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.

中文翻译：

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居住在新西兰 Aotearoa 的毛利人和太平洋人的线粒体遗传变异和痛风

目的线粒体在诱导痛风中枢的NLRP3炎症小体反应中起重要作用。目的是测试新西兰 Aotearoa 的新西兰毛利人和太平洋（波利尼西亚人）人的线粒体遗传变异和拷贝数是否与痛风易感性有关。方法 对来自新西兰 Aotearoa 的毛利人和太平洋人（主要是男性）（327 人有痛风，110 人没有痛风）的 437 个完整线粒体基因组进行了测序。线粒体 DNA 拷贝数变异是通过使用全基因组测序（32 个病例，43 个对照）和尿酸基因座的靶向重测序（151 个病例，222 个对照）产生的数据评估相对读取深度来确定的。进行了定量 PCR 以在 1159 名毛利人和太平洋地区男性和女性（612 例，547 名对照）的扩展样本集中复制拷贝数结果。结果 线粒体遗传多样性相对较少，本研究中约 96% 的测序属于 B4a1a 和衍生亚谱系。发现高变区 I 中的 AB 单倍群异质性与线粒体测序样本组中较高的痛风风险相关（位置 16181：OR=1.57，P=0.001）。发现增加的线粒体 DNA 拷贝可以预防痛风风险，并且在三个独立样本组中的每一个中使用高尿酸血症对照时效果一致（OR = 0.89，P = 0.007；OR = 0.90，P = 0.002；OR = 0.76， P=0.03）。矛盾的是，在用于拷贝数分析的两个较大样本组中，线粒体 DNA 的增加也与痛风患者痛风发作频率的增加有关（β=0.003，P=7.1×10-7；β=0.08，P=1.2 ×10–4）。结论 拷贝数减少与高尿酸血症痛风的关联在三个波利尼​​西亚样本组中得到重复。我们的数据与新兴研究一致，表明线粒体对 NLRP3 和 ASC 炎症小体亚基的共定位很重要，这是痛风中产生白细胞介素 1β 必不可少的过程。