Associations between cytokines and the risk of female and male infertility: A two-sample Mendelian randomization analysis

Lei Zhang; Honglin Li; Zhijuan Wu; Letian Han; Jianwei Zhang

doi:10.1016/j.jri.2024.104238

Associations between cytokines and the risk of female and male infertility: A two-sample Mendelian randomization analysis

J Reprod Immunol. 2024 Mar 8:163:104238. doi: 10.1016/j.jri.2024.104238. Online ahead of print.

Authors

Lei Zhang¹, Honglin Li¹, Zhijuan Wu¹, Letian Han², Jianwei Zhang³

Affiliations

¹ The First Clinical College, Shandong University of Traditional Chinese medicine, Jinan, China.
² Reproductive and Genetic Center of Integrated Traditional and Western Medicine, Hospital Affiliated to Shandong University of Traditional Chinese Medicine, Jinan, China; Shandong Qidu Pharmaceutical Co. Ltd., Shandong Provincial Key Laboratory of Neuroprotective Drugs, Zibo, China.
³ The First Clinical College, Shandong University of Traditional Chinese medicine, Jinan, China; Reproductive and Genetic Center of Integrated Traditional and Western Medicine, Hospital Affiliated to Shandong University of Traditional Chinese Medicine, Jinan, China. Electronic address: zjw_1970@sina.com.

PMID: 38479056
DOI: 10.1016/j.jri.2024.104238

Abstract

Purpose: Observational studies have linked cytokines to the occurrence of female and male infertility. However, it is not clear how biomarkers of inflammation are causally related to infertility. To explore whether genetic variants in circulating cytokines are associated with the pathogenesis of infertility, we performed two-sample Mendelian randomization (MR) analysis.

Methods: A total of 31,112 individuals of European ancestry were included in a genome-wide association study (GWAS) of 47 circulating cytokines as instrumental variables (IVs). Outcome data were female infertility, including four different subtypes, and male infertility, from the FinnGen consortium. Five MR methods, including inverse-variance weighted (IVW), MR-Egger, simple mode, weighted median, and weighted mode were employed to examine the genetic association between cytokines and the risk of female infertility and male infertility. The false discovery rate (FDR) was controlled using the Benjamini-Hochberg method.

Results: After FDR correction, cis-protein quantitative trait locus (cis-pQTL) instruments showed that the cytokines GROa and MCSF were positively associated with female infertility. In analyses of subtypes of female infertility, eotaxin and sICAM were inversely associated with ovulation-related infertility; MCP3 alone was positively associated with uterus-related infertility; GROa and MCSF were positively correlated with infertility of cervical, vaginal, and other or unspecified origin; and MIP1a was negatively correlated with tubal origin infertility. The cytokines HGF, IL-2ra, and RANTES were positively correlated with male infertility. Similar findings were obtained in sensitivity analyses. There was no evidence of pleiotropy or heterogeneity in the results.

Conclusion: These findings contribute to current understanding of the role of cytokine biomarkers in the etiology of female and male infertility. Furthermore clinical experimental validation is required to evaluate the potential of these cytokines as biomarkers.

Keywords: Cytokines; GWAS; Infertility; Mendelian randomization.