Two-sample Mendelian randomization analysis of the relationship between statins and the risk of osteoarthritis

doi:10.12307/2024.440

Abstract

Abstract: BACKGROUND: Observational studies have suggested that statins may have a protective effect against osteoarthritis, including knee osteoarthritis and hip osteoarthritis. However, the association between statins and the risk of osteoarthritis remains unclear.
OBJECTIVE: To investigate the association between statins and the risk of osteoarthritis through Mendelian randomization analysis using summary data from large-scale population-based genome-wide association studies (GWAS).
METHODS: Firstly, single nucleotide polymorphism data related to statins were obtained from the latest 9th edition of the FinnGen database, while data of osteoarthritis, knee osteoarthritis and hip osteoarthritis were obtained from the IEU Open GWAS, UK Biobank, and ArcOGEN (Genetics of Osteoarthritis) databases, respectively. The inverse variance weighted method was used as the primary analysis approach to evaluate the causal effects. The weighted median method, simple median method, weighted mode-based method, and MR-Egger regression were used as supplementary analyses. The causal relationship between statins and the risk of osteoarthritis, knee osteoarthritis and hip osteoarthritis was assessed using odds ratios (OR) with 95% confidence intervals (CI). Sensitivity analyses were conducted to validate the reliability of the results, including the Cochran’s Q test for heterogeneity and the MR-Egger-intercept test for horizontal pleiotropy, as well as leave-one-out analysis to identify potentially influential single nucleotide polymorphisms.
RESULTS AND CONCLUSION: The inverse variance weighted analysis demonstrated a negative causal relationship between genetically predicted statins and the risk of osteoarthritis (OR=0.998, 95% CI: 0.996-0.999, P=0.01), knee osteoarthritis (OR=0.964, 95% CI: 0.940-0.989, P=0.005), and hip osteoarthritis (OR=0.928, 95% CI: 0.901-0.955, P=4.28×10-7). MR-Egger intercept analysis did not detect potential horizontal pleiotropy (osteoarthritis: P=0.658; knee osteoarthritis: P=0.600; hip osteoarthritis: P=0.141). The results of this study provide evidence that statins reduce the risks of osteoarthritis, knee osteoarthritis and hip osteoarthritis as described in observational studies. Further research is needed to explore the specific mechanisms of statin treatment for osteoarthritis.

Key words: statins, osteoarthritis, Mendelian randomization, genome-wide association study, single nucleotide polymorphism, causal relationship

CLC Number:

Wu Ruiqi, Zhang Xuan, Zhou Yi, Meng Lin, Li Hongyu. Two-sample Mendelian randomization analysis of the relationship between statins and the risk of osteoarthritis[J]. Chinese Journal of Tissue Engineering Research, 2024, 28(26): 4106-4112.

Figures/Tables 6

2.1 工具变量根据此次研究工具变量筛选标准，首先从他汀类药物暴露数据集中共筛选出128个密切相关且无连锁不平衡的单核苷酸多态性，经过几次筛选，骨关节炎结局数据集获得115个单核苷酸多态性，利用PhenoScanner数据库检索有关的表型，剔除其对应表型与骨关节炎具有相关意义的1个单核苷酸多态性(rs1415991)，并删除回文单核苷酸多态性(n=23)，同时经MR-PRESSO分析后剔除1个离群值(rs117814720)，单一单核苷酸多态性对应的F统计量分布范围22.10-257.72，表明在MR分析中没有弱的工具变量，最终纳入90个单核苷酸多态性作为工具变量来评估他汀类药物和骨关节炎之间的关联。膝骨关节炎结局数据集获得128个单核苷酸多态性，剔除其对应表型与膝骨关节炎具有相关意义的2个单核苷酸多态性(rs78087637、rs998584)，并删除回文单核苷酸多态性单核苷酸多态性(n=22)，同时经MR-PRESSO分析后剔除3个离群值(rs12112877、rs115478735、rs9849171)，单一单核苷酸多态性单核苷酸多态性对应的F统计量分布范围25.50-366.85，表明在MR分析中没有弱的工具变量，最终纳入101个单核苷酸多态性作为工具变量来评估他汀类药物和膝骨关节炎之间的关联。髋骨关节炎结局数据集获得128个单核苷酸多态性，剔除其对应表型与髋骨关节炎具有相关意义的1个单核苷酸多态性(rs1415991)，并删除回文单核苷酸多态性(n=23)，同时经MR-PRESSO分析后剔除3个离群值(rs112108223、rs213484、rs217181)，单一单核苷酸多态性对应的F统计量分布范围25.67.10-378.92，表明在MR分析中没有弱的工具变量，最终纳入101个单核苷酸多态性作为工具变量来评估他汀类药物和髋骨关节炎之间的关联。 2.2 他汀类药物对骨关节炎疾病的影响 IVW法分析结果显示，遗传预测的他汀类药物与骨关节炎(OR=0.998，95%CI：0.996-0.999，P=0.01)、膝骨关节炎(OR=0.964，95%CI：0.940-0.989，P=0.005)和髋骨关节炎(OR=0.928，95%CI：0.901-0.955，P=4.28×10-7)之间可能呈负向因果效应，且具有统计学意义，同时应用其他4种分析方法(MR-Egger、WM、WME和SM)来确认结果的稳健性，其中，WM、SM和WME方法分析的结果与IVW相似，MR-Egger分析虽不支持他汀类药物与骨关节炎(OR=0.997，95%CI：0.995-1.000，P=0.089)和膝骨关节炎(OR=0.968，95%CI：0.930-1.008，P=0.121)之间具有因果关系，但IVW、MR-Egger、WM、WME和SM 5种分析方法的结果方向一致(OR值均 < 1)，详见表2。此外，MR-PRESSO方法在异常值校正前后的因果估计是一致的，散点图同样显示了遗传预测的他汀类药物对骨关节炎、膝骨关节炎、髋骨关节炎风险得到的回归线基本一致，见图2。以上表明MR分析的结果是可靠的。"

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