Perspectives on the Genetic Associations of Ankylosing Spondylitis

^{Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford Institute of Musculoskeletal Sciences, Oxford, United Kingdom,}

^{Botnar Research Centre, Nuffield Orthopaedic Centre, Oxford, United Kingdom,}

^{Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom,}

Edited by: Maxime Breban, Université de Versailles Saint-Quentin-en-Yvelines, France

Reviewed by: Huji Xu, Tsinghua University, China; Nigil Haroon, University of Toronto, Canada

*Correspondence: B. Paul Wordsworth, ku.ca.xo.smrodn@htrowsdrow.luap

This article was submitted to Cytokines and Soluble Mediators in Immunity, a section of the journal Frontiers in Immunology

Edited by: Maxime Breban, Université de Versailles Saint-Quentin-en-Yvelines, France

Reviewed by: Huji Xu, Tsinghua University, China; Nigil Haroon, University of Toronto, Canada

Received 2020 Sep 7; Accepted 2021 Jan 5.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Abstract

Ankylosing spondylitis (AS) is a common form of inflammatory spinal arthritis with a complex polygenic aetiology. Genome-wide association studies have identified more than 100 loci, including some involved in antigen presentation (HLA-B27, ERAP1, and ERAP2), some in Th17 responses (IL6R, IL23R, TYK2, and STAT3), and others in macrophages and T-cells (IL7R, CSF2, RUNX3, and GPR65). Such observations have already helped identify potential new therapies targeting IL-17 and GM-CSF. Most AS genetic associations are not in protein-coding sequences but lie in intergenic regions where their direct relationship to particular genes is difficult to assess. They most likely reflect functional polymorphisms concerned with cell type-specific regulation of gene expression. Clarifying the nature of these associations should help to understand the pathogenic pathways involved in AS better and suggest potential cellular and molecular targets for drug therapy. However, even identifying the precise mechanisms behind the extremely strong HLA-B27 association with AS has so far proved elusive. Polygenic risk scores (using all the known genetic associations with AS) can be effective for the diagnosis of AS, particularly where there is a relatively high pre-test probability of AS. Genetic prediction of disease outcomes and response to biologics is not currently practicable.

Keywords: epigenetics, aetiology, pathogenesis, spondyloarthropathy, interleukin-23

Abstract

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