国际口腔医学杂志

国际口腔医学杂志 ›› 2026, Vol. 53 ›› Issue (2): 205-215.doi: 10.7518/gjkq.2026003

• 论著 • 上一篇    

采用孟德尔随机化法研究线粒体功能障碍对口腔扁平苔藓发病机制的影响

姚曼曼(),路月亭(),吴景景,刘铁军,仇永乐,尚宏悦,董博   

  1. 河北医科大学第四医院口腔科 石家庄 050000
  • 收稿日期:2024-11-05 修回日期:2024-12-30 出版日期:2026-03-01 发布日期:2026-02-13
  • 通讯作者: 路月亭
  • 作者简介:姚曼曼，主治医师，硕士，Email：49103567@hebmu.edu.cn
  • 基金资助:
    中央引导地方科技发展资金(246Z7762G);河北省中医药管理局科学研究课题计划(2026349);河北省医学科学研究课题计划(20260512)

Exploring the impact of mitochondrial dysfunction on the pathogenesis of oral lichen planus using Mendelian randomization

Manman Yao(),Yueting Lu(),Jingjing Wu,Tiejun Liu,Yongle Qiu,Hongyue Shang,Bo Dong   

  1. Dept. of Stomatology, the Fourth Hospital of Hebei Medical University, Shijiazhuang 050000, China
  • Received:2024-11-05 Revised:2024-12-30 Online:2026-03-01 Published:2026-02-13
  • Contact: Yueting Lu
  • Supported by:
    Central Government Guides Local Funds Supported by S&T Program of Hebei(246Z7762G);Research Plan of Hebei Provincial Administration of Traditional Chinese Medicine(2026349);Medical Science Research Project of Hebei Province(20260512)

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摘要：

目的 采用孟德尔随机化（MR）法研究特定线粒体功能与口腔扁平苔藓（OLP）存在之间的因果关系，探讨线粒体功能障碍对OLP的影响，为深入了解OLP的发病机制和寻找潜在的治疗靶点提供参考。 方法 本研究的数据来源于开放全基因组关联研究（IEU）和芬兰基因组研究计划（FINNGEN）数据库。从IEU数据库中筛选出69种与线粒体功能相关的遗传变异位点，从FINNGEN数据库中获得了包含587例病例和411 594例对照的OLP数据。采用R语言4.3.2进行MR分析，采用逆方差加权 （IVW）、MR Egger 回归法（MR Egger）和加权中位数法，评估线粒体变异与OLP之间的因果关系。工具变量的选择设置了P<5e-5的统计学阈值，消除连锁不平衡的标准包括设置r²>0.001和去除1 000 kb范围内的单核苷酸多态性（SNP）；同时还进行了异质性检验和定向水平多效性检验。 结果 MR分析发现特定线粒体功能与OLP之间的关联存在统计学意义。比值比（OR）小于1时，提示对OLP具有保护作用。谷氧还蛋白-2（Grx2）（IVW，OR=0.768，P=0.036）和线粒体肽蛋氨酸亚砜还原酶（MPMSR）（IVW，OR=0.680，P=0.044）均小于1；相反，丙二酰辅酶A脱羧酶（MCD）（IVW，OR=1.591，P=0.022）、39S核糖体蛋白L34（MRPL34）（IVW，OR=1.826，P=0.034）和核糖体再循环因子（RRF）（IVW，OR=1.498，P=0.004 9）的OR值大于1，提示这些因素是OLP的危险因素。进一步的反向验证强调了MCD与OLP的相关性具有统计学意义（IVW，OR=1.134，P=0.045），表明OLP也是这种线粒体功能的危险因素。 结论 本研究基于MR发现特定线粒体功能与OLP之间的因果关联存在统计学意义，其中Grx2和MPMSR等与氧化还原稳态相关的线粒体蛋白显示出对OLP的保护作用，而MCD、MRPL34和RRF等则可能增加OLP的患病风险。此外，反向MR结果支持MCD功能变化与OLP存在因果关系，提示二者存在潜在的双向调控关系。这些结果提示线粒体氧化代谢与蛋白质合成等功能异常可能在OLP发病中发挥关键作用。

关键词: 口腔扁平苔藓, 孟德尔随机化分析, 线粒体

Abstract:

