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The Genetics of Ankylosing Spondylitis and Axial Spondyloarthritis


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Ankylosing spondylitis (AS) and spondyloarthritis are strongly genetically determined. The long-standing association with HLA-B27 is well described, although the mechanism by which that association induces AS remains uncertain. Recent developments include the description of HLA-B27 tag single nucleotide polymorphisms in European and Asian populations. An increasing number of non-MHC genetic associations have been reported, which provided amongst other things the first evidence of the involvement of the IL-23 pathway in AS. The association with ERAP1 is now known to be restricted to HLA-B27 positive disease. Preliminary studies on the genetics of axial spondyloarthritis demonstrate a lower HLA-B27 carriage rate compared with AS. Studies with larger samples and including non-European ethnic groups are likely to further advance the understanding of the genetics of AS and spondyloarthritis.
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The Genetics of Ankylosing
Spondylitis and Axial
Philip C. Robinson, MBChB, FRACP,
Matthew A. Brown, MBBS, MD, FRACP*
The spondyloarthropathies (SpA) share characteristic clinical and histopathologic
manifestations, and have long been thought to share genetic causes, including
HLA-B27 and non-B27 genes. As more is learned about the genetics of ankylosing
spondylitis (AS), inflammatory bowel disease (IBD), and psoriasis, the known extent
of this sharing is expanding. This article outlines what is known about the genetics
of AS and related SpA and diseases.
AS is a highly heritable polygenic disease, in which environmental factors in developed
countries play only a minor role in determining risk of developing the disease. The
prevalence of AS varies according to some genetic and as yet undescribed
Conflict of interest: The University of Queensland has applied for patents related to the genetic
findings in AS.
University of Queensland Diamantina Institute, Princess Alexandra Hospital, Ipswich Road,
Brisbane, Woolloongabba, Queensland 4102, Australia
* Corresponding author.
E-mail address:
Genetics Genomics Ankylosing spondylitis Axial spondyloarthritis Arthritis
Ankylosing spondylitis is a polygenic disease with a strong association with HLA-B27.
Thirteen non-MHC loci are now also associated with ankylosing spondylitis.
The MHC class I presentation, IL-23, and tumor necrosis factor pathways are implicated in
the cause of AS.
The carriage rate of HLA-B27 is lower in cohorts of axial spondyloarthritis compared with
cohorts of ankylosing spondylitis.
Rheum Dis Clin N Am 38 (2012) 539–553
0889-857X/12/$ – see front matter Crown Copyright Ó2012 Published by Elsevier Inc. All rights reserved.
environmental factors. Differences in HLA-B27 prevalence drives most of the variation
in prevalence seen worldwide.
For example, the carriage rate of HLA-B27 is approx-
imately 8% to 10% in white European populations and the prevalence of AS is esti-
mated at 0.1% to 1%.
When the HLA-B27 carriage rate is increased, then SpA
prevalence rises accordingly. For example, in the Canadian Haida Indians the HLA-
B27 carriage rate is around 50% and the SpA prevalence is 5% to 6%.
There has beengene-phenotype discordance reported, for example in the Fula ethnic
group, which inhabit The Gambia in Africa.
Although in most African ethnicities HLA-
B27 is rare, among the Fula HLA-B27 carriage was 6%, yet no cases of AS were found
or have been reported. Cases of AS have been reported in American Africans carrying
the European HLA-B27 subtype B*2705, and the African subtype B*2703, indicating
that the paucity of AS in HLA-B27–positive Africans is likely not caused by protective
genetic effects. Rather, this suggests that although AS has a high heritability, environ-
mental factors do play a role in determining susceptibility in some populations.
