Ancient Genetic Variants and Modern Pollutants in Endometriosis Risk

Environmental Pollutants and Ancestral Genetic Variants mayJointly Influence Susceptibility to Endometriosis.

Key Points

Highlights:

• Endometriosis may arise from the interaction between modern environmental pollutants and ancient regulatory genetic variants inherited from archaic hominins.
• Several pollutant-responsive genes—including IL6, CNR1, IDO1, and KISS1R—carry variants that may heighten susceptibility to inflammation, immune dysregulation, and aberrant tissue responses.

Importance:

• This study reframes endometriosis as a condition shaped by gene–environment interactions, where evolutionarily conserved variants might now predispose individuals to disease in the context of contemporary environmental exposures.

What's Done Here?

• This original research study used a dual-phase approach combining literature review and genomic analysis to explore gene–environment interactions in endometriosis.
• First, a structured review was performed to identify genes implicated in endometriosis and known to respond to endocrine-disrupting chemicals (EDCs). Five genes—IL6, CNR1, IDO1, TACR3, and KISS1R—were selected based on tissue expression, pathway relevance, and pollutant sensitivity.
• Second, whole-genome sequencing (WGS) data from the Genomics England 100,000 Genomes Project were analyzed in 19 females with clinically confirmed endometriosis. 
• Functional effects of enriched variants were assessed using public regulatory annotation databases, focusing on promoter and enhancer disruption.

Key Results:

• The study identified regulatory variants in IL6, CNR1, IDO1, TACR3, and KISS1R enriched in individuals with early-stage endometriosis.
• These variants are located in enhancer and promoter regions known to respond to endocrine-disrupting chemicals (EDCs) and other contemporary environmental pollutants, especially those acting through inflammatory, neuroendocrine, or hormone-related pathways.
• Several enriched variants appear to have archaic hominin ancestry, suggesting evolutionary inheritance that may now influence sensitivity to modern environmental exposures.
• The findings support a potential model in which genetic predisposition modifies an individual’s biological response to today’s pollutant exposures, contributing to disease susceptibility.

Strengths and Limitations: 

• Strengths are: innovative integration of genetics, environmental biology, and regulatory annotation; focus on pollutant-responsive pathways relevant to endometriosis; identification of enriched regulatory variants not previously described.
• Limitations are: small sample size, absence of direct pollutant exposure data, and reliance on secondary datasets without functional validation, limiting causal interpretation.

From the Editor-in-Chief – EndoNews

"It is still unclear why some people develop endometriosis and others with similar hormonal environments do not. This study contributes a compelling conceptual advance by positioning endometriosis within a gene–environment interaction framework, where inherited regulatory variants influence biological sensitivity to contemporary environmental exposures. Rather than searching for a single causal factor, the authors identify a convergence of evolutionary genetics and modern pollutants that may shape disease susceptibility in subtle but meaningful ways.

The methodological strength of the study lies in its integration of literature-derived gene selection with whole-genome sequencing analysis, revealing enriched regulatory variants in pathways central to inflammation, immune tolerance, nociception, and neuroendocrine signaling. These findings are provocative because they involve regulatory elements—the molecular switches that determine how dynamically a gene responds to environmental cues. The presence of archaic hominin–derived variants adds an evolutionary dimension, raising the possibility that genetic features once advantageous may now create vulnerability in environments saturated with endocrine-disrupting chemicals.

At the same time, this work should be viewed as hypothesis-generating, not definitive. The sample size is small, functional validation is lacking, and no direct pollutant exposure data were collected. These limitations do not diminish the conceptual significance but rather highlight the importance of future research aimed at clarifying the magnitude and biological relevance of these interactions.

What this study achieves, however, is intellectually important: it reframes endometriosis as a condition potentially shaped by both biological inheritance and modern environmental pressures. Such a perspective encourages the field to move beyond siloed models of hormonal imbalance, inflammation, or immune dysfunction and toward a more integrated understanding of disease origins. If validated, this framework could inform prevention strategies, environmental policy discussions, and ultimately individualized approaches to risk assessment.

The authors provide the field with a thought-provoking hypothesis—one that invites deeper mechanistic exploration and challenges us to consider whether the genetic architecture shaped by our ancestral past may intersect in unexpected ways with the chemical landscape of the present." 

Lay Summary

Researchers are increasingly examining how genetic susceptibility interacts with modern environmental pollutants to influence the development of endometriosis. In a new study published in the European Journal of Human Genetics, a team led by Dr.A.Mantzouratou investigated whether inherited regulatory variants may heighten biological sensitivity to today’s chemical exposures.

The investigators began by reviewing scientific literature to identify genes that both contribute to endometriosis biology and respond to endocrine-disrupting chemicals (EDCs)—a diverse group of pollutants known to affect hormonal, inflammatory, and immune pathways. Five genes emerged as strong candidates: IL6, CNR1, IDO1, TACR3, and KISS1R, each involved in inflammation, pain processing, neuroendocrine signaling, or reproductive regulation.

To test whether variants in these genes are enriched in endometriosis, the researchers analyzed whole-genome sequencing data from the Genomics England 100,000 Genomes Project, focusing on 19 women with clinically confirmed disease. They identified six regulatory variants significantly more common in patients than in matched controls or the broader Genomics England population.

These variants were located in promoter and enhancer regions—the molecular “switches” that modulate how strongly genes respond to biological signals, including environmental exposures. Notably, several variants showed signatures of archaic hominin ancestry, suggesting they originated from ancient Neanderthal or Denisovan DNA. Variants that may have been advantageous in past environments could, in the presence of modern industrial chemicals, confer increased susceptibility to inflammatory or hormonal dysregulation.

The authors propose that endometriosis may partly arise through gene–environment interactions, where inherited regulatory architecture amplifies physiological responses to contemporary environmental pollutants. Although additional validation is needed, this work provides an important conceptual framework for understanding why some individuals develop early-stage disease while others with similar exposures do not.

By integrating genomics, environmental toxicology, and evolutionary biology, this study highlight new directions for research that may ultimately improve risk assessment, prevention strategies, and personalized approaches to endometriosis care.

Research Source: https://pubmed.ncbi.nlm.nih.gov/41266756/