A Mendelian randomization study: Genetically predicted dopamine 4-sulfate to dopamine 3-O-sulfate ratio mediates the association between chemokine C-C motif ligand 11 and polycystic ovary syndrome

This Mendelian randomization (MR) study aims to elucidate the causal pathways between circulating chemokine C-C motif ligand 11 (CCL11) levels and the pathogenesis of polycystic ovary syndrome (PCOS), with a specific focus on the mediating role of dopamine sulfate isomers. Using genome-wide association data from 14,824 European participants (for CCL11 quantitative trait loci) and 2,01,005 individuals (including 1424 PCOS cases), we performed 2-sample MR analyses, with inverse-variance weighting as the primary estimator. Sensitivity analyses included MR-Egger regression and weighted median approaches. Genetic predisposition to elevated CCL11 concentrations was significantly associated with an increased risk of PCOS (odds ratio = 1.28 per standard deviation increase, 95% confidence interval [CI]: 1.04-1.58, P = .021). Reverse causality analysis showed no significant association (odds ratio = 0.98, 95% CI: 0.95-1.01). Two-step mediation MR revealed that 8.8% (95% CI: 2.1-15.5%) of CCL11's effect on PCOS is mediated through altered dopamine 4-sulfate/3-O-sulfate ratios, indicating partial neuroendocrine mediation. Our findings identify CCL11 as an etiological factor in PCOS development, with dopamine metabolite imbalance representing a novel intermediary pathway. The predominant mechanisms underlying this association require further characterization, necessitating exploration of additional inflammatory and metabolic mediators. These results enhance understanding of chemokine-neuroendocrine interactions in PCOS pathophysiology and highlight potential therapeutic targets.