Revealing Novel Protein Biomarkers for Female Infertility through an Integrated Analysis of Plasma Proteomics and Mendelian Randomization

Background Female infertility is a prevalent reproductive health issue, the incidence of which has been rising in recent years. However, there remains a lack of highly effective and targeted treatments. This study employs a proteome-wide Mendelian randomization (MR) analysis to investigate the causal relationships between plasma proteins and female infertility and to identify and validate potential therapeutic targets. Methods We utilized pQTL data from DECODE Genetics, covering 35,559 proteins in 4,907 individuals. Summary data for female infertility were extracted from the FinnGen project, including 14,759 cases and 111,583 controls. A two-sample MR analysis was conducted, using single nucleotide polymorphisms (SNPs) as genetic instruments to estimate the causal effects of plasma proteins on female infertility. Sensitivity analyses were performed to assess the stability and reliability of the MR results. PPI networks were constructed, and drug-gene interaction systems were integrated to elucidate potential links between the identified proteins and existing treatments for female infertility. Results The MR analysis indicated significant associations between the expression levels of two plasma proteins and the risk of female infertility. Higher levels of Cardiotrophin-1 (CTF1) (OR = 0.68, CI 0.53–0.87, P = 2.54× ¹⁰⁻³ ) were associated with a reduced risk of female infertility, whereas higher levels of Insulin-like growth factor-binding protein 5 (IGFBP5) (OR = 1.35, CI 1.09–1.66, P = 5.54× ¹⁰⁻³ ) were associated with an increased risk of female infertility. Sensitivity analyses showed no evidence of pleiotropy or heterogeneity. Conclusion This study identified two plasma proteins associated with the risk of female infertility, providing new insights into the potential pathogenesis of the condition.