Cytokine Gene Polymorphisms in Recurrent Pregnancy Loss

Recurrent pregnancy loss (RPL) affects around 1–2 per cent of couples attempting to conceive and remains largely unexplained in half of cases. Emerging evidence implicates genetic variation within cytokine genes as a determinant of maternal immune tolerance and placental function. Variants in genes encoding interleukins, tumour necrosis factor-alpha and interferon-gamma can alter transcriptional activity and cytokine secretion profiles at the maternal–foetal interface. A shift towards a pro-inflammatory milieu or impaired regulatory signalling may compromise trophoblast invasion, spiral artery remodelling and embryo implantation. Meta-analyses and case–control studies have identified associations between single nucleotide polymorphisms in IL1B, IL6, IL10, IL18, TNF and IFNG and RPL risk, although effect sizes vary by ethnicity and study design. Functional assays have linked specific alleles to altered cytokine levels in serum and decidual tissue, suggesting mechanistic pathways through which these polymorphisms influence pregnancy maintenance. Understanding the global distribution of risk and protective alleles offers prospects for personalised risk assessment, biomarker development and the design of targeted immunomodulatory therapies to reduce the burden of RPL.

Research from Nature Portfolio

A foundational analysis examined IL-33 gene variants and serum concentrations in a large cohort of idiopathic recurrent miscarriage cases compared with controls. A specific promoter polymorphism was associated with significantly lower circulating IL-33 levels and a heightened risk of repeated early pregnancy loss. Functional investigations demonstrated that the risk allele corresponded with reduced IL-33 transcription in endometrial cells, implicating diminished IL-33 signalling in impaired decidualisation and maternal tolerance. This work underscores the contribution of IL-33 pathway variation to idiopathic RPL and highlights IL-33 as a candidate for therapeutic intervention.

Cytokine Gene Polymorphisms in Recurrent Pregnancy Loss publication trend

The graph below shows the total number of articles in cytokine gene polymorphisms in recurrent pregnancy loss across all publications each year (not limited to Nature Index journals).

Technical terms

Cytokine gene polymorphism: A variation in DNA sequence within a cytokine-encoding gene that may affect cytokine expression or function.

Interleukin (IL): A family of small signalling proteins that regulate immune cell development and inflammatory responses.

Tumour necrosis factor-alpha (TNF-α): A pro-inflammatory cytokine involved in systemic inflammation and immune regulation at the maternal–foetal interface.

Single nucleotide polymorphism (SNP): A common type of genetic variation where a single base pair in the genome differs between individuals.

Trophoblast: Fetal cells forming the outer layer of the blastocyst that invade the maternal endometrium and establish the placenta.

Recurrent pregnancy loss (RPL): The occurrence of two or more consecutive clinical pregnancy losses before 20 weeks’ gestation.

References

1. Association between Genetic Polymorphisms in Interleukin Genes and Recurrent Pregnancy Loss – A Systematic Review and Meta-Analysis. PLOS ONE (2017).
2. Association of TNF-α genetic polymorphisms with recurrent pregnancy loss risk: a systematic review and meta-analysis. Reproductive Biology and Endocrinology (2016).
3. Association between TNF, IL1B, IL6, IL10 and IFNG polymorphisms and recurrent miscarriage: a case control study. Reproductive Biology and Endocrinology (2017).
4. Genetic variant in IL-33 is associated with idiopathic recurrent miscarriage in Chinese Han population. Scientific Reports (2016).
5. Association of IL-33 gene rs16924159 polymorphism and recurrent pregnancy loss in Iranian Azeri women. Hormone Molecular Biology and Clinical Investigation (2020).
6. Polymorphisms in interleukin genes and their association with the risk of recurrent pregnancy loss. Genes & Genetic Systems (2019).