Evidence of shared genetic factors in the etiology of gastrointestinal disorders and endometriosis…, 2023, Yang et al.

[SNT Gatchaman]

Evidence of shared genetic factors in the etiology of gastrointestinal disorders and endometriosis and clinical implications for disease management
Fei Yang; Yeda Wu; Richard Hockey; Jenny Doust; Gita D. Mishra; Grant W. Montgomery; Sally Mortlock

In clinical practice, the co-existence of endometriosis and gastrointestinal symptoms is often observed. Using large-scale datasets, we report a genetic correlation between endometriosis and irritable bowel syndrome (IBS), peptic ulcer disease (PUD), gastro-esophageal reflux disease (GORD), and a combined GORD/PUD medicated (GPM) phenotype. Mendelian randomization analyses support a causal relationship between genetic predisposition to endometriosis and IBS and GPM.

Identification of shared risk loci highlights biological pathways that may contribute to the pathogenesis of both diseases, including estrogen regulation and inflammation, and potential therapeutic drug targets (CCKBR; PDE4B). Higher use of IBS, GORD, and PUD medications in women with endometriosis and higher use of hormone therapies in women with IBS, GORD, and PUD, support the co-occurrence of these conditions and highlight the potential for drug repositioning and drug contraindications.

Our results provide evidence of shared disease etiology and have important clinical implications for diagnostic and treatment decisions for both diseases.

Highlights

• Endometriosis and gastrointestinal disorders are genetically correlated

• MR analyses support a causal relationship between endometriosis and IBS and GPM

• Shared risk loci highlight biological pathways and therapeutic drug targets

• Potential for drug repositioning and contraindications between diseases

Link | PDF (Cell Reports Medicine)

 

[SNT Gatchaman]

It has often been observed that many women diagnosed with endometriosis also experience symptoms associated with gastrointestinal (GI) disorders including abdominal pain, bloating, constipation, heartburn, dyspepsia, vomiting, painful bowel movements, diarrhea, and nausea. 4–6 Studies have shown that while these symptoms do not necessarily involve bowel lesions associated with endometriosis, symptoms such as cyclic-related bloating, constipation, and diarrhea can get worse during menstruation.

GI symptoms, similar to those described in endometriosis, are also commonly associated with irritable bowel syndrome (IBS), peptic ulcer disease (PUD), gastro-esophageal reflux disease (GORD), and inflammatory bowel disease (IBD).

Inevitably, the overlap in symptomology between endometriosis and these GI diseases presents challenges for clinicians to accurately diagnose these conditions in women.

The application of genetic data in a Mendelian randomization (MR) framework provides a valuable approach to understand shared disease etiology.

Endometriosis and GI diseases are common multifactorial diseases with environmental and genetic risk factors both playing roles in the development of these diseases. Twin and family studies have shown a heritable component to endometriosis, IBS, GORD, PUD, and IBD, with reported heritability estimates of 51%, 31%, 57%, 62%, and 70%, respectively.

 

[SNT Gatchaman]

As a result, for endometriosis and IBS, we identified that two genes, MYSM1 and FN1, which were the nearest genes to independent genome-wide significant SNPs, have functional evidence from either of the SMR or EpiMap analyses.

Another locus, FN1 on chromosome 2 shared by endometriosis and IBS, is involved in various cellular processes including cell proliferation, motility, invasion, and migration, processes reported to be associated with molecular mechanisms leading to endometriosis. FN1 is a genetic risk factor for endometriosis but not previously reported for IBS.

MYSM1 (GeneCards)

NCBI Gene Summary for MYSM1 Gene
Enables histone binding activity; peptidase activity; and transcription coactivator activity. Involved in several processes, including chromatin remodeling; monoubiquitinated histone H2A deubiquitination; and positive regulation of transcription by RNA polymerase II. Located in nucleolus and nucleoplasm. Part of protein-containing complex. Implicated in diabetic retinopathy.

GeneCards Summary for MYSM1 Gene
MYSM1 (Myb Like, SWIRM And MPN Domains 1) is a Protein Coding gene. Diseases associated with MYSM1 include Bone Marrow Failure Syndrome 4 and Congenital Progressive Bone Marrow Failure-B-Cell Immunodeficiency-Skeletal Dysplasia Syndrome. Among its related pathways are Metabolism of proteins and Deubiquitination. Gene Ontology (GO) annotations related to this gene include chromatin binding and protein-containing complex binding. An important paralog of this gene is SMARCC1.

