Over the past decade, a number of studies have shown that women with endometriosis are at increased risk for developing various diseases as comorbidities, including asthma (1), various types of cancer, such as ovarian and breast cancer, as well as cutaneous melanoma (2), cardiovascular and psychiatric diseases (3,4), hypothyroidism and fibromyalgia (1). In addition, other studies have reported an association between different autoimmune diseases, including autoimmune thyroid disorder, Crohn's disease and ulcerative colitis, Sjogren's syndrome (SS), systemic lupus erythematosus (SLE), multiple sclerosis, ankylosing spondylitis (AS), coeliac disease and rheumatoid arthritis (RA), and an increased risk for endometriosis (5-9).

Endometriosis is a common yet enigmatic inflammatory, multifactorial, estrogen-dependent gynecological condition with an unknown etiology, affecting up to 10% of women of reproductive age worldwide and 9 million women in the USA (10). Endometriosis is characterized by the presence of ectopic endometrial tissue (endometrial glands and stroma) on other organs, predominantly external to the uterine cavity and most commonly in the pelvic cavity, due to the ectopic localization of endometrial cells. Endometriosis can appear as peritoneal lesions, ovarian endometriotic cysts and deeply infiltrative endometrial lesions (11). Furthermore, endometriosis is associated with chronic pelvic pain, dysmenorrhea, dyspareunia, heavy or irregular menstrual bleeding, urinary tract symptoms, subfertility and infertility in 30% of patients (11,12). Endometriosis-associated gene polymorphisms, epigenetic modifications (such as methylation, acetylation, phosphorylation and modifications to the histone proteins associated with DNA packaging in chromatin), proinflammatory factors (including cytokines like IL-1β, IL-6, IL-8 and TNF-α, as well as prostaglandins), hormonal factors (including an imbalance between estrogen and progesterone) and environmental factors (including organic pollutants, polyhalogenated aromatic hydrocarbons, tobacco, heavy metals and pesticides) contribute to the development of the disease and trigger its specific clinical symptoms (11,12). Nowadays, a large amount of evidence indicates that dysregulation of the immune system leads to chronic inflammatory response in the ectopic endometrium, thus resulting in the subsequent development of endometriosis (13,14).

According to previous studies, women with endometriosis are at a higher risk for developing a concomitant autoimmune disease, considering the deregulation of the immune system observed in these patients (2,4,5,10,12). In this context, both proinflammatory and mitogenic proteins from endometriotic lesions, including cytokines (RANTES, IL-1, IL-6, TNF-a) and VEGF, as well as associated activated immune cells, such as pelvic macrophages and lymphocytes, can cause an imbalance in the immune system, which contributes to the enhanced inflammatory reaction that is associated with the development of endometriosis (15). Accordingly, functional abnormalities in almost all types of immune cells have been identified in endometriosis, including neutrophils, macrophages, natural killer (NK) cells, B and T lymphocytes, as well as dendritic cells (DCs) (13). Moreover, a series of anti-nuclear, anti-phospholipid and anti-endometrial antibodies are produced in endometriosis (14). This link of endometriosis with aberrant immune responses and the subsequent development of autoimmune diseases has led to the suggestion that endometriosis itself may be classified as a typical autoimmune disorder (14,16). Alternatively, another concept suggests that an underlying abnormal immune response may contribute to the development of endometriosis (5).

