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 authors have declared no competing interest.

Bournemouth University funded the writing of this manuscript granted to the first author of this manuscript.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study received ethical approval by the Bournemouth University institutional ethical approval panel, ethics ID: 45978.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Research on the de-identified patient data used in this publication can be carried out in the Genomics England Research Environment subject to a collaborative agreement that adheres to patient led governance. All interested readers will be able to access the data in the same manner that the authors accessed the data. For more information about accessing the data, interested readers may contact research-network@genomicsengland.co.uk or access the relevant information on the Genomics England website: https://www.genomicsengland.co.uk/research.

https://www.genomicsengland.co.uk/research.