Objective　This study aimed to investigate the potential causal relationship between specific mitochondrial functions and oral lichen planus (OLP) via Mendelian randomization (MR) analysis. To explore the effect of mitochondrial dysfunction on OLP, provi-ding new insights into its pathogenesis and identifying potential therapeutic targets. Methods　Genetic variants related to mitochondrial function were obtained from the integrative epidemiology unit open GWAS project （IEU） database, and OLP summary-level data (587 cases and 411 594 controls) were retrieved from the FINNGEN database. A total of 69 mitochondrial-related genetic variants were selected for analysis. MR analysis was performed using R software (version 4.3.2), applying the inverse variance weighted (IVW) method, MR Egger regression, and the weighted median approach to estimate the causal effects of mitochondrial variants on OLP. Instrumental variables were selected with a significance threshold of P<5e-5. To eliminate linkage disequilibrium, single-nucleotide polymorphisms (SNPs) within 1 000 kb and with r²>0.001 were excluded. Heterogeneity and horizontal pleiotropy were also assessed. Results　MR analysis identified significant associations between specific mitochondrial functions and OLP. Odds ratios (OR) less than 1 suggested a protective effect on OLP. Glutaredoxin-2 (Grx2) (IVW, OR: 0.768, P=0.036) and mitochondrial peptide methionine sulfo-xide reductase (MPMSR) (IVW, OR: 0.680, P=0.044) had ORs less than 1. Conversely, malonyl-CoA decarboxylase (MCD) (IVW, OR: 1.591, P=0.022), 39S ribosomal protein L34 (MRPL34) (IVW, OR: 1.826, P=0.034), and ribosome-recycling factor (RRF) (IVW, OR: 1.498, P=0.004 9) exhibited OR greater than 1, indicating that they were risk factors for OLP. Further reverse validation showed that MCD was significantly associated with OLP (IVW, OR: 1.134, P=0.045), suggesting that OLP was a risk factor for this mitochondrial function. Conclusion　This MR study identified a causal relationship between specific mitochondrial functions and OLP. Mitochondrial proteins involved in redox homeostasis, such as Grx2 and MPMSR, appear to have a protective effect, whereas dysregulation of mitochondrial metabolic and translational functions, including MCD, MRPL34, and RRF, may contribute to increased disease risk. The bidirectional association between MCD and OLP further highlights the complexity of mitochondrial involvement in OLP pathogenesis. These findings provide novel insights into potential causal pathways and therapeutic targets for OLP.

Key words: oral lichen planus, Mendelian randomization analysis, mitochondria

中图分类号: 

  • R781.5

图 1

线粒体与OLP的相关性热图"

表 1

OLP相关的线粒体全基因组关联分析数据"

编号（GWAS ID）年份线粒体因子样本量SNP数量
prot-a-19532018MPMSR3 30110 534 735
prot-a-19072018MCD3 30110 534 735
prot-a-12202018Grx23 30110 534 735
prot-a-19432018MRPL343 30110 534 735
prot-a-19452018RRF3 30110 534 735

图 2

线粒体与OLP之间的因果关系的森林图（集成的5种算法）"

图3

线粒体与OLP之间的因果关系的森林图（IVW算法）"

表 2

异质性和多效性检验结果"

编号

线粒体

因子

结局异质性检验水平多效性检验
MR EggerIVW
Egger截距SEP值
QQ_dfQ_PQQ_dfQ_P
prot-a-1220Grx2OLP10.1100.43412.4110.333-0.0910.060.159
prot-a-1953MPMSROLP6.5170.4816.5280.5890.0100.1010.926
prot-a-1907MCPOLP10.770.15110.980.205-0.0310.0840.723
prot-a-1943MRPL34OLP0.05620.9723.35830.3400.6480.3570.211
prot-a-1945RRFOLP6.8290.6567.55100.6720.0450.0530.412

图 4

5种关键线粒体因子与OLP因果关系的森林图A：Grx2；B：MPMSR；C：MCD；D：MRPL34；E：RRF。"

图5

5种关键线粒体因子与OCP因果关系的散点图A：Grx2；B：MPMSR；C：MCD；D：MRPL34；E：RRF。"

图 6

5种关键线粒体因子与OCP因果关系的留一法森林图A：Grx2；B：MPMSR；C：MCD；D：MRPL34：E：RRF。"

图7

5种关键线粒体因子与OLP因果关系的漏斗图A：Grx2；B：MPMSR；C：MCD；D：MRPL34；E：RRF。"

图 8

MCD与OLP的反向验证因果关系森林图A：MCD与OLP因果关系的森林图（5种算法）；B：MCD与OLP因果关系的森林图（IVW算法）；C：MCD与OLP因果关系的散点图；D：MCD与OLP因果关系的留一法森林图；E：MCD与OLP因果关系的漏斗图。"

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