Recently, Chen et al (17) attempted to clarify whether patients with endometriosis have a higher risk of developing antiphospholipid syndrome (APS), by conducting a retrospective cohort study. It was demonstrated, for the first time to the best of our knowledge, that patients with endometriosis have a higher risk (2.84-fold) of developing subsequent APS compared with women without endometriosis (17). However, the existing information refers only to epidemiological and clinical aspects of this detected association. APS is a systemic autoimmune disease characterized by the occurrence of vascular or arterial thromboses at different localizations, including the brain, heart, lungs, kidneys and limbs, obstetric complications in women of childbearing age including miscarriages, recurrent fetal deaths and premature birth, and the presence of circulating antiphospholipid (aPL) antibodies (18). As an autoimmune disease, APS is developed by an interplay of genetic and antigenic factors, while specific autoantibodies are present and used for its diagnosis, such as lupus anticoagulant, anti-cardiolipin (aCL) antibodies, anti-β2 glycoprotein-I (β2GPI) antibodies and anti-phosphatidylserine/prothrombin antibodies (19,20). The genetic predisposition of APS has been demonstrated by studies in monozygotic twins, gene-association and genome-wide association studies (GWAS) as well as whole-exome sequencing (WES) approaches (21-25). Importantly, APS can occur as a single disorder where there is no clinical or laboratory evidence of another underlying disease, called ‘primary APS’ (PAPS), but it can also be associated with another autoimmune disease, and referred to in this case as ‘secondary APS’ (26). Consequently, APS may, in part, share a common mechanism for disease development or progression with other autoimmune or immunity-related diseases.

The recent data regarding the increased risk of subsequent APS in women with endometriosis posed an interesting question concerning the putative role of shared genetic factors in the co-occurrence of both conditions (17). Notably, our previous studies have focused on the delineation of the genetic components that are involved in the co-occurrence of endometriosis with various autoimmune diseases, including SLE (27), RA (7), AS (8), SS (9), as well as psoriasis and psoriatic arthritis (28). In the present review, prompted by the findings of Chen et al (17), the present review sought to delineate the genetic basis of the co-occurrence of endometriosis with APS by systematically searching the literature for genes involved in the development of both diseases, aiming to shed light on the functional significance of the shared polymorphisms and unravel the underlying molecular and pathogenetic mechanisms of these diseases.

In the current review, a potential shared genetic background regarding the co-occurrence of endometriosis and APS was investigated. To the best of our knowledge, the present review is the first study in the literature focusing on the genetic basis of the subsequent development of APS in patients with endometriosis. The present review included case-control, GWAS, whole-genome sequencing and WES studies, as well as systematic reviews and cross-sectional studies. Notably, case report series, editorial letters, expert opinions and conference abstracts were excluded. The articles included were written in the English language and published from 2000-2025. Five electronic databases were used, namely PubMed (https://pubmed.ncbi.nlm.nih.gov/), PubMed Central (https://pmc.ncbi.nlm.nih.gov/), Google Scholar (https://scholar.google.com/), Web of Science (https://www,webofscience.com/wos/) and MEDLINE (https://www.nlm.nih.gov/medline/medline_home.html/). The keywords used for the search were as follows: ‘Endometriosis’, ‘antiphospholipid syndrome’, ‘antiphospholipid antibodies’, ‘genetics’, ‘gene polymorphisms’, ‘association studies’ and ‘GWAS’. Two authors worked individually to extract the data following the specified criteria and no disagreements arose during this process.

Accordingly, certain genes were identified as potential risk factors for developing endometriosis and APS, which are involved in inflammatory and/or interferon (IFN)-inducible processes, immune system dysregulation and thrombosis (Fig. 1). The identified gene-related risk factors included the human leukocyte antigen (HLA)-DQB1*0301 (29,30) and HLA-DQA1*0301 alleles (29,31), the 4G/5G polymorphism of the serpin family E member 1 (SERPINE1) gene [encoding plasminogen activator inhibitor type 1 (PAI-1) protein] (32,33), methylenetetrahydrofolate reductase (MTHFR) rs1801133 (34,35), signal transducer and activator of transcription 4 (STAT4) rs7574865 (36,37) and toll-like receptor 4 (TLR4) rs4986790 (38,39) single nucleotide polymorphisms (SNPs). The shared gene polymorphisms and the function of the respective genes are demonstrated in Table I.

To the best of our knowledge, the present review is the first study attempting to delineate the genetic basis of the co-occurrence of endometriosis and APS. Although only a few shared gene polymorphisms for these disorders were identified, the present review highlighted a number of loci involved in inflammatory and/or IFN-inducible processes, immune system deregulation and thrombosis. Genetic factors are important in the development of both endometriosis and APS, as has been demonstrated previously by the familiar occurrence of these health conditions and their association with various gene polymorphisms. The identification of further genetic factors associated with these diseases is of emerging interest and may help to better delineate the mechanisms leading to their clinical association. These results are important not only for future genetic and clinical studies, but also for directing future function/structure studies on the molecular cause of endometriosis and APS. Moreover, the increasing number of disease-associated variants may contribute to the development and validation of gene risk scores for both diseases, thus improving the risk assessment and tailored management of these disorders.

