Objective Mitochondria have an important role in the induction of the NLRP3 inflammasome response central in gout. The objective was to test whether mitochondrial genetic variation and copy number in New Zealand Māori and Pacific (Polynesian) people in Aotearoa New Zealand associate with susceptibility to gout.
Methods 437 whole mitochondrial genomes from Māori and Pacific people (predominantly men) from Aotearoa New Zealand (327 people with gout, 110 without gout) were sequenced. Mitochondrial DNA copy number variation was determined by assessing relative read depth using data produced from whole genome sequencing (32 cases, 43 controls) and targeted resequencing of urate loci (151 cases, 222 controls). Quantitative PCR was undertaken for replication of copy number findings in an extended sample set of 1159 Māori and Pacific men and women (612 cases, 547 controls).
Results There was relatively little mitochondrial genetic diversity, with around 96% of those sequenced in this study belonging to the B4a1a and derived sublineages. A B haplogroup heteroplasmy in hypervariable region I was found to associate with a higher risk of gout among the mitochondrial sequenced sample set (position 16181: OR=1.57, P=0.001). Increased copies of mitochondrial DNA were found to protect against gout risk with the effect being consistent when using hyperuricaemic controls across each of the three independent sample sets (OR=0.89, P=0.007; OR=0.90, P=0.002; OR=0.76, P=0.03). Paradoxically, an increase of mitochondrial DNA also associated with an increase in gout flare frequency in people with gout in the two larger sample sets used for the copy number analysis (β=0.003, P=7.1×10–7; β=0.08, P=1.2×10–4).
Conclusion Association of reduced copy number with gout in hyperuricaemia was replicated over three Polynesian sample sets. Our data are consistent with emerging research showing that mitochondria are important for the colocalisation of the NLRP3 and ASC inflammasome subunits, a process essential for the generation of interleukin-1β in gout.
- gene polymorphism
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Handling editor Josef S Smolen
Contributors All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. TRM had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design: ALG, JB, EAM-S, TRM. Acquisition of data: ALG, JB, JHH, LKS, ND, EAM-S, HKC, TRM. Analysis and interpretation of data: ALG, JB, EAM-S, TRM.
Competing interests None declared.
Ethics approval Ethical approval for the collection of the samples and subsequent analyses was obtained from the NZ Multi-Region Ethics Committee (MREC 05/10/130) and also the Northern Y Regional Health Research Ethics Committee, the latter granting ethical approval for the Ngāti Porou Hauora Charitable Trust recruitment (NTY07/07/074).
Provenance and peer review Not commissioned; externally peer reviewed.
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