ReviewGenetics of ankylosing spondylitis☆
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.
References (148)
- et al.
Acute anterior uveitis and HL-A 27
Lancet
(1973) - et al.
Ankylosing spondylitis and HL-A 27
Lancet
(1973) - et al.
Defective T-cell receptor gamma gene rearrangement in interleukin-7 receptor knockout mice
Immunology Letters
(1997) - et al.
An aminopeptidase, ARTS-1, is required for interleukin-6 receptor shedding
Journal of Biological Chemistry
(2003) - et al.
Ubch9 conjugates SUMO but not ubiquitin
FEBS Letters
(1997) - et al.
Interleukin 1 gene cluster polymorphisms in multiplex families with spondylarthropathies
Cytokine
(2001) - et al.
Functional interaction of the ankylosing spondylitis-associated endoplasmic reticulum aminopeptidase 1 polymorphism and HLA-B27 in vivo
Molecular and Cellular Proteomics
(2012) - et al.
Secretion of endoplasmic reticulum aminopeptidase 1 is involved in the activation of macrophages induced by lipopolysaccharide and interferon-gamma
Journal of Biological Chemistry
(2011) - et al.
Complementation with HLA-A and HLA-D locus alleles in ankylosing spondylitis with peripheral arthritis
Journal of Rheumatology
(1985) - et al.
IL-23 is critical for induction of arthritis, osteoclast formation, and maintenance of bone mass
Journal of Immunology
(2011)
Census of cytosolic aminopeptidase activity reveals two novel cytosolic aminopeptidases
Medical Microbiology and Immunology
Balancing selection maintains a form of ERAP2 that undergoes nonsense-mediated decay and affects antigen presentation
PLoS Genetics
Susceptibility to ankylosing spondylitis is independent of the Bw4 and Bw6 epitopes of HLA-B27 alleles
Tissue Antigens
Histocompatibility antigens in psoriasis, psoriatic arthropathy, and ankylosing spondylitis
Annals of the Rheumatic Diseases
Cytokine polymorphism in noninfectious uveitis
Investigative Ophthalmology and Visual Science
Autoantibodies against CD74 in spondyloarthritis
Annals of the Rheumatic Diseases
High prevalence of anti-CD74 antibodies specific for the HLA class II-associated invariant chain peptide (CLIP) in patients with axial spondyloarthritis
Annals of the Rheumatic Diseases
Genetics of psoriasis: evidence for epistatic interaction between skin barrier abnormalities and immune deviation
Journal of Investigative Dermatology
The crystal structure of human endoplasmic reticulum aminopeptidase 2 reveals the atomic basis for distinct roles in antigen processing
Biochemistry
Immunodominant, protective response to the parasite Toxoplasma gondii requires antigen processing in the endoplasmic reticulum
Nature Immunology
Th1/Th17 polarization and acquisition of an arthritogenic phenotype in arthritis-susceptible BALB/c, but not in MHC-matched, arthritis-resistant DBA/2 mice
International Immunology
Loss of Runx3 function in leukocytes is associated with spontaneously developed colitis and gastric mucosal hyperplasia
Proceedings of the National Academy of Sciences of the United States of America
Ankylosing spondylitis: interaction between genes, joints, age at onset, and disease expression
Journal of Rheumatology
Breakthroughs in genetic studies of ankylosing spondylitis
Rheumatology
Genetics and the pathogenesis of ankylosing spondylitis
Current Opinion in Rheumatology
HLA class I associations of ankylosing spondylitis in the white population in the United Kingdom
Annals of the Rheumatic Diseases
Susceptibility to ankylosing spondylitis in twins: the role of genes, HLA, and the environment
Arthritis and Rheumatism
The effect of HLA-DR genes on susceptibility to and severity of ankylosing spondylitis
Arthritis and Rheumatism
Recurrence risk modelling of the genetic susceptibility to ankylosing spondylitis
Annals of the Rheumatic Diseases
