Identification of genetic association between mitochondrial dysfunction and knee osteoarthritis through integrating multi-omics: a summary data-based Mendelian randomization study.
| Autor: | Xie J; Department of Joint Surgery, HongHui Hospital, Xian Jiaotong University, Xian, Shaanxi, China., Ma R; Department of Joint Surgery, HongHui Hospital, Xian Jiaotong University, Xian, Shaanxi, China., Xu X; Department of Joint Surgery, HongHui Hospital, Xian Jiaotong University, Xian, Shaanxi, China., Yang M; Department of Joint Surgery, HongHui Hospital, Xian Jiaotong University, Xian, Shaanxi, China., Yu H; Department of Joint Surgery, HongHui Hospital, Xian Jiaotong University, Xian, Shaanxi, China., Wan X; Department of Joint Surgery, HongHui Hospital, Xian Jiaotong University, Xian, Shaanxi, China., Xu K; Department of Joint Surgery, HongHui Hospital, Xian Jiaotong University, Xian, Shaanxi, China., Guo J; Department of Joint Surgery, HongHui Hospital, Xian Jiaotong University, Xian, Shaanxi, China., Xu P; Department of Joint Surgery, HongHui Hospital, Xian Jiaotong University, Xian, Shaanxi, China. sousou369@163.com. |
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| Jazyk: | angličtina |
| Zdroj: | Clinical rheumatology [Clin Rheumatol] 2024 Nov; Vol. 43 (11), pp. 3487-3496. Date of Electronic Publication: 2024 Sep 11. |
| DOI: | 10.1007/s10067-024-07136-7 |
| Abstrakt: | Objective: Association between mitochondrial dysfunction and osteoarthritis (OA) has been consistently investigated, yet their genetic association remains obscure. In this study, mitochondrial-related genes were used as instrumental variables to proxy for mitochondrial dysfunction, and summary data of knee OA (KOA) were used as outcome to examine their genetic association. Methods: We obtained 1136 mitochondrial-related genes from the human MitoCarta3.0 database. Genetic proxy instruments for mitochondrial-related genes from studies of corresponding gene expression (n = 31,684) and protein (n = 35,559) quantitative trait locus (eQTLs and pQTLs), respectively. Aggregated data for KOA (62,497 KOA cases and 333,557 controls) were extracted from the largest OA genome-wide association study (GWAS). We integrated QTL data with KOA GWAS data to estimate their genetic association using summary data-based Mendelian randomization analysis (SMR). Additionally, we implemented Bayesian colocalization analysis to reveal whether suggestive mitochondrial-related genes and KOA were driven by a same genetic variant. Finally, to validate the primary findings, replication study (24,955 cases and 378,169 controls) and multi-SNP-based SMR (SMR-multi) test was performed. Results: Through SMR analysis, we found that the expression levels of 2 mitochondrial-related genes were associated with KOA risk. Specifically, elevated gene expression levels of the IMMP2L (odds ratio [OR] = 1.056; 95% confidence interval [CI] = 1.030-1.082; P- Conclusions: In summary, our analyses revealed the genetic association between mitochondrial dysfunction proxied by mitochondrial-related genes and KOA, providing new insight into potential pathogenesis of KOA. Furthermore, these identified candidate genes offer the possibility of clinical drug target development for KOA. Key points • This is the first SMR study to explore the genetic association between mitochondrial dysfunction proxied by mitochondrial-related genes and KOA. • Sufficient evidence to support genetic association between the expression levels of AKAP10 and IMMP2L, and KOA • Our MR analysis may provide novel new insight into potential pathogenesis of KOA. • These identified candidate genes offer the possibility of clinical drug target development for KOA. (© 2024. The Author(s).) |
| Databáze: | MEDLINE |
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