Circulating adiponectin levels in systemic sclerosis: A meta-analysis and bidirectional Mendelian randomization study.

Background: 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.

Methods: 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.

Results: 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, p = 0.07); however, the decrease was statistically significant in diffuse cutaneous systemic sclerosis (p = 0.003) but not limited cutaneous systemic sclerosis (p = 0.81) subgroup. Forward Mendelian randomization analysis did not suggest a causal effect of adiponectin on systemic sclerosis risk (odds ratio = 1.21, p = 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, p = 6.8E-06).

Conclusion: 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.