HLA-B Alleles
The association of HLA-B27 with AS was described in 1973, and remains one of the
strongest genetic associations with any common human disease. Nonetheless, only
a minority (likely <5%) of B27-positive individuals develop AS. The discovery that
allelic variation of HLA-DRB1*01 and *04 influenced the risk of rheumatoid arthritis
stimulated research into variation in HLA-B27 itself. There are now known to be
more than 90 subtypes of HLA-B*27, which have arisen from the common ancestral
subtype, HLA-B*2705. Unlike the situation in rheumatoid arthritis, for the most part
in AS B*27 subtype variation plays little role in influencing disease risk. There is strong
evidence to suggest that HLA-B*2706 (found in east Asian populations) and B*2709
(found in Sardinia) have reduced strength of association with AS. The common white
European subtypes, B*2705 and B*2702, are equally strongly associated with AS. The
primarily Asian subtype B*2704 is at least as strongly associated with AS as B*2705 in
the same populations, with some studies suggesting that it may be more strongly
associated. B*2707, also mainly found in Asians, seems equally strongly associated
with AS as B*2705. Although AS cases have been reported carrying many other
B27 subtypes, for most alleles the number of cases reported is too few to definitely
comment on their relative strength of association with the disease.
There are currently four main theories as to how HLA-B27 is involved in AS etiopa-
thogenesis. The arthritogenic peptide hypothesis proposes that HLA-B27 presents
a pathogenic peptide that initiates disease. This hypothesis is consistent with the
antigen presentation function of HLA-B27, and also is consistent with the gene-
gene interaction (epistasis) seen with ERAP1 (discussed later). Despite extensive
efforts, no definitive “arthritogenic peptide” has been identified. There are many
potential explanations for this including that the peptide may only be present at partic-
ular phases in the disease pathogenesis or at particular sites, that it may only repre-
sent a small fraction of HLA class I presented peptides, or that more than one
peptide may be involved. Because the arthritogenic peptide is proposed to be pre-
sented to CD8 T-lymphocytes, the finding that in the HLA-B27 transgenic rat model
of SpA disease is independent of CD8 cells is inconsistent with this hypothesis.
However, no animal model perfectly captures human AS, and the relevance of this
finding to human AS is not entirely certain.
It has been shown that HLA-B27 heavy chains, either alone or as heavy chain homo-
dimers, can form on the cell surface and then interact with antigen-presenting cells
Robinson & Brown
carrying receptors, such as killer-cell immunoglobulin-like receptors.
antigen-presenting cells can then initiate a pathogenic T-helper 17 (Th17) response.
These homodimers are thought to occur when unstable HLA-B27:peptide complexes
dissociate on the cell surface.
ERAP1-deficient cells have more unstable HLA-
peptide complexes on the cell surface, which one would expect to promote cell
surface homodimer formation, but the AS-protective alleles of the ERAP1 variants
are associated with decreased function, which is inconsistent with this hypothesis.
Endoplasmic reticulum (ER) stress, which occurs when misfolding leads to accumu-
lation of HLA-B27 heavy chains in the ER, precipitates a stress response called the
unfolded protein response. The unfolded protein response is a homeostatic mecha-
nism that the cell initiates to clear the misfolded proteins and return the ER environ-
ment to normal. ER stress has been shown to be present in the HLA-B27 transgenic
rat model of SpA,
and has been shown to induce interleukin (IL)-23 production,
providing a potent link between HLA-B27 and AS.
Finally, HLA-B27 may tag a nearby disease-causative gene, the association of HLA-
B27 with AS being caused by linkage disequilibrium with this nearby “linked gene.”
This theory was made much less likely by the findings of the Australian-Anglo-
American (TASC) genomewide association study (GWAS) that confirmed the highest
association with AS was with HLA-B27 and not a linked gene.
There are mixed reports on whether homozygosity for HLA-B27 influences clinical
and although some reports have suggested an increased risk of
AS among HLA-B27 homozygotes, the sample sizes involved in these studies were
not sufficient to produce definitive results either way.
An association with HLA-
B60 has also been described in HLA-B27–positive and HLA-B27–negative individ-
although the strength of association reported was not definitive.
