Plasma cytokine levels and PCOS risk: Mendelian randomization analysis reveals IL6R as a preventive factor

Polycystic ovary syndrome is a prevalent gynecological condition affecting primarily women of childbearing age. It is characterized by elevated androgen levels, ovulatory dysfunction, and morphological abnormalities. Despite extensive research from various perspectives, the etiology and pathogenesis of PCOS remain unclear. While controversial, many believe that individuals with PCOS exhibit a chronic low-grade inflammatory state. Cytokines play diverse roles in the initiation and progression of inflammation, contributing to this inflammatory milieu. Therefore, the aim of this study was to utilize publicly available genome-wide association study data to explore the potential causal relationship between cytokines and PCOS.

To accurately investigate the causal relationship between cytokines and PCOS, we initially defined cytokines using the GeneCrad and then identified cytokines in two independent large-scale plasma proteins. Subsequently, we employed a two-sample Mendelian randomization analysis framework. A series of quality control procedures were implemented to select eligible instrumental variables closely associated with the exposure. MR analysis was conducted using genome-wide association studies of PCOS in two independent European ancestry groups. Cochran, s Q test, MR-Egger and intercept test were employed to assess heterogeneity and pleiotropy in PCOS. Co-localization analysis, summary-data-based Mendelian randomization analysis, and HEIDI testing were utilized to further corroborate the relationship between positive findings and PCOS. Finally, systematical Mendelian randomization analysis between healthy lifestyle factors and PCOS-related proteins was conducted to identify which proteins could act as interventional targets by lifestyle changes.

In our investigation, we performed Mendelian randomization analysis on 33 cytokines in relation to PCOS using data from the deCODE and the Fenland. Our findings revealed that the plasma level of IL6R emerges as a notable protective factor against PCOS, exhibiting a substantial effect size. Moreover, we identified CCL22 as a significant risk factor for PCOS, a finding that was similarly validated and supported by independent cohorts.

Our Mendelian randomization analysis, leveraging genome-wide association study data from a sizable population cohort, unequivocally delineated a causal relationship between IL6R and PCOS. These results underscore the involvement of cytokines in the pathogenesis of PCOS and highlight their potential as promising therapeutic targets for addressing this intricate disease.