Further exploration of immune cell signatures and/or cytokine profiles has emphasized the pivotal role of immune dysregulation in the immune-mediated mechanisms leading to endometriosis and APS. The specific immune cell signature of APS is characterized by activated neutrophils and an enhanced type I IFN response, while the involvement of other types of immune cells, including DCs, T and B cells, monocytes and NK cells has been also reported in the pathogenesis of APS (63,64). In endometriosis, distinct immune cells signatures have been found in the peritoneal cavity, including increased numbers of CD8⁺ T cells and activated NK cells, along with follicular Th cells. By contrast, M2 macrophages and resting mast cells were observed at low levels in eutopic endometria. Moreover, activated CD4⁺ T and B cells form part of the immune signatures associated with endometriosis (65,66), while neutrophils, macrophages, NK cells and DCs also serve a role in endometriosis (13). Cytokine profiles in APS often show an imbalance, with increased levels of pro-inflammatory cytokines, such as TNF-α and IL-6, and potentially decreased levels of anti-inflammatory cytokines, such as IL-10. Furthermore, notably elevated levels of IL-7, IL-8, IL-10, IL-16, IL-17 and IL-12/IL-23p40 and decreased levels of IL-22 and IL-31 have been detected in patients with APS compared with those in healthy controls (67,68). In women with endometriosis, elevated levels of pro-inflammatory cytokines are frequently observed in both peritoneal fluid and serum. Pro-inflammatory cytokines, such as IL-1β, IL-6, IL-8 and TNF-α, have been found to be increased in the peritoneal fluid of women with endometriosis, while some anti-inflammatory cytokines, such as IL-10 and IL-33, may also appear at elevated levels in endometriosis. IL-25 (also known as IL-17E), IL-33 and thymic stromal lymphopoietin, which are involved in Th2 cell development, are increased in the peripheral blood, endometrium and peritoneal fluid of patients with endometriosis compared with women without endometriosis. Furthermore, women with advanced endometriosis (stage 3-4) exhibit markedly increased levels of IL-1α and IL-6 in the endometrial fluid compared with those in women without endometriosis (69,70).

In recent years, genomic and epigenomic research in endometriosis and APS has grown (11,12,21,23,25,71-73), driven by novel high-throughput technologies that may identify new potential signatures and therapeutic targets for further exploration in detail. Notably, Murrin et al (74) performed a systematic analysis of the contribution of genetics to multimorbidity based on representative primary care data on 72 chronic diseases, involving individuals aged ≥65 years from two large primary-care databases. All diseases were compared between each other in pairs. The study concluded that most pairs of chronic conditions show evidence of a shared genetics background and shared pathogenetic mechanisms. Therefore, it was suggested that the identified patterns of shared genetics may provide a foundation for future multimorbidity research. Importantly, the shared genetic polymorphisms have potential implications for therapeutic interventions and a better clinical management of the patients, as further analysis of gene expression patterns and future advanced pharmacogenomic approaches may refine personalized treatment strategies for women with both conditions (74).

In a retrospective cohort study of 50,078 women with endometriosis conducted by Chen et al (17), patients showed a notably increased risk of APS regardless of the presence or absence of SLE. This is an interesting but unexpected finding, taking into account that some of the shared gene polymorphisms identified in the present study, such as the MTHFR rs1801133 and STAT4 rs7574865 SNPs also represent SLE-associated risk factors (27,75-77). Notably, STAT4 rs7574865, apart from its association with the co-occurrence of endometriosis and APS, has been also associated with the co-occurrence of endometriosis with SLE, RA, AS and SS (78).

