Genetics, Epigenetics, and Gender Impact in Axial-Spondyloarthritis Susceptibility: An Update on Genetic Polymorphisms and Their Sex Related Associations

Abstract

Spondyloarthritis (SpA) is a group of chronic inflammatory rheumatic disease that can be divided into predominantly axial or predominantly peripheral involvement, with or without associated psoriasis, inflammatory bowel disease or previous infection. Axial SpA (axSpA) encompasses ankylosing spondylitis (AS) with radiological sacroiliitis, and a type without radiographic sacroiliitis, called “non-radiographic axial SpA” (nr-axSpA). Males and females show large differences in their susceptibility to SpA, such as distinctions in clinical patterns, phenotypes and in therapeutical response, particularly to TNF inhibitors (TNFi). Several studies indicate that AS women have doubled risk to failure TNFi compared with males. This diversity in drugs’ efficacy among women and men may be caused by differences in the balance of sex hormones and in gene-specific expression likely triggered by X-chromosome instability and gene-specific epigenetic modifications. Evidence reported that polymorphisms in microRNAs on X- and other chromosomes, such as miR-146a, miR-155, miR-125a-5p, miR-151a-3p and miR-22-3p, miR-199a-5p could be involved in the different clinical presentation of SpA, as well as disease activity. In addition, association with non−response to TNFi treatment and presence of IRAK3 and CHUCK genes in SpA patients was recently detected. Finally, polymorphisms in genes involved in IL-23/IL-17 pathway, such as in drug pharmacodynamics and pharmacokinetics may have a role in response to TNFi, IL17i, and IL23i. A major understanding of genomic variability could help in the development of new therapeutic targets or in taking advantages of different mechanisms of action of biological drugs. Moving from the multifactorial etiology of disease, the present review aims at evaluating genetic and epigenetic factors and their relationship with sex and bDMARDs response, helping to investigate the different expression among males and females of genes on X- and other chromosomes, as well as mi-RNA, to highlight relationships between sex and occurrence of specific phenotypes and symptoms of the disease. Moreover, the role of the epigenetic modification in relation to immune-regulatory mechanisms will be evaluated.

Genetic and Molecular Distinctions Between Axial Psoriatic Arthritis and Radiographic Axial Spondyloarthritis: Post Hoc Analyses from Four Phase 3 Clinical Trials

“…The differences observed in class I HLA alleles between axPsA and r-axSpA were consistent with previous reports demonstrating that axPsA and r-axSpA overlap with respect to the contribution of HLA-B27 but also have distinct genetic risk factors [ 1 , 24 ]. Previous studies have reported that approximately 80% of patients with r-axSpA are HLA-B27- positive [ 25 , 26 ], whereas approximately 20% of patients with axPsA are HLA-B27- positive [ 26 , 27 ].…”

An Update Evolving View of Copy Number Variations in Autoimmune Diseases

“…Ankylosing spondylitis (AS) is an inflammatory AID causing spondyloarthritis of the spine and sacroiliac joints and prevalent mainly in men with a ratio of 10:1 at the age of 20–30 years old in respect to women ( Chimenti et al, 2021 ). Because the exact pathology of AS is still unclear, there are incoming data about the relationship between CNVs of these genes and AS, including CCL3L1 , FCGR3A , FCGR3B , TLR7 , UGT2B17 , BMP8A , and so on.…”

Identification of gut dysbiosis in axial spondyloarthritis patients and improvement of experimental ankylosing spondyloarthritis by microbiome-derived butyrate with immune-modulating function

“…Axial spondyloarthritis (axSpA) is a type of systemic inflammatory arthritis, which presents with joint and extra-articular symptoms such as inflammatory bowel disease ( 1 ). The most well-known marker gene for axSpA is HLA-B27, and several other genes are known to be associated with axSpA pathogenesis ( 2 ). In addition, environmental factors are known to play a role in inducing axSpA ( 1 ).…”