Fatima Tahzeeb, Överdahl Cecilia, Maglio Cristina
Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Rheumatology Clinic, Sahlgrenska University Hospital, Gothenburg, Sweden.
J Scleroderma Relat Disord. 2025 Jul 17:23971983251352341. doi: 10.1177/23971983251352341.
Previous data on the relationship between adiponectin and systemic sclerosis are inconsistent and do not establish a causal link. We aimed to perform an updated meta-analysis to estimate the association between circulating adiponectin and systemic sclerosis. Using a two-sample, bidirectional, Mendelian randomization approach, we also tested for a causal relationship between genetically predicted adiponectin levels and systemic sclerosis risk.
We conducted a systematic literature search of PubMed, Embase, and Web of Science (up to September 2024) to identify studies for meta-analysis. Pooled standardized mean differences were calculated. For bidirectional Mendelian randomization, genetic instruments for circulating adiponectin levels and liability to systemic sclerosis were constructed using publicly available genome-wide association study summary statistics. Causal estimates were primarily summarized using the inverse variance-weighted method, with weighted median, simple median, MR-Egger, and MR-PRESSO as sensitivity analyses. Both meta- and Mendelian randomization analyses were stratified for systemic sclerosis subtypes: diffuse cutaneous and limited cutaneous systemic sclerosis.
Seven studies (439 systemic sclerosis cases, 274 controls) were included in the meta-analysis, indicating lower circulating adiponectin levels in systemic sclerosis patients (standardized mean difference = -0.16, = 0.07); however, the decrease was statistically significant in diffuse cutaneous systemic sclerosis ( = 0.003) but not limited cutaneous systemic sclerosis ( = 0.81) subgroup. Forward Mendelian randomization analysis did not suggest a causal effect of adiponectin on systemic sclerosis risk (odds ratio = 1.21, = 0.57), whereas reverse Mendelian randomization provided evidence for a causal effect of genetic liability to systemic sclerosis on lowering circulating adiponectin levels (ß = -0.027, = 6.8E-06).
Our meta-analysis of observational studies confirmed that systemic sclerosis patients have lower adiponectin levels. Using Mendelian randomization, we established a causal link between genetic liability to systemic sclerosis and lower adiponectin levels. These findings, limited to European ancestry, warrant further research to explore the relationship between systemic sclerosis and adiponectin levels in diverse populations.
先前关于脂联素与系统性硬化症之间关系的数据并不一致，也未确立因果联系。我们旨在进行一项更新的荟萃分析，以评估循环脂联素与系统性硬化症之间的关联。使用两样本双向孟德尔随机化方法，我们还检验了基因预测的脂联素水平与系统性硬化症风险之间的因果关系。
我们对PubMed、Embase和Web of Science进行了系统的文献检索（截至2024年9月），以确定纳入荟萃分析的研究。计算合并的标准化均值差。对于双向孟德尔随机化，利用公开可用的全基因组关联研究汇总统计数据构建循环脂联素水平和系统性硬化症易感性的遗传工具。因果估计主要采用逆方差加权法汇总，加权中位数、简单中位数、MR-Egger和MR-PRESSO作为敏感性分析。荟萃分析和孟德尔随机化分析均按系统性硬化症亚型分层：弥漫性皮肤型和局限性皮肤型系统性硬化症。
荟萃分析纳入了7项研究（439例系统性硬化症病例，274例对照），表明系统性硬化症患者的循环脂联素水平较低（标准化均值差=-0.16，P=0.07）；然而，在弥漫性皮肤型系统性硬化症亚组中下降具有统计学意义（P=0.003），而在局限性皮肤型系统性硬化症亚组中则无统计学意义（P=0.81）。正向孟德尔随机化分析未提示脂联素对系统性硬化症风险有因果效应（优势比=1.21，P=0.57），而反向孟德尔随机化提供了证据，表明系统性硬化症的遗传易感性对降低循环脂联素水平有因果效应（β=-0.027，P=6.8×10⁻⁶）。
我们对观察性研究的荟萃分析证实，系统性硬化症患者的脂联素水平较低。利用孟德尔随机化，我们确立了系统性硬化症的遗传易感性与较低脂联素水平之间的因果联系。这些仅限于欧洲血统的研究结果，需要进一步研究以探索不同人群中系统性硬化症与脂联素水平之间的关系。