The huge volume of genetic information produced by GWASs has allowed
researchers to examine further questions of interest relating to heritability of disease
and disease-genotype correlations. If one considers the known AS associations, there
is not a higher burden of genetic associations in familial AS than sporadic AS, except
for HLA-B27.
HLA-B27–negative AS makes up only about 10% of AS cohorts, but does demon-
strate that an essentially identical disease can be evident without the major genetic
risk factor being present. HLA-B27–negative AS is less likely to be familial, has a later
disease onset, and is less likely to respond to anti–tumor necrosis factor (TNF) treat-
but controlling for disease duration has similar disease severity (measured
by the Bath Ankylosing Spondylitis Functional Index), activity (measured by the Bath
Ankylosing Spondylitis Disease Activity Index),
and radiographic severity (measured
by the modified Stoke Ankylosing Spondylitis Severity Score).
AS has been shown to have similar, although not identical, genetic associations
with HLA-B27–positive AS,
the main exception being the association with ERAP1,
which is restricted to HLA-B27–positive AS.
HLA-B27 Typing for Clinical Practice
Accurate HLA-typing is technically challenging and difficult to establish as a high
throughput method. This has reduced enthusiasm for the use of HLA-B27 in popula-
tion screening for risk of AS. Recently, an major histocompatibility complex (MHC) tag
single nucleotide polymorphism (SNP) rs4349859 was shown to be able to identify
HLA-B27 in those of European descent with a sensitivity of 98% and a specificity of
99%, within the likely boundaries of accuracy of direct HLA-B27 genotyping itself.
Another SNP, rs13202464, was then reported that showed high sensitivity and spec-
ificity in east Asian populations.
The use of these SNPs has significant advantages
The Genetics of Ankylosing Spondylitis 541
over the current methods for HLA-B27 typing in cost and complexity. Further research
incorporating other ethnic groups may lead to additional ethnicity-neutral HLA-B27
tag SNPs. This discovery has implications for potential screening of high-risk cohorts
either in the primary care or population-based settings. It may be able to be integrated
into referral strategies, by taking advantage of point-of-care testing, which is currently
being developed.
Rapid progress has been made in identifying new non-MHC gene associations in
recent years through GWAS. Several these are in genomic regions and involve path-
ways not thought to be associated with AS, and this further validates the hypothesis-
free approach this type of study design affords. The contribution of the described
associations to the heritability of AS, as calculated by the variance in liability method,
is shown in Table 1.
Antigen-Presentation Genes
ERAP1 is a member of the MHC class I presentation pathway and trims peptides before
presentation on MHC class I molecules, such as HLA-B27 (Fig. 1). ERAP1 has been
robustly associated with AS in multiple studies and populations including Europeans,
Hungarians, Portuguese, Taiwanese, Han Chinese, and Koreans.
Recently, it
has been demonstrated that the association of ERAP1 with AS is restricted to HLA-
B27–positive disease.
ERAP1 is also associated with psoriasis, and the association
in psoriasis is restricted to HLA-Cw6 carriers.
The AS-protective SNPs in ERAP1
result in reduced peptide trimming function of the ERAP1 enzyme.
It is not yet clear
whether the protective variants of ERAP1 lead to just quantitative reductions in trimmed
peptide availability, or if they also lead to qualitative changes in the peptides.
Table 1
Contribution of genome-wide genetic associations to the heritability of AS in populations of
white European descent
Gene/Region Heritability % Function
HLA-B27 23.3 Antigen presentation
2p15 0.54 Unknown
ERAP1 0.34 Antigen presentation
IL23R 0.31 IL-23/Th17 pathway
KIF21B 0.25 Possibly NF-kb pathway
IL1R2 0.12 Innate immune responses
RUNX3 0.12 Antigen presentation
IL12B 0.11 IL-23/Th17 pathway
TNFRI/LTBR 0.08 TNF pathway
ANTXR2 0.05 Possibly skeletal involvement
PTGER4 0.05 Innate immune responses
TBKBP1/NPEPPS/TBX21 0.05 TNF pathway/antigen presentation/Th1
21q22 0.04 Unknown
CARD9 0.03 Innate immune responses
Data from Evans DM, Spencer CC, Pointon JJ, et al. Interaction between ERAP1 and HLA-B27in anky-
losing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility.
