Luo Jing, Pan Jingjing, Yao Guanqun, Xu Zenghao, Jiang Shan, Peng Jian, Shang Xiaopeng, Wu Huaxiang, Liao Xin
Department of Rheumatology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
Zhejiang Provincial Centers for Disease Control and Prevention, Hangzhou, China.
Int J Rheum Dis. 2025 Aug;28(8):e70383. doi: 10.1111/1756-185x.70383.
Mitochondrial dysfunction has been implicated in the pathogenesis of autoimmune disorders (AIDs), but its causal role in disease susceptibility and progression remains unclear. This study explores potential causal associations between mitochondrial-related genes and AIDs using integrated multi-omics evidence from Mendelian randomization (MR) and colocalization analyses.
Summary-level datasets from 10 common AIDs (303 590-456 348 participants) and quantitative trait loci (QTL) at the DNA methylation, gene expression, and protein abundance levels (mQTL, eQTL, and pQTL, respectively; 1 980-35 559 participants), as well as mitochondrial DNA copy number (465 809 participants), were analyzed. Instrumental variables were selected from cis-acting variants near 1136 mitochondrial-related genes with strong associations (p < 5e-08). Summary-data-based MR (SMR) and Bayesian colocalization analyses were applied to identify causal effects, followed by validation assessments integrating multi-omics SMR results.
Four Grade-II mitochondrial genes were causally linked to multiple AIDs. ATAD3A (OR: 1.41; 95% CI: 1.13-1.76, p = 1.64e-03) and TOP1MT (OR: 1.42; 95% CI: 1.10-1.84, p = 4.60e-03) were strongly associated with multiple myositis, while SND1 (OR: 1.08; 95% CI: 1.04-1.12, p = 4.05e-03) was linked to osteoarthritis. Notably, TOP1MT expression conferred protective effects against primary Sjögren's syndrome (OR: 0.57; 95% CI: 0.35-0.95, p = 8.21e-03). Crucially, only UQCRH was identified with the same variant (rs41292543) exhibiting inverse effects on multiple myositis, including causal effects through cg11235697 methylation (OR: 1.56; 95% CI: 1.23-1.98, p = 3.02e-04) and protective effects through gene expression (OR: 0.83; 95% CI: 0.72-0.95, p = 2.78e-04).
These findings provide robust evidence of mitochondrial dysfunction's causal role in AIDs and identify potential pharmacological targets for treatment, offering new insights into precision medicine for AIDs.
线粒体功能障碍与自身免疫性疾病（AIDs）的发病机制有关，但其在疾病易感性和进展中的因果作用仍不清楚。本研究利用孟德尔随机化（MR）和共定位分析的综合多组学证据，探索线粒体相关基因与AIDs之间的潜在因果关联。
分析了来自10种常见AIDs（303590 - 456348名参与者）的汇总数据集以及DNA甲基化、基因表达和蛋白质丰度水平（分别为mQTL、eQTL和pQTL；1980 - 35559名参与者）的数量性状位点（QTL），以及线粒体DNA拷贝数（465809名参与者）。从1136个线粒体相关基因附近具有强关联（p < 5e - 08）的顺式作用变体中选择工具变量。应用基于汇总数据的MR（SMR）和贝叶斯共定位分析来确定因果效应，随后进行整合多组学SMR结果的验证评估。
四个二级线粒体基因与多种AIDs存在因果联系。ATAD3A（OR：1.41；95%CI：1.13 - 1.76，p = 1.64e - 03）和TOP1MT（OR：1.42；95%CI：1.10 - 1.84，p = 4.60e - 03）与多发性肌炎密切相关，而SND1（OR：1.08；95%CI：1.04 - 1.12，p = 4.05e - 03）与骨关节炎有关。值得注意的是，TOP1MT表达对原发性干燥综合征具有保护作用（OR：0.57；95%CI：0.35 - 0.95，p = 8.21e - 03）。至关重要的是，仅发现UQCRH具有相同变体（rs41292543），对多种肌炎表现出相反作用，包括通过cg11235697甲基化的因果效应（OR：1.56；95%CI：1.23 - 1.98，p = 3.02e - 04）和通过基因表达的保护作用（OR：0.83；95%CI：0.72 - 0.95，p = 2.78e - 04）。
这些发现为线粒体功能障碍在AIDs中的因果作用提供了有力证据，并确定了潜在的治疗药理学靶点，为AIDs的精准医学提供了新的见解。