There are a few limitations to be considered in the present study. Firstly, there is a definite epidemiological lack of replication studies thus far in the literature, concerning the development of APS in women with endometriosis in different racial and/or ethnic populations. Secondly, there is a lack of information in the literature about the role of the already identified gene polymorphisms in women with endometriosis and APS of different ethnic origins. This is an important point, taking into account the differential level of contribution of the various polymorphisms involved in the development of these disorders according to the ancestry of the populations under examination (71,79). In this framework, in a previous investigation, we showed that the availability of a number of endometriosis-associated SNPs (302 SNPs were examined) provided the opportunity for the study of this condition through SNP genomic disease genomic ‘grammar’ (DGG). Thus, the genomic pedigree of endometriosis was identified using its DGG through the reported SNPs for five major groups of the world human population, including Europeans, Africans, Americans, East Asians and South Asians, and notable ‘key’ genetic targets of endometriosis were revealed with the evidence of population-based heterogeneity (71). Thirdly, the search strategy was restricted to the English language only; therefore, there is a possibility of excluding eligible studies published in other languages. Furthermore, the source of the inter-individual susceptibility to endometriosis or APS does not lie exclusively in genetics, considering that epigenetics mechanisms, such as methylation, acetylation, phosphorylation and modifications to the histone proteins associated with DNA packaging in chromatin, or others that have been analyzed in APS, are now widely believed to participate also in the susceptibility to these diseases (70,80,81). Regarding APS, hypomethylation of ETS1 and EMP2 genes in APS neutrophils, downregulation of miR-19b and miR-20a, as well as significant reduction in methylation of the IL-8 promoter and significantly increased methylation of the tissue factor (F3) gene, have been reported so far (80,81). Thus, the role of potential shared epigenetic factors has to be investigated in future studies, considering that this issue was beyond the scope of the present preliminary study.

Despite the high number of environmental exposure factors identified for endometriosis and APS, no common factors have been reported so far. Notably, most endometriosis-associated environmental factors refer to endocrine disruptors and organic pollutants, such as polyhalogenated aromatic hydrocarbons, tobacco smoking and exposure to heavy metals, pesticides and organohalogen compounds (82,83). By contrast, the environmental triggers for APS refer to bacteria, viruses, parasites, vaccines and drugs (such as antiepileptic, antipsychotic, antihypertensive, antiarrhythmic drugs and antibiotics), as well as other factors that are potentially capable of inducing a variety of pathogenic aPL antibodies, and causing thrombosis, pregnancy loss and APS through a range of mechanisms (84).

In conclusion, the observed association between endometriosis and APS suggests that clinicians and scientists conducting research on endometriosis need to be aware of potential subsequent APS when endometriosis is diagnosed. Thus, as suggested recently, clinicians should review thoroughly the symptoms and assess risk factors for APS when evaluating women with endometriosis (17). A better functional characterization of the disease-associated genes may lead to the detection of new therapeutic targets for pharmaceutical intervention and ultimately result in improved therapeutic management for the patients by designing and producing monoclonal antibodies targeting selected genes, specific inhibitors or mimicking molecules. Notably, transcriptomic profiling and analysis have allowed for improved understanding of the mechanisms underlying endometriosis and have created opportunities for drug repurposing (85). As an example, fenoprofen, an uncommonly prescribed NSAID, was the top therapeutic candidate for further investigation, which was tested in an established rat model of endometriosis and successfully alleviated endometriosis-associated vaginal hyperalgesia (85). In the same framework, the identification of altered transcriptome signatures in samples from patients with APS and analysis using bioinformatics tools have significantly enhanced the understanding of APS pathology and led to the identification of potential therapeutic targets related to the role of the IFN pathway in this disease (81). Particularly, the upregulation of genes associated with IFN pathways suggested the potential for targeted therapeutic interventions aimed at modulating the IFN signaling pathway in patients with APS (81). Moreover, the distinct gene signatures associated with different thrombosis types and disease manifestations suggested the possibility of further tailored treatment strategies based on the patient's thrombotic profile (81). Therefore, integrating clinical and molecular data using high-throughput technologies, in combination with the employment of computational and bioinformatics tools, can advance precision medicine for patients with endometriosis and APS.