Nat Genet 2011;43:761–7; and Reveille JD, Sims AM, Danoy P, et al. Genome-wide association study of
ankylosing spondylitis identifies non-MHC susceptibility loci. Nat Genet 2010;42:123–7.
Robinson & Brown
The ERAP1 enzyme has also been described to have two other functions. First, it
has been described to act as a sheddase to cleave cytokine receptors, such as
IL-6, TNF, and IL-1b, from the cell surface.
Studies of ERAP1-deficient mice
have demonstrated that the levels of TNF receptor and IL-6 receptor are no different
to control animals and in patients with AS there is no difference in serum cytokines
based on ERAP1 genotypes.
Second, ERAP1 has also been described to be
secreted from macrophages in response to interferon-gand lipopolysaccharide and
assists in phagocytosis.
Deficiency in phagocytosis could impair responses to
commensal or invasive microbes and HLA-B27’s restricted repertoire may interact
to exacerbate this, or push it over a disease-causing threshold.
ERAP2 encodes an aminopeptidase, which is encoded at chromosome 5p15 imme-
diately adjacent to ERAP1, and has also been shown to be associated with AS,
although whether this is independent of the ERAP1 association is not clear.
ERAP2 association has been described with Crohn disease.
ERAP2 is an aminopep-
tidase similar to ERAP1, which also trims peptides in the ER before their MHC class I
presentation on the cell surface. It has a different peptide preference from ERAP1 and
has been shown to form heterodimers with ERAP1.
T-Helper 17 Pathway Genes
The association of multiple genes in the pathogenic T-helper 17 (Th17) cell pathway,
including IL23R,STAT3, and IL12B, suggests this is an important pathway in AS. The
preliminary report of the effective use of anti–IL-17 therapy is also a pragmatic demon-
stration that clinically this is a pathway that deserves further attention.
IL-23 is made up of two subunits, IL-23p19 and IL-12p40. IL-12p40 is encoded by
IL12B. IL-23 signals through its receptor IL-23R, present on a wide range of cells, but
importantly on gamma-delta T cells and Th17 cells.
This receptor, once activated,
signals through STAT3 by promoting its phosphorylation. This STAT3 phosphorylation
then promotes IL-17 production by Th17 cells.
In cells of the innate immune system and gs T cells, pattern recognition receptors,
such as dectin-1, signal through CARD9 after b-glucan stimulation (Fig. 2). The SKG
mouse model develops an SpA phenotype when stimulated with b-glucan, character-
ized by axial and peripheral spondyloarthritis, IBD, and unilateral iritis.
After this
pathway is activated this promotes the production of prostaglandin E
Fig. 1. The antigen presentation pathways with ERAP1 (and ERAP2) trimming the peptide
before loading onto the MHC class I molecule.
The Genetics of Ankylosing Spondylitis 543
Prostaglandin E
is a proinflammatory mediator that can signal through the aracha-
donic acid pathway and promote inflammation. Prostaglandin E
can also upregulate
IL-23 and IL-17 by signally through prostaglandin E receptor 4, subtype EP4
(PTGER4). This receptor has been associated with AS at genomewide levels of signif-
Nonsteroidal anti-inflammatory drugs inhibit cyclooxygenase enzymes and
consequently the production of prostaglandins. The finding that nonsteroidal anti-
inflammatory drugs retard radiographic progression in AS and that nonsteroidal
anti-inflammatory drugs are used to reduce heterotopic ossification is a clinical
demonstration of the importance of this pathway to bone formation and
Potential Skeletal Structure and Mineralization Genes
ANTXR2, which encodes protein capillary morphogenesis protein 2, is an
AS-associated gene with potential impacts on bone and the skeleton. Defects in
this gene cause the human syndromes infantile systemic hyalinosis and juvenile
hyaline fibromatosis.
