Elsevier

Molecular Immunology

Volume 57, Issue 1, January 2014, Pages 2-11
Molecular Immunology

Review
Genetics of ankylosing spondylitis

https://doi.org/10.1016/j.molimm.2013.06.013Get rights and content

Abstract

Ankylosing spondylitis (AS) is a chronic inflammatory arthritis that affects the spine and sacroiliac joints. It causes significant disability and is associated with a number of other features including peripheral arthritis, anterior uveitis, psoriasis and inflammatory bowel disease (IBD). Significant progress has been made in the genetics of AS have in the last five years, leading to new treatments in trial, and major leaps in understanding of the aetiopathogenesis of the disease.

Introduction

Ankylosing spondylitis (AS) is a chronic inflammatory arthritis that affects the spine and sacroiliac joints. It causes significant disability and is associated with a number of other features including peripheral arthritis, anterior uveitis, psoriasis and inflammatory bowel disease (IBD). Significant progress has been made in the genetics of AS have in the last five years, leading to new treatments in trial, and major leaps in understanding of the aetiopathogenesis of the disease.

Section snippets

Major Histocompatibility Complex Genetics of AS

It has long been known that AS runs strongly in families, with the risk of disease in first-degree relatives of AS cases being >52 times that of unrelated subjects (Brown et al., 2000). Whether this cofamiliality was due to shared environmental or genetic factors was unclear until the demonstration in the early 1970s of association of the HLA-B27 allele with the disease (Brewerton et al., 1973b, Schlosstein et al., 1973). Heterozygote HLA-B27 carriage has an odds ratio of ∼50 for AS, and

Non-MHC genetic associations

Strong epidemiological evidence of the existence of significant non-MHC genetic associations of AS was presented well before any such genes were convincingly identified. HLA-B27 positive first-degree relatives of AS cases are 5.6–16 times more likely to develop disease themselves than HLA-B27 positive carriers in the general community (Calin et al., 1983, van der Linden et al., 1983). Identical twins are much more likely to be concordant for AS (60–75%) than HLA-B27-positive dizygotic twins

Age of symptom onset

The age at which AS patients develop their first symptoms is significantly influenced by genetics, with family studies suggesting the heritability of age of onset is 33–50% (Brown et al., 2003, Sims et al., 2007). Many studies have found HLA-B27 positive patients develop symptoms 3–9 years earlier than their B27-negative counterparts (Feldtkeller et al., 2003, Jaakkola et al., 2006, Queiro et al., 2008). A large Finnish family study also found association between HLA-DRB1 alleles and age at

Axial spondyloarthritis

Axial spondyloarthritis (axSpA) is a new classification criteria that has been published that captures both AS and early and/or abortive forms of inflammatory axial arthritis (Rudwaleit et al., 2009). The demographics of axSpA are quite different from AS itself, with a higher proportion of affected women and lower HLA-B27 prevalence (reviewed in Robinson et al., 2013). These distinctions also vary considerably between cohorts meeting the same classification criteria, suggesting substantial

Psoriasis and inflammatory bowel disease

Psoriasis is present in 10–30% of AS patients and IBD occurs in about 10% of AS patients, but up to 70% have histological evidence of bowel inflammation at colonoscopy (Costello et al., 2013). Both these conditions share risk alleles with AS that implicate shared pathogenic pathways. The notable shared associations between AS and psoriasis and IBD are the IL-23 pathway (IL23R, IL12B, STAT3, JAK2) and the MHC class I pathway (MHC, ERAP1, ERAP2) (Danoy et al., 2010, Robinson and Brown, 2012). In

Pleiotropy

Family studies have not only shown high cofamiliality of AS, but also of other seronegative diseases with each other; it has also been shown that the classical autoimmune diseases tend to co-occur in families and in individual subjects. This suggests that for each set of conditions there may exist an underlying set of predisposing genetic variants, with disease-specific variants determining the ultimate disease phenotype that results (Visscher et al., 2012). As increasing numbers of

Conflict of interest

The University of Queensland has applied for patents related to the genetic findings in AS.

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    This article belongs to Special Issue on The Pathogenetic Role of HLA-B27 and other Genes in Ankylosing Spondylitis.

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