Causal relationship between visceral adipose tissue and osteoarthritis

doi:10.12307/2025.374

Abstract

Abstract: BACKGROUND: Although obesity is associated with osteoarthritis, it remains unclear whether visceral adipose tissue has a causal relationship with osteoarthritis.
OBJECTIVE: To investigate the causal relationship between visceral adipose tissue and osteoarthritis using two-sample Mendelian randomization methods.
METHODS: A total of 221 single nucleotide polymorphisms strongly associated with visceral adipose tissue without linkage disequilibrium were screened from the genome-wide association study (GWAS). Pooled data for osteoarthritis were derived from a large genome-wide association analysis that included up to 826 690 subjects (177 517 osteoarthritis patients and 649 173 controls) from nine different populations. We conducted two-sample Mendelian randomization analyses to assess the causal associations between visceral adipose tissue and early-onset any-site osteoarthritis (before age 45), any-site osteoarthritis, knee osteoarthritis, hip osteoarthritis, knee or hip osteoarthritis, spinal osteoarthritis, thumb osteoarthritis, and finger osteoarthritis. Inverse variance weighting was employed as the primary Mendelian randomization analysis method, with weighted median and MR-Egger methods used for supplementary clarification.
RESULTS AND CONCLUSION: Inverse variance weighting results revealed a positive causal effect of visceral adipose tissue on eight types of osteoarthritis: early-onset any-site osteoarthritis [odds ratio (OR)=1.91, 95% confidence interval (CI): 1.64-2.24, P=6.04×10-16], any-site osteoarthritis (OR=1.44, 95% CI: 1.38-1.49, P=3.65×10-75), knee osteoarthritis (OR=1.87, 95% CI: 1.75-2.00, P=1.29×10-79), hip osteoarthritis (OR=1.34, 95% CI: 1.24-1.45, P=2.84×10-14), knee or hip osteoarthritis (OR=1.71, 95% CI: 1.62-1.80, P=2.97×10-83), spinal osteoarthritis (OR=1.42, 95% CI: 1.31-1.54, P=8.89×10-17), thumb osteoarthritis (OR=1.26, 95% CI: 1.10-1.44, P=6.21×10-4), and finger osteoarthritis (OR=1.29, 95% CI: 1.13-1.49, P=2.68×10-4). Sensitivity analyses showed no heterogeneity, pleiotropy, or outliers in the causal effects of visceral adipose tissue on the eight types of osteoarthritis. These findings indicate that visceral adipose tissue is a risk factor of osteoarthritis, and excessive visceral adipose tissue may increase the risk of 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: visceral adipose tissue, osteoarthritis, genome-wide association study, Mendelian randomization, causal association, single nucleotide polymorphism

CLC Number:

Sun Pengcheng, Zhang Xiaoyun, Li Zhengpeng, Li Yongjin, Gao Zhengang, Li Kunjian . Causal relationship between visceral adipose tissue and osteoarthritis[J]. Chinese Journal of Tissue Engineering Research, 2025, 29(12): 2631-2640.

Figures/Tables 6

2.1 工具变量根据此次研究工具变量的筛选标准，首先从暴露数据中筛选出221个与内脏脂肪组织强相关且无连锁不平衡的单核苷酸多态性，然后分别从8个骨关节炎表型中提取结局数据，并删除回文序列，利用Radial-MR包识别并剔除异常值(图2)，使用PhenoScanner数据库手动筛选和删除与混杂因素(吸烟、创伤、低密度脂蛋白胆固醇、骨质疏松)和骨关节炎结局相关的单核苷酸多态性，经过一系列地筛选，最终纳入孟德尔随机化分析的单核苷酸多态性数如下：早期任意部位骨关节炎177个单核苷酸多态性、任意部位骨关节炎156个单核苷酸多态性、膝骨关节炎153个单核苷酸多态性、髋骨关节炎180个单核苷酸多态性、膝/髋骨关节炎154个单核苷酸多态性、脊柱骨关节炎168个单核苷酸多态性、拇指骨关节炎177个单核苷酸多态性、手指骨关节炎179个单核苷酸多态性。 2.2 内脏脂肪组织对骨关节炎的影响逆方差加权法分析结果显示，内脏脂肪组织对早期任意部位骨关节炎(OR=1.91，95%CI：1.64-2.24，P=6.04×10-16)、任意部位骨关节炎(OR=1.44，95%CI：1.38-1.49，P=3.65×10-75)、膝骨关节炎(OR=1.87，95%CI：1.75-2.00，P=1.29×10-79)、髋骨关节炎(OR=1.34，95%CI：1.24-1.45，P=2.84×10-14)、膝/髋骨关节炎(OR=1.71，95%CI：1.62-1.80，P=2.97×10-83)、脊柱骨关节炎(OR=1.42，95%CI：1.31-1.54，P=8.89×10-17)、拇指骨关节炎(OR=1.26，95%CI：1.10-1.44，P=6.21×10-4)、手指骨关节炎(OR=1.29，95%CI：1.13-1.49，P=2.68×10-4)具有正向因果效应，结果表明遗传预测的内脏脂肪组织与8种骨关节炎可能存在因果关联(P < 0.006 25)。在孟德尔随机化其他分析结果中，虽然早期任意部位骨关节炎中MR-Egger结果(OR=1.78，95%CI：1.10-2.88，P=1.89×10-2)、脊柱骨关节炎中MR-Egger结果(OR=1.22，95%CI：0.95-1.56，P=1.27×10-1)、拇指骨关节炎中MR-Egger结果(OR=1.22，95%CI：0.81-1.82，P=3.38×10-1)和加权中位数法结果(OR=1.31，95%CI：1.04-1.65，P=2.41×10-2)并不支持内脏脂肪组织与其骨关节炎相关表型的因果关联(P > 0.00 625)，但早期任意部位骨关节炎、脊柱骨关节炎和拇指骨关节炎中3种孟德尔随机化分析方法的因果效应方向均一致(OR > 1)(图3)。此外，图4的散点图也显示相同的结果，随着内脏脂肪组织的增加，骨关节炎的发病风险升高。总的来说，从遗传的角度来看，内脏脂肪组织可能会增加骨关节炎的风险。 2.3 敏感性分析为了验证结果的稳健性，进行了一系列的敏感性分析，以评估潜在的水平多效性和异质性。MR-Egger截距和MR-PRESSO分析结果显示，内脏脂肪组织与早期任意部位骨关节炎、任意部位骨关节炎、膝骨关节炎、髋骨关节炎、膝/髋骨关节炎、脊柱骨关节炎、拇指骨关节炎、手指骨关节炎均不存在潜在的水平多效性(P > 0.05)。Cochran’s Q检验显示，内脏脂肪组织与8种骨关节炎的逆方差加权法和MR-Egger分析结果均不存在潜在的异质性(P > 0.05)。同时，Steiger方向性检验表明此次研究不存在反向因果关系(P < 0.05)(表2)。此外，图5漏斗图整体上比较对称，表明此次研究受异质性影响造成结果偏倚的可能性较小。留一法敏感性分析也显示此次研究不存在单个单核苷酸多态性对整体因果估计效应产生影响。"

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