UniProtKB/Swiss-Prot Summary for MYSM1 Gene
Metalloprotease with deubiquitinase activity that plays important regulator roles in hematopoietic stem cell function, blood cell production and immune response (PubMed:24062447, 26220525, 28115216). Participates in the normal programming of B-cell responses to antigen after the maturation process (By similarity). Within the cytoplasm, plays critical roles in the repression of innate immunity and autoimmunity (PubMed:33086059). Removes 'Lys-63'-linked polyubiquitins from TRAF3 and TRAF6 complexes (By similarity). Attenuates NOD2-mediated inflammation and tissue injury by promoting 'Lys-63'-linked deubiquitination of RIPK2 component (By similarity). Suppresses the CGAS-STING1 signaling pathway by cleaving STING1 'Lys-63'-linked ubiquitin chains (PubMed:33086059). In the nucleus, acts as a hematopoietic transcription regulator derepressing a range of genes essential for normal stem cell differentiation including EBF1 and PAX5 in B-cells, ID2 in NK-cell progenitor or FLT3 in dendritic cell precursors (PubMed:24062447). Deubiquitinates monoubiquitinated histone H2A, a specific tag for epigenetic transcriptional repression, leading to dissociation of histone H1 from the nucleosome (PubMed:17707232).

FN1 (GeneCards)

NCBI Gene Summary for FN1 Gene
This gene encodes fibronectin, a glycoprotein present in a soluble dimeric form in plasma, and in a dimeric or multimeric form at the cell surface and in extracellular matrix. The encoded preproprotein is proteolytically processed to generate the mature protein. Fibronectin is involved in cell adhesion and migration processes including embryogenesis, wound healing, blood coagulation, host defense, and metastasis. The gene has three regions subject to alternative splicing, with the potential to produce 20 different transcript variants, at least one of which encodes an isoform that undergoes proteolytic processing. The full-length nature of some variants has not been determined.

GeneCards Summary for FN1 Gene
FN1 (Fibronectin 1) is a Protein Coding gene. Diseases associated with FN1 include Spondylometaphyseal Dysplasia, Corner Fracture Type and Glomerulopathy With Fibronectin Deposits 2. Among its related pathways are Signaling downstream of RAS mutants and Integrin Pathway. Gene Ontology (GO) annotations related to this gene include heparin binding and protease binding. An important paralog of this gene is TNC.

UniProtKB/Swiss-Prot Summary for FN1 Gene
Fibronectins bind cell surfaces and various compounds including collagen, fibrin, heparin, DNA, and actin (PubMed:3024962, 3900070, 3593230, 7989369). Fibronectins are involved in cell adhesion, cell motility, opsonization, wound healing, and maintenance of cell shape (PubMed:3024962, 3900070, 3593230, 7989369). Involved in osteoblast compaction through the fibronectin fibrillogenesis cell-mediated matrix assembly process, essential for osteoblast mineralization (By similarity). Participates in the regulation of type I collagen deposition by osteoblasts (By similarity). Acts as a ligand for the LILRB4 receptor, inhibiting FCGR1A/CD64-mediated monocyte activation (PubMed:34089617). ( FINC_HUMAN,P02751 )
[Anastellin]: Binds fibronectin and induces fibril formation. This fibronectin polymer, named superfibronectin, exhibits enhanced adhesive properties. Both anastellin and superfibronectin inhibit tumor growth, angiogenesis and metastasis. Anastellin activates p38 MAPK and inhibits lysophospholipid signaling. ( FINC_HUMAN,P02751 )
Secreted by contracting muscle, induces liver autophagy, a degradative pathway for nutrient mobilization and damage removal, and systemic insulin sensitization via hepatic ITGA5:ITGB1 integrin receptor signaling. ( FINC_HUMAN,P02751 )

 

[SNT Gatchaman]

Fibronectin may have a role in ME/CFS. See Increased circulating fibronectin, depletion of natural IgM and heightened EBV, HSV-1 reactivation in ME/CFS and long COVID (2023, Preprint)