Immune cells mediate the association between different lipids and knee osteoarthritis: a genome-wide association analysis of European individuals

doi:10.12307/2025.678

Abstract

Abstract: BACKGROUND: Observational studies have found a dual effect of lipids and immune cells on osteoarthritis progression, but the exact mechanism of action is not yet clear.
OBJECTIVE: To investigate whether the causal relationship between lipids and knee osteoarthritis is regulated by immune cells.
METHODS: 179 lipids were obtained from the Linda Ottensman database, 731 immune cell-associated single nucleotide polymorphisms were obtained from Open GWAS as instrumental variables, and genome-wide association data for knee osteoarthritis were obtained from the Osteoarthritis Genetics Consortium. First, we used a two-sample Mendelian randomization method to investigate the causal relationships between lipids and knee osteoarthritis, between immune cells and knee osteoarthritis, and between lipids and immune cells from a genetic perspective. In addition, Bayesian-weighted Mendelian randomization verified the causal relationship between lipids and knee osteoarthritis, and reverse Mendelian randomization and Steiger directionality test assessed the positive relationship. Second, sensitivity analyses were performed, including Cochran’s Q test to eliminate heterogeneity, MR-PRESSO global test and MR-Egger intercept to rule out horizontal pleiotropy, and leave-one-out method to assess the effect of individual single nucleotide polymorphism drivers on random estimates. Finally, the mediating effect of specific immune cell traits in the causal relationship between lipids and knee osteoarthritis was determined by a two-step Mendelian randomization method.
RESULTS AND CONCLUSION: The inverse variance weighting method and Bayesian-weighted algorithm together identified eight lipid species that were causally associated with knee osteoarthritis. The results of Cochran’s Q, MR-PRESSO, and MR-Egger intercept were not statistically significant (P < 0.05). Meanwhile, a total of three sets of mediated relationships were calculated, with the lowest mediation percentage of 11.85% and the highest of 45.48%. These findings indicate the level of immune cells plays a potential role in the regulatory process of lipids and knee osteoarthritis, which provides new perspectives for in-depth exploration of knee osteoarthritis.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

Key words: lipids, knee osteoarthritis, Mendelian randomization, immune cells, mediation analysis, causal relationship, engineered tissue construction

CLC Number:

Huo Jiang, Ding Yu, Yuan Jie. Immune cells mediate the association between different lipids and knee osteoarthritis: a genome-wide association analysis of European individuals[J]. Chinese Journal of Tissue Engineering Research, 2025, 29(18): 3934-3940.

Figures/Tables 2

2.1 工具变量的选择在选择全基因组独立(r2=0.001，window size=10 000 kb)和P < 1×10-5后，179个脂质的显著工具变量数量在12-44之间。在r2=0.001，window size=10 000 kb和P < 5×10-8后，731个免疫细胞的显著工具变量在1-450之间。反向孟德尔随机化分析中，膝骨关节炎的显著工具变量为136个。这些单核苷酸多态性的F值最小为19.53，表明弱仪器偏差的概率最小。 2.2 179种脂质对膝骨关节炎的影响在逆方差加权方法和贝叶斯加权分析(P < 0.05)下，最终确定了8种脂质与膝骨关节炎之间存在因果效应(图2A，B)。结果显示，甾醇酯(27:1/20:2)、胆固醇、二酰甘油(16:1_18:1)、磷脂酰胆碱(14:0_18:2)/(16:0_20:2)、磷脂酰乙醇胺 (O-16:1_22:5)与膝骨关节炎呈负向关联趋势，即随着前者表达水平升高，后者的发生风险会降低，而磷脂酰胆碱(O-16:0_22:5)/(O-17:0_15:0)的表达水平对膝骨关节炎存在一个正向调控。此外，反映这些因果关系的贝塔估计值的方向在5种孟德尔随机化方法中是一致的，这增加了此次研究结果的稳健性。敏感性检验显示，这些因果关联中不存在异质性和水平多效性(P > 0.05；P MRPRESSO global tests > 0.05)，见表1。 2.3 八种脂质对膝骨关节炎的逆向孟德尔随机化分析和Steiger方向性测试通过前面的标准，确定了136个与膝骨关节炎相关的单核苷酸多态性，将膝骨关节炎视为暴露，与筛选出的有显著因果的脂质进行双样本孟德尔随机化，P > 0.05视为不存在反向因果关系(图2C)。Steiger方向性测试可以在正向或反向孟德尔随机化过程进行分析，如果在正向即脂质到膝骨关节炎的孟德尔随机化分析中进行测试，Correct_causal_direction的结果应显示为TRUE并统计学显著(Steiger_P < 0.05)，见表1。此次结果表明膝骨关节炎对得出的8种脂质没有因果作用。 2.4 两步孟德尔随机化分析为探索免疫细胞相关性状作为中介因素在脂质与膝骨关节炎因果效应中的介导作用，首先在P < 0.05的统计学标准下，此次研究进行了免疫细胞和膝骨关节炎之间的孟德尔随机化分析并确定了与其存在因果效应的45种免疫细胞；随后，再次进行孟德尔随机化分析评估8种脂质与45种免疫细胞性状的因果关系。分析结果显示，一共鉴定出4种脂质与7种免疫细胞之间的8个因果关系对(图3)，提示二酰甘油(16:1_18:1)与CD14 on CD14+CD16-单"

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