Endometriosis and Sjögren's syndrome: Genetics insights on the observed bidirectional association of these diseases

Abstract

We read with great interest the article by Ma et al.¹ aiming to investigate the association between endometriosis and the risk of primary Sjögren syndrome (pSS) as well as the risk of endometriosis in female patients with pSS. In the framework of this population-based cohort article, which included patients with SS, endometriosis, and the respective controls, the authors conducted an elegant, retrospective study and revealed a bidirectional association between endometriosis and pSS.¹ These findings are in accordance with recent epidemiological studies, which demonstrated that endometriosis can increase the susceptibility to SS,^{2, 3} but whether this relationship is genetic or causal remains unknown. Although the etiology of this co-occurrence remains poorly defined, it has been hypothesized that immunological deregulation and chronic inflammation characterizing endometriosis may lead to SS, while similarities appearing between molecular and cellular pathways of these diseases may implicate a partially shared genetic background.³ Taking into account the long-term interest of our research group in the analysis of the genetic components involved in the co-occurrence of endometriosis with various autoimmune diseases, we wish to add some pieces of updated information referring to the role of various genetic factors in this association of endometriosis with SS.

To put all relevant data into context, our group performed previously a search in the literature and managed to identify a number of shared genes, including the interferon regulatory factor 5 (IRF5), signal transducer and activator of transcription-4 (STAT4), protein tyrosine phosphatase, nonreceptor type 2 (PTPN22), tyrosine kinase 2 (TYK2), tumor necrosis factor-alpha (TNF-α), hypoxia-inducible factor-1α (HIF-1 α ), X Kell blood group complex subunit-related family member 6 (XKR6), as well as the HLA-associated DQB1 and DRB1 genes.³ Moreover, in the present study, we searched further for endometriosis and SS shared susceptibility loci and we found that interleukin-1 receptor antagonist (IL1-Ra), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), nuclear factor kappa B subunit 1 (NF-kB1), B-cell activating factor (BAFF) (also known as tumor necrosis factor ligand superfamily member 13B; TNFSF13B), HLA-DQA1 and HLA-DRA also represent risk gene factors for both diseases. These data were confirmed by gene association studies or genome-wide association studies (GWAS).^{4, 5} However, the causal relationships between these diseases have not yet been verified and it is still unclear whether endometriosis and SS share mediators that are involved in their pathogenesis or whether some consequences of endometriosis influence strongly the risk of developing SS.

In conclusion, apart from the remarkable biological complexity of endometriosis and SS, our data provide evidence for a partially shared genetic background regarding the co-occurrence of both diseases. The bidirectional association detected between these conditions may be driven, as suggested by the authors of the article under discussion, by autoimmune-related pathways including activation of dendritic cell maturation, and chronic inflammatory pathologies, including the fibrosis signaling pathway.¹ Interestingly, despite the aforementioned pathways, it has been documented that tissue remodeling, angiogenesis, apoptosis' disturbance, and cellular proliferation pathways are also involved in the co-occurrence of endometriosis and SS³. The information derived from these studies at the intersection between endometriosis, SS and shared genetic factors may be important for the detection of novel potential drug targets for alternative therapeutic application.