Circulating Inflammatory Cytokines and Female Reproductive Diseases: A Mendelian Randomization Analysis.

Context: Extensive studies have provided considerable evidence suggesting the role of inflammation in the development of female reproductive diseases. However, causality has not been established.
Objective: To explore whether genetically determined circulating levels of cytokines are causally associated with female reproductive diseases and discover potential novel drug targets for these diseases.
Methods: Instrumental variables (IVs) for 47 circulating cytokines were obtained from a genome-wide association study (GWAS) meta-analysis of 31 112 European individuals. Protein quantitative trait loci and expression quantitative trait loci close to genes served as our IVs. Summary data of 9 female reproductive diseases were mainly derived from GWAS meta-analysis of the UK biobank and FinnGen. We elevated the association using the Wald ratio or inverse variance-weighted Mendelian randomization (MR) with subsequent assessments for MR assumptions in several sensitivity and colocalization analyses. We consider a false discovery rate <0.05 as statistical significance in MR analyses. Replication studies were conducted for further validation, and phenome-wide association studies were designed to explore potential side effects.
Results: Our results indicated that high levels of macrophage colony-stimulating factor (MCSF), growth-regulated oncogene-alpha (GROα), and soluble intercellular adhesion molecule-1 were associated with increased risks of endometriosis, female infertility, and pre-eclampsia, respectively. High platelet-derived growth factor-BB (PDGF-BB) levels that reduced the risk of ovarian aging were also supported. Replication analysis supported the relationship between GROα and female infertility, and between MCSF and endometriosis.
Conclusion: We identified 4 correlated pairs that implied potential protein drug targets. Notably, we preferred highlighting the value of PDGF-BB as a drug target for ovarian aging, and MCSF as a drug target for endometriosis.
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