sequencing and resequencing of urate loci. Quantitative PCR was undertaken for replication in an extended sample set of 1070 Polynesians (540 cases/530 controls).
Findings: Within Polynesia, there is relatively little mitochondrial genetic diversity, with around 96% of those sequenced here belonging to the B4a1a derived sub-lineages. A lineage-specific heteroplasmy in hypervariable region I was found to associate with a three-fold higher risk of gout (eg. heteroplasmy at position 16179: OR 3.28, P = 0.009). Quantitative PCR of mtDNA from the 1070 Polynesian gout cases and controls showed that individuals with gout possess less mtDNA, on average than healthy controls. With each unit increase in ΔCt (which reflects a decrease in mtDNA content), there was a 33% increase in gout risk (OR 1.33, P = 0.003). The effect was stronger when looking at those who possessed urate levels exceeding 0.40 mmolL-1 (n = 422, OR 1.69, P = 0.0005).
Significance: It is unclear whether the reduced mtDNA copy number in gout is a result of the pathology directly (ie. via inflammatory processes) or whether the reduced amount of mtDNA contributes to gout risk. The increased risk using hyperuricemic controls suggests that reduced mtDNA copy number plays a role in inflammation. Given emerging research is showing that mitochondria play a central role in the induction of the NLRP3 inflammasome, in particular with the co-localisation of the NLRP3 and ASC sub-units, a process essential for the generation of IL-1β, these observations are significant.