How variants of this gene are involved in AS is unclear.
A recent GWAS in east Asians
found GWAS-significant associations in two loci
harboring bone and cartilage related genes. The first associated locus harbors the
genes HAPLN1 and EDIL3 (P5910
; odds ratio [OR] 51.2). HAPLN1 encodes
hyaluronan and proteoglycan link protein 1, potentially relevant to AS etiology through
bone effects. EDIL3 encodes EGF-like repeats and discoidin I-like domains 3, which
promotes endothelial cell adhesion. The second association lies in an intron of ANO6
;OR51.3), which encodes a transmembrane protein involved in phos-
phatidylserine regulation on the cell surface. Phosphatidylserine exposure is involved
in macrophage phagocytosis of apoptotic cells, potentially mediating immune
In addition, phosphatidylserine is involved in osteoclastogenesis.
will be valuable to see if these loci replicate in other east Asian or European cohorts.
TNF-Associated Genes
Multiple genes in the TNF pathway have been associated with AS, consistent with this
pathway playing a major role in AS etiopathogenesis. Association has been described
Fig. 2. The interaction of microbial b-glucan and dectin-1, which signals through CARD9 to
promote pathogenic proinflammatory cytokines.
Robinson & Brown
at the 17q21 locus, which was attributed to TBKBP1, a member of the TNF signaling
pathway. There are, however, two other plausible candidate genes at this locus include
NPEPPS, an aminopeptidase similar to ERAP1 and ERAP2, and TBX21, a Th1 transcrip-
tion factor. Further follow-up studies are required to clarify the association at this locus.
Association has also been reported at chromosome 12p13 at a locus containing two
TNF-receptors, TNFRSF1A and LTBR
.LTBR encodes the lymphotoxin beta receptor;
lymphotoxin is a member of the TNF family. Further TNF genes that have been associ-
ated with AS include TBKBP1, which is a component of the TNF signaling pathway, and
another TNF receptor protein has also been associated. An animal model
of extreme supraphysiologic TNF overexpression causes an SpA phenotype; how this
correlates to human SpA is not yet clear.
Several factors implicate this biologic
pathway in AS including raised TNF-ain patients with AS and the effectiveness of ther-
apies that block TNF, such as anti-TNF biologics and thalidomide.
Other Genetic Associations
Two intergenic regions at 2p15 and 21q22 have now been robustly associated with
AS at genomewide levels of significance.
Proteasome assembly chaperone 1
(PSGM1) gene is found near the 21q22 locus; the proteasome is part of the MHC class
I presentation pathway. It is therefore plausible that the association operates through
this gene. Against this, the association is not in close proximity to the gene. At chro-
mosome 2p15 there is no nearby candidate gene. RNA-sequencing studies identified
long noncoding RNA transcripts at both loci, and it may that the associations operate
through cis-ortrans-gene regulation, potentially through noncoding RNA (ncRNA).
RUNX3 encodes Runt-related transcription factor 3, which has been shown to be
expressed in thymocytes on signaling by IL-7.
These IL-7–stimulated CD4 and
CD8 double-positive cells then differentiate into CD8 positive lymphocytes. Further
evidence to support this finding is the moderate level of association found in the IL-
7 receptor (P5810
) in the TASC AS GWAS.
Consistent with this it will be infor-
mative to examine other components of this pathway, such as the cytokine IL-7 itself,
for association in future experiments.
IL1R2 encodes the IL-1 receptor 2, the biologic action of which is to inhibit IL-1 by
acting as a decoy receptor. This protein exists in two forms, a long membrane-bound
form and a shorter soluble form, which is produced by alternate splicing.
The longer
membrane-bound form is the functionally active inhibitory molecule. IL-1bis stimu-
lated by conserved microbial sequences, such as pathogen-associated molecular
patterns or damage-associated molecular patterns. Inhibition of an appropriate
response to microbial colonization or infection may be the mechanism by which this
association acts.
KIF21B has been associated with AS and with other autoimmune disorders
including multiple sclerosis,
Crohn disease,
and ulcerative colitis.
It is expressed
in a variety of tissues, but best characterized in dendrites. It is involved in trafficking of
components within the cell. It is also expressed in B cells, T cells, and natural killer
Preliminary evidence suggests KIF21B and a nearby open reading frame
C1orf106 at the 1q32 locus are involved in ER stress and the NF-kb pathway but
further functional work is required.
There is overlap of important risk variants between AS and a whole host of other
immune-mediated diseases including but not limited to psoriasis, IBD, multiple scle-
rosis, rheumatoid arthritis, and anterior uveitis (see Table 1).
The Genetics of Ankylosing Spondylitis 545
Psoriasis is a chronic inflammatory autoimmune skin condition present in 3% to 4%
of the general population; about 15% of patients with AS have psoriasis. Psoriasis has
a major class I MHC association in HLA-Cw6, and in a directly analogous situation to
AS, there is also an epistatic association with ERAP1.
The IL-23 pathway is also a common component of several autoimmune diseases.
Genetic associations with IL23R,IL12B,PTGER4,CARD9,STAT3, and JAK2, which
have been reported variously with AS, psoriasis, and IBD, likely operate through
effects on IL-23 signaling. Various components of this pathway have been described
to be associated with psoriasis, IBD, ulcerative colitis, Crohn disease, and multiple
sclerosis. The downstream mechanisms by which these associations operate,
including the key cytokines involved (IL-17 or IL-22) and cell types (Th17 or noncanon-
ical IL-17–expressing cells, such as gamma-delta cells, mast cells, neutrophils, or
dendritic cells), are not clear. Nonetheless, blockade of the pathway including with
anti–IL-12p40 and IL-17 antibodies is effective in these conditions (Table 2).
Consistent with the differences in the clinical phenotypes seen in patients with SpA
there are differences in the genetics between AS and axial SpA. To date the only pub-
lished data on the genetics of axial SpA is on HLA-B27 carriage rate. A summary of the
published cohorts of patients with SpA is presented in Table 3. One of the limitations
of examining the HLA-B27 carriage rate in cohorts of patients with axial SpA is the
ascertainment bias that may result from recruiting patients based on their HLA-B27
status, as would occur with the HLA-B27 arm of the 2009 ASAS Axial SpA criteria.
From these data it is clear that the HLA-B27 carriage rate is lower is axial SpA than in
AS cohorts, with a 58% to 75% carriage rate compared with 82% to 89% in AS
cohorts. Because classification criteria for axial SpA include patients with AS, it is
likely that there are significant genetic overlaps between axial SpA and AS.
Studies on the heritability of radiographic change in AS have found that there is a good
correlation (r50.86) between siblings, and the additive heritability of radiographic
disease severity based on the Bath Ankylosing Spondylitis Radiographic Index
(BASRI) is 0.62.
Haroon and colleagues
genotyped 13 coding SNPs from antigen-presentation
genes (ERAP1,LMP2,LMP7,TAP1, and TAP2) in the Spondyloarthritis Research
Consortium of Canada cohort with the aim of investigating the genetic predictors of
radiographic progression. In multivariate analysis allele G of rs17587 in large multi-
functional peptidase 2 (LMP2) was associated with the baseline modified Stoke
Table 2
Shared genetic associations and pathways in multiple immune mediated
Spondylitis Psoriasis
Inflammatory Bowel
MHC class I antigen
IL-23 pathway IL23R, IL12B, CARD9,
IL12B, IL23R IL12B, IL23R, CARD9,
Suggestive level of association.
Robinson & Brown
Ankylosing Spondylitis Spinal Score but not with progression. This result has not been
Bartolome and colleagues
investigated 384 SNPs from 190 genes and reported
that SNPs in the MHC,TAP2,NELL1, and ADRB1, and clinical factors, such as gender
and later