甲状腺功能障碍与膝关节骨性关节炎因果关系的双向两样本孟德尔随机化分析

Bidirectional two sample Mendelian randomization analysis on the causal relationship between thyroid dysfunction and knee osteoarthritis

目的:使用孟德尔随机化(MR)分析甲状腺功能障碍(包括甲状腺功能亢进和甲状腺功能减退)与膝关节骨性关节炎(KOA)之间的相关性。方法:从布里斯托尔大学的IEU全基因组关联研究(GWAS)数据库中选择甲状腺功能亢进、甲状腺功能减退与KOA的GWAS数据。通过设置关联强度和消除连锁不平衡,筛选出最后作为工具变量(IVs)的单核苷酸多态性(SNPs)。在正向MR分析中,研究以甲状腺功能亢进和甲状腺功能减退作为暴露,分别获取了5个、28个SNPs作为IVs,以KOA作为结局。在反向MR分析中,以KOA作为暴露获取了6个SNPs作为IVs,以甲状腺功能亢进和甲状腺功能减退作为结局。双向MR分析将逆方差加权(IVW)作为主要分析方法,其他4种方法(Weighted Mode、Weighted Median、Simple Mode、MR-Egger)作为辅助分析,来评估甲状腺功能障碍与KOA之间的因果关系。同时还采用了异质性和多效性检验,并使用留一法分析评估结果的稳定性。结果:遗传预测的甲状腺功能亢进与KOA的风险增加相关(IVW:OR=1.048,95%CI 1.026~1.070,P<0.001),未发现甲状腺功能减退与KOA(IVW:OR=1.029,95%CI 0.983~1.077,P=0.221)以及KOA与甲状腺功能亢进(IVW:OR=0.748,95%CI 0.205~2.736,P=0.661)和甲状腺功能减退(IVW:OR=0.997,95%CI 0.646~1.539,P=0.989)存在因果关联。结论:甲状腺功能亢进与KOA之间存在因果关系,在甲状腺功能减退对KOA的研究及反向研究中并未发现因果关联,该研究结果需要进一步的实验室研究进行验证,以及未来更大样本量的研究提供证据支持。

Objective:To investigate the correlation between thyroid dysfunction(including hyperthyroidism and hypothyroidism)and knee osteoarthritis(KOA)using Mendelian randomization(MR)analysis.Methods:Genome-wide association studies(GWAS)data for hyperthyroidism,hypothyroidism,and KOA from the IEU GWAS database at the University of Bristol was collected.By setting association strength and eliminating linkage imbalance,single nucleotide polymorphisms(SNPs)were selected as instrumental variables(IVs).In the forward MR analysis,the study used hyperthyroidism and hypothyroidism as exposures,and obtained 5 and 28 SNPs as IVs,respectively,with KOA as the outcome.In reverse MR analysis,six SNPs were obtained as IVs using KOA as exposure,with hyperthyroidism or hypothyroidism as outcomes.Bidirectional MR analysis uses inverse variance weighting(IVW)as the primary analysis method,and the other four methods(weighted mode,weighted median,simple mode,MR Egger)as auxiliary analyses to evaluate the causal relationship between thyroid dysfunction and KOA.Heterogeneity and pleiotropy tests were also used,and the stability of the results was evaluated using the retention method.Results:Genetic prediction of hyperthyroidism was associated with an increased risk of KOA(IVW:OR=1.048,95%CI 1.026-1.070,P<0.001).No evidence was found of causal relationships for hypothyroidism on KOA(IVW:OR=1.029,95%CI 0.983-1.077,P=0.221),as well as KOA on hyperthyroidism(IVW:OR=0.748,95%CI 0.205-2.736,P=0.661)and KOA on hypothyroidism(IVW:OR=0.997,95%CI 0.646-1.539,P=0.989).Conclusion:This result indicates a causal relationship between hyperthyroidism and KOA,and no causal relationship was found in the study and reverse study of hypothyroidism on KOA.The findings of this study require further validation through laboratory research,as well as evidence support from future studies with larger sample sizes.