Endometriosis - on the intersection of modern environmental pollutants and ancient genetic regulatory variants

Endometriosis is a chronic gynaecological disease characterised by inflammation and can cause infertility and severe chronic pelvic pain. It is a complex disease and potentially multifactorial and tends to affect women in the same family with heritability shown to be between 47-51%. Previous studies have identified over forty single nucleotide polymorphisms associated with advanced stages of endometriosis; however, no variants have been associated with earlier endometriosis stages to date. Due to being a multifactorial condition, it is also likely that interactions with the modern environment may lead to an altered genetic susceptibility to endometriosis. The aim of this study was to identify endometriosis risk variants in selected human populations within the Genomics England database and investigate the pathways these variants could act upon within the presence of modern environmental stressors and pollutants. This study focussed on the variants of regulatory sequences of the genome likely to be impacted by environmental and genetic influencers of endometriosis. A combination of systematic analysis and data interrogation in the Genomics England 100,000 genomes project were undertaken. Participant data was extracted from participants with a diagnosis of endometriosis at various stages. Variant frequency analysis and statistical testing identified six novel regulatory variants significantly enriched in the endometriosis cohort. The strongest association was observed for two IL-6 variants, which co-localized more frequently than expected by chance, suggesting a potential regulatory interaction. Although the sample size was limited, this study provides novel insights into how genetic regulatory variation and environmental pollutants may collectively influence endometriosis risk. The findings suggest that genetic susceptibility to endometriosis may be shaped by modern industrial exposures, with potential implications for personalised risk assessment and prevention strategies. Future research should validate these findings in larger populations and explore functional mechanisms underlying gene - environment interactions to develop targeted interventions for individuals at risk.

The study introduces a unique perspective by linking ancient Neanderthal and Denisovan genetic variants to modern disease risk in the context of environmental exposure. We propose those industrial pollutants—particularly endocrine-disrupting chemicals (EDCs)—may epigenetically disrupt immune and reproductive gene regulation, thereby amplifying disease risk in genetically susceptible individuals. This is an early-stage, hypothesis-generating study and has not yet undergone peer review. Findings should not be interpreted as clinical advice or diagnostic tools. Future research with larger cohorts and functional validation is warranted.