Association between plasma metabolites and osteoarthritis

doi:10.12307/2026.821

Abstract

Abstract: BACKGROUND: In recent years, metabolic disorders have been confirmed to be closely related to the onset of osteoarthritis, but the causal relationship between plasma metabolites and osteoarthritis has not been systematically elucidated.
OBJECTIVE: To explore the causal relationship between 1 400 plasma metabolites and 9 types of osteoarthritis using two-sample Mendelian randomization.
METHODS: A genome-wide association study of 1 400 metabolites was used as the exposure. Nine types of arthritis, namely any-site osteoarthritis, early osteoarthritis, knee and/or hip osteoarthritis, knee osteoarthritis, hip osteoarthritis, spinal osteoarthritis, finger osteoarthritis, hand osteoarthritis, and thumb osteoarthritis, were set as the outcomes. Single nucleotide polymorphisms were used as instrumental variables, and sensitive single nucleotide polymorphisms were selected for Mendelian randomization analysis. The inverse variance weighted method was used as the main analysis approach. Meanwhile, four methods, namely MR-Egger, weighted median, simple mode, and weighted mode, were employed for cross-validation. Sensitivity and pleiotropy tests were conducted using MR-PRESSO and Cochran’s Q test, and the obtained data were further corrected using the false discovery rate method.
RESULTS AND CONCLUSION: Mendelian randomization analysis showed that no false discovery rate (< 0.05) was found for finger osteoarthritis, hand osteoarthritis, hip osteoarthritis, or spinal osteoarthritis. Any-site osteoarthritis, early osteoarthritis, knee and/or hip osteoarthritis, knee osteoarthritis, and thumb osteoarthritis were significantly causally related to multiple metabolites. Glycine, serine, homostachydrine, and sulfate metabolites were all closely related to various types of osteoarthritis. Compared with some non-weight-bearing joint osteoarthritis (such as finger and hand osteoarthritis), plasma metabolites showed greater sensitivity to weight-bearing joint osteoarthritis (such as knee osteoarthritis and hip osteoarthritis). This study provides a theoretical basis for metabolic intervention strategies for osteoarthritis in Chinese population and a methodological paradigm for conducting mechanistic research on complex diseases in China.

Key words: plasma metabolites, osteoarthritis, Mendelian randomization, instrumental variable, causality, pathogenesis

CLC Number:

Li Yunpeng, Lyu Yuqiang, Zhang Jialin, Tang You, Wang Kai, Zhao Wenzhi. Association between plasma metabolites and osteoarthritis[J]. Chinese Journal of Tissue Engineering Research, 2026, 30(28): 7437-7446.

Figures/Tables 8

2.1 工具变量筛选结果根据标准对1 400种血浆代谢物进行筛选，每个代谢物得到的单核苷酸多态性数量从10-169个不等，得到的工具变量F > 10，说明所得到的单核苷酸多态性存在弱工具变量的可能性较小，均可进行下一步孟德尔随机化分析。 2.2 孟德尔随机化分析结果以逆方差加权法作为孟德尔随机化的主要分析方法，筛选PIVW < 0.05的结果，将获得的结局数据以圈图(图2，3)及表格(表2，3)的形式呈现，圈图中最外圈代表代谢物的ID，对每个代谢物都使用5种方法(逆方差加权法、MR-Eggeer、简单中位数法、加权中位数法、加权众数法) 进行孟德尔随机化分析，得到5种方法的P值及置信区间(OR)，格子颜色代表P值，红色越深说明P值越小，蓝色越深说明P值越大。经过FDR矫正之后，手指骨关节炎、手部骨关节炎、髋骨关节炎、脊柱骨关节炎均无符合FDR < 0.05的数据；早期骨关节炎筛选后仅丝氨酸与苏氨酸的比率符合FDR < 0.05；任何部位骨关节炎、膝和/或髋骨关节炎、膝骨关节炎、拇指骨关节炎均有数量不等满足FDR < 0.05的血浆代谢物，绘制相应的森林图进行呈现(图4)。任何部位骨关节炎：符合逆方差加权法P < 0.05的血浆代谢物有160个，最敏感的血浆代谢物为甘氨酸与丝氨酸的比率(FDR=8.04×10-14)；经筛选之后，符合逆方差加权法P < 0.05的血浆代谢物有14个，最敏感血浆代谢物为高水苏碱水平(FDR=1.90×10-4)。早期骨关节炎：符合逆方差加权法P < 0.05的血浆代谢物有112个，最敏感的血浆代谢物为甘氨酸水平(FDR=1.84×10-3)；经筛选之后，符合逆方差加权法P < 0.05 的血浆代谢物有1个，为丝氨酸与苏氨酸的比率(FDR=1.84×10-3)。膝骨关节炎：符合逆方差加权法P < 0.05 的血浆代谢物有165个，最敏感的血浆代谢物为甘氨酸与丝氨酸的比率(FDR=5.98×10-8)；经筛选之后，符合逆方差加权法P < 0.05 的血浆代谢物有6个，最敏感血浆代谢物仍为甘氨酸与丝氨酸的比率(FDR=5.98×10-8)。膝和/或髋骨关节炎：符合逆方差加权法P < 0.05的血浆代谢物有168个，最敏感的血浆代谢物为甘氨酸与丝氨酸的比率(FDR=4.57×10-12)；经筛选之后，符合逆方差加权法P < 0.05的血浆代谢物有5个，最敏感血浆代谢物仍为甘氨酸与丝氨酸的比率(FDR=4.57×10-12)。髋骨关节炎：符合逆方差加权法P < 0.05 的血浆代谢物有139个，最敏感血浆代谢物为4-胍基丁酸水平(逆方差加权法P=8.93×10-5、FDR=0.051)。脊柱骨关节炎：符合逆方差加权法P < 0.05的血浆代谢物有76个，最敏感血浆代谢物为ADP与AMP的比(逆方差加权法P=1.73×10-4、FDR=0.228)。手指骨关节炎：符合逆方差加权法P < 0.05的血浆代谢物有83个，最敏感血浆代谢物为抗坏血酸2-硫酸盐水平(逆方差加权法P=8.45×10-4、FDR=0.454)。手部骨关节炎：符合逆方差加权法P < 0.05的血浆代谢物有121个，最敏感血浆代谢物为咪唑酸盐水平(逆方差加权法P=8.50×10-5、FDR=0.050)。"

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