OP0158 Mitochondrial Genetic Variation and Susceptibility To Gout in Polynesians

BackgroundMitochondria appear to play a central role in the induction of an NLRP3 inflammatory response, an immune response critical for the development of gouty pathology. Mitochondria are in part self-encoding, possessing a 16.5 kB circular genome which encodes 36 genes. Therefore mitochondrial genetic variation may contribute to susceptibility to gout.ObjectivesThe objective of this study was to test whether mitochondrial genetic variation and copy number among New Zealand Polynesians may be contributing to susceptibility to gout. The Māori and Pacific (Polynesian) populations of New Zealand exhibit a high prevalence of gout (6 and 8%, respectively).Methods439 whole mitochondrial genomes belonging to Māori and Pacific men from New Zealand (327 cases, 112 controls) were sequenced to explore whether mitochondrial DNA (mtDNA) variation may contribute risk to gout. 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 540 Polynesian male and female cases and 530 controls.ResultsWithin Polynesia, there is relatively little mitochondrial genetic diversity, with around 96% of those sequenced in this study belonging to the B4a1a and derived sub-lineages. A lineage-specific heteroplasmy in hypervariable region I was found to associate with a greater than three-fold higher risk of gout among the mitochondrial sequenced sample set (e.g. heteroplasmy at position 16179: OR 3.28, P=0.009; heteroplasmy at position 16181: 3.86, P=9x10–5; heteroplasmy at position 16182: 3.43, P=0.005).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 participants who possessed urate levels exceeding 0.40 mmol L–1 (n=422, OR 1.69, P=0.0005).ReferencesIt is unclear whether the reduced mtDNA copy number in gout is a result of the gouty pathology directly (i.e. the reduced mtDNA copy number is caused by the inflammatory processes underlying gout) or whether the reduced mtDNA copy number contributes to the risk of gout. The latter possibility is supported by the increase in risk using hyperur