Causal Role of Oxidative Stress-Related Genes in Osteoarthritis
DOI:
https://doi.org/10.54097/ghj4c127Keywords:
Osteoarthritis, Oxidative Stress, Mendelian Randomization, Colocalization AnalysisAbstract
Background: Osteoarthritis (OA) is a common joint disease, primarily affecting the elderly. Oxidative stress (OS), resulting from an imbalance between oxidants and antioxidants, plays a significant role in OA progression. This study aimed to explore the causal relationship between OS-related genes and OA using summary-based Mendelian randomization (SMR).
Methods: OS-related genes were selected from the GeneCards database with a relevance score ≥ 7. GWAS data for OA, including 24,955 cases and 378,169 controls, were retrieved from the IEU database. eQTL data were obtained from the eQTLGen Consortium. SMR analysis was conducted to assess the causal effects of gene expression on OA, with the HEIDI test used to confirm the absence of heterogeneity. Colocalization and enrichment analyses were performed, and regulatory networks for key genes were predicted. Results: SMR analysis identified 26 OS-related genes with causal links to OA. Seven genes were associated with an increased risk of OA, while 19 were protective. Enrichment analysis revealed pathways such as "response to oxidative stress" and "cellular oxidant detoxification." Colocalization analysis indicated LYRM4 and MAPK3 likely share causal variants with OA, and regulatory network predictions highlighted genes like NFS1 and ELK1 as potential regulators of LYRM4 and MAPK3. Conclusion: This study identified several OS-related genes potentially contributing to OA, with LYRM4 and MAPK3 as key candidates. These findings offer insights into OA pathogenesis, suggesting that mitochondrial dysfunction and inflammatory signaling play crucial roles. Further research is needed to validate these results and explore potential therapeutic strategies targeting these genes.
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References
[1] Tang, X., et al. Acute Respiratory Distress Syndrome in China: Results From the China Health and Retirement Longitudinal Study. Arthritis Rheumatol., 2016. 68: p. 648-653.
[2] Chang, L., et al. TDP-43 and Its Role in Maintaining Chondrocyte Homeostasis and Alleviating Cartilage Degradation in Osteoarthritis. Osteoarthritis Cartilage, 2021. 29: p. 1036-1047.
[3] Sies, H. Oxidative Stress: A Concept in Redox Biology and Medicine. Redox Biol., 2015. 4: p. 180-183.
[4] Riegger, J., et al. Oxidative Stress as a Key Modulator of Cell Fate Decision in Osteoarthritis and Osteoporosis: A Narrative Review. Cell. Mol. Biol. Lett., 2023. 28: p. 76.
[5] Saha, S., and N. Y. Rebouh. Anti-Osteoarthritis Mechanism of the Nrf2 Signaling Pathway. Biomedicines, 2023. 11: p. 3176.
[6] Sun, J., et al. Glutaredoxin 1 (GRX1) Inhibits Oxidative Stress and Apoptosis of Chondrocytes by Regulating CREB/HO-1 in Osteoarthritis. Mol. Immunol., 2017. 90: p. 211-218.
[7] Davies, N. M., et al. Reading Mendelian Randomisation Studies: A Guide, Glossary, and Checklist for Clinicians. BMJ, 2018. Article: k601. doi:10.1136/bmj.k601
[8] Lawlor, D. A. Commentary: Two-Sample Mendelian Randomization: Opportunities and Challenges. Int. J. Epidemiol., 2016. 45: p. 908-915.
[9] Zhu, Z., et al. Integration of Summary Data from GWAS and eQTL Studies Predicts Complex Trait Gene Targets. Nat. Genet., 2016. 48: p. 481-487.
[10] Qiu, X., et al. Identification of Hub Prognosis-Associated Oxidative Stress Genes in Pancreatic Cancer Using Integrated Bioinformatics Analysis. Front. Genet., 2020. 11: p. 595361.
[11] Sun, X., et al. Oxidative Stress-Related lncRNAs Are Potential Biomarkers for Predicting Prognosis and Immune Responses in Patients With LUAD. Front. Genet., 2022. 13: p. 909797.
[12] Tachmazidou, I., et al. Identification of New Therapeutic Targets for Osteoarthritis through Genome-Wide Analyses of UK Biobank. Nat. Genet., 2019. 51: p. 230.
[13] Võsa, U., et al. Large-Scale cis- and trans-eQTL Analyses Identify Thousands of Genetic Loci and Polygenic Scores that Regulate Blood Gene Expression. Nat. Genet., 2021. 53: p. 1300.
[14] Zhu, Z., et al. Integration of Summary Data from GWAS and eQTL Studies Predicts Complex Trait Gene Targets. Nat. Genet., 2016. 48: p. 481-487.
[15] Zhou, Y., et al. Metascape Provides a Biologist-Oriented Resource for the Analysis of Systems-Level Datasets. Nat. Commun., 2019. 10: p. 1523.
[16] Giambartolomei, C., et al. Bayesian Test for Colocalisation between Pairs of Genetic Association Studies Using Summary Statistics. PLoS Genet., 2014. 10: p. e1004383.
[17] Franz, M., et al. GeneMANIA Update 2018. Nucleic Acids Res., 2018. 46: p. W60.
[18] Ivanova, A., et al. A Mitochondrial LYR Protein Is Required for Complex I Assembly. Plant Physiol., 2019. 181: p. 1632-1650.
[19] Stefely, J. A., and D. J. Pagliarini. Biochemistry of Mitochondrial Coenzyme Q Biosynthesis. Trends Biochem. Sci., 2017. 42: p. 824-843.
[20] Kudryavtseva, A. V., et al. Mitochondrial Dysfunction and Oxidative Stress in Aging and Cancer. Oncotarget, 2016. 7: p. 44879-44905.
[21] Liu, L., et al. The Physiological Metabolite α-Ketoglutarate Ameliorates Osteoarthritis by Regulating Mitophagy and Oxidative Stress. Redox Biol., 2023. 62: p. 102663.
[22] Blanco, F. J., et al. The Role of Mitochondria in Osteoarthritis. Nat. Rev. Rheumatol., 2011. 7: p. 161-169.
[23] Son, Y., et al. Mitogen-Activated Protein Kinases and Reactive Oxygen Species: How Can ROS Activate MAPK Pathways? J. Signal Transduct., 2011. Article: 792639.
[24] A, L., et al. Inhibition of Interleukin-1-Stimulated MAP Kinases, Activating Protein-1 (AP-1) and Nuclear Factor Kappa B (NF-Kappa B) Transcription Factors Down-Regulates Matrix Metalloproteinase Gene Expression in Articular Chondrocytes. Matrix Biol. J. Int. Soc. Matrix Biol., 2017. 21: p.
[25] Dong, Y., et al. PRMT5 Inhibition Attenuates Cartilage Degradation by Reducing MAPK and NF-κB Signaling. Arthritis Res. Ther., 2020. 22: p. 201.
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