Identification of major loci controlling clinical manifestations of ankylosing spondylitis
Arthritis and Rheumatism
Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants
Nature Genetics
Human lymphocyte antigen association in ankylosing spondylitis
Nature
Genetic differences between B27 positive patients with ankylosing spondylitis and B27 positive healthy controls
Arthritis and Rheumatism
The ER aminopeptidase, ERAP1, trims precursors to lengths of MHC class I peptides by a “molecular ruler” mechanism
Proceedings of the National Academy of Sciences of the United States of America
The dynamic genome of Hydra
Nature
ARTS1 polymorphisms are associated with ankylosing spondylitis in Koreans
Annals of the Rheumatic Diseases
Overexpression of interleukin-23, but not interleukin-17, as an immunologic signature of subclinical intestinal inflammation in ankylosing spondylitis
Arthritis and Rheumatism
Interleukin-22 and interleukin-22-producing NKp44+ natural killer cells in subclinical gut inflammation in ankylosing spondylitis
Arthritis and Rheumatism
Autophagy, but not the HLA-B27 misfolding or the unfolded protein response, regulates the expression of IL-23 in the gut of patients with Ankylosing Spondylitis and subclinical gut inflammation
Annals of the Rheumatic Diseases
Microbes, the gut and ankylosing spondylitis
Arthritis Research & Therapy
Pervasive sharing of genetic effects in autoimmune disease
PLoS Genetics
Runx3 and T-box proteins cooperate to establish the transcriptional program of effector CTLs
Journal of Experimental Medicine
Identification of ARTS-1 as a novel TNFR1-binding protein that promotes TNFR1 ectodomain shedding
Journal of Clinical Investigation
Shedding of the type II IL-1 decoy receptor requires a multifunctional aminopeptidase, aminopeptidase regulator of TNF receptor type 1 shedding
Journal of Immunology
Association of variants at 1q32 and STAT3 with ankylosing spondylitis suggests genetic overlap with Crohn's disease
PLoS Genetics
Association of ERAP1, but not IL23R, with ankylosing spondylitis in a Han Chinese population
Arthritis and Rheumatism
Association of STAT3 and TNFRSF1A with ankylosing spondylitis in Han Chinese
Annals of the Rheumatic Diseases
High throughput sequencing of IL23R reveals a low-frequency non-synonymous SNP that is associated with Ankylosing spondylitis in a Han Chinese population
Arthritis and Rheumatism
Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels
Circulation
HLA-B27 misfolding and the unfolded protein response augment interleukin-23 production and are associated with Th17 activation in transgenic rats
Arthritis and Rheumatism
Cited by (108)
HLA from Benchtop to Bedside
2021, HLA from Benchtop to BedsideClinical utility of next generation sequencing based HLA typing for disease association and pharmacogenetic testing
2020, Human ImmunologyCitation Excerpt :At the time of validation of this laboratory developed test, the generic primers were capable of detecting 170 of the 192 B*27 alleles (Supplementary Table 12) identified in the IMGT database [34], and 21 of the 22 B*27 alleles that cannot be detected are considered to be rare [15]. Recent evidence suggests that not all HLA-B*27 alleles are associated with AS; specifically, HLA-B*27:02, 27:04, 27:05, 27:07 show association, while 27:06 and 27:09 do not [35,36]. Nonetheless, all of these alleles amplify in the melting curve assay, being reported as positive.
A Review of Laboratory Practices Using the HLA-B27 Survey by the College of American Pathologists How Important Is Allele-Level Typing?
2024, Archives of Pathology and Laboratory MedicineHuman Leukocyte Antigen B27-Negative Axial Spondyloarthritis: What Do We Know?
2023, ACR Open Rheumatology
- ☆
This article belongs to Special Issue on The Pathogenetic Role of HLA-B27 and other Genes in Ankylosing Spondylitis.