Germline and somatic mtDNA mutation spectrum of rheumatoid arthritis patients in the Taizhou area, China
Germline and somatic mtDNA mutation spectrum of rheumatoid arthritis patients in the Taizhou area, China
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台州地区类风湿性关节炎患者种系及体细胞mtDNA突变谱
DOI：
10.1093/rheumatology/keaa063
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发表时间：
2020-10-01
期刊：
影响因子：
5.5
通讯作者：
Shen, Bo
中科院分区：
文献类型：
--
作者：
Du, Juping;Yu, Sufei;Shen, Bo
Objective.活性氧被认为参与了类风湿关节炎的发病，最近已经揭示了核编码的线粒体呼吸链相关变体与类风湿关节炎之间的关联。然而，鲜为人知的是，景观的线粒体DNA（mtDNA）的变异在RA。对中国泰州地区124例RA患者和123例年龄和性别匹配的健康对照者进行了线粒体DNA生殖系和体细胞变异的下一代测序。采用Fisher精确检验、SKAT和SKAT-O进行基因负荷检验，以研究RA相关的线粒体基因变异。应用预测工具对mtDNA变异体的致病性进行评估，并根据PhyloTree数据库中的mtDNA突变进行单倍型群的划分。采用卡方分析比较各组mtDNA单倍型群的频率分布。我们确定了467个RA独特的和341个健康对照独特的mtDNA变异，其中443个常见变异。通过Fisher精确检验、SKAT和SKAT-O仅鉴定出具有显著变体负荷的MT-ATP 6，即使在Bonferroni调整后，并且MT-ATP 6中的富集变体主要由m.8830C>A、m.8833G>C和m.8843T>A变体驱动。此外，MT-ND 5的上述三个变异体和m.14135T>G等四个低异质性变异体仅在RA中检测到;除m.8830C>A外，基于功能预测，它们被认为是潜在的致病性。经Bonferroni校正后的χ 2分析显示，F1/F1 a单倍型与RA呈负相关（P < 0.05）。这些结果描绘了RA的种系和体细胞mtDNA变异的景观，并支持线粒体基因对RA的影响。
Objective. Reactive oxygen species are believed to be involved in the onset of RA, and the association between nuclear-encoded mitochondrial respiratory chain-related variants and RA has recently been revealed. However, little is known about the landscape of mitochondrial DNA (mtDNA) variants in RA.Methods. Next-generation sequencing was conducted to profile mtDNA germline and somatic variants in 124 RA patients and 123 age- and sex-matched healthy controls in the Taizhou area, China. Fisher's exact test, SKAT and SKAT-O were used for gene-burden tests to investigate RA-related variants of mitochondrial genes. Predictive tools were applied to evaluate the pathogenicity of mtDNA variants, and mtDNA haplogroups were assigned according to mtDNA mutations recorded in PhyloTree database. The frequency distribution of mtDNA haplogroups between the groups was compared using chi(2) analysis.Results. We identified 467 RA-unique and 341 healthy control-unique mtDNA variants, with 443 common variants. Only MT-ATP6 with a significant burden of variants was identified by Fisher's exact test, SKAT and SKAT-O, even after Bonferroni adjustment, and the enrichment variants in MT-ATP6 was mainly driven by m.8830C>A, m.8833G>C and m.8843T>A variants. Besides, four frequently low-heteroplasmic variants including the three variants above and m.14135T>G of MT-ND5 were detected in RA only; except for m.8830C>A, they are considered potential pathogenicity based on functional predictions. chi(2) analysis before Bonferroni adjustment revealed haplogroup F1/F1 a to be negatively associated with RA (P < 0.05).Conclusion. These results profiled the landscape of germline and somatic mtDNA variants in RA and supported the effects of mitochondrial genes on RA.