Blood-based inflammatory markers in female infertility: evidence from Mendelian randomization analysis

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Investigate causal associations between blood-based inflammatory markers and female infertility using Mendelian Randomisation (MR). MR using Genome-Wide-Association-Study data. Large female-only cohorts of European ancestry. Blood-based inflammatory markers (C-reactive protein, interleukins, monocyte chemoattractant protein-1, tumour necrosis factor-α, interferon-γ). Anovulatory infertility (1054 cases and 117,098 controls); female infertility of other/unspecified origin (5,667 cases and 117,098 controls); and medical treatment for female infertility (2,706 cases and 120,873 controls). Total causal effects were assessed using univariable two-sample methods including inverse variance weighted (IVW) as the primary analysis, as well as other secondary analyses (Mendelian Randomisation-Egger (MRE), weighted median (WMe), etc.), with relevant quality assessments. Interleukin-8 demonstrated a positive association with anovulatory infertility via IVW (odds ratio, 95% confidence interval: 1.51 [1.04, 2.21], p=0.032) and WMe (1.64 [1.05, 2.57], p=0.028) methods. Monocyte chemoattractant protein-1 was associated with anovulatory infertility via MRE (2.06 [1.13, 3.77], p=0.038). Inverse associations were found for interleukins-12 and -18 via IVW, with higher interleukin-12 being associated with lower medical treatment for female infertility (0.75 [0.59, 0.94], p=0.013), while higher interleukin-18 was associated with lower female infertility of other/unspecified origin (0.90 [0.83, 0.97], p=0.008). This is the first study to examine causal relationships between inflammation and female infertility using MR. Monocyte chemoattractant protein-1 and interleukin-8 are implicated in anovulatory infertility; however, only the relationship with interleukin-8 was evident in the primary analysis. Interleukins-12 and -18 demonstrated inverse associations with infertility outcomes. Further research is needed to uncover the mechanistic functions of these markers to confirm causality and examine their therapeutic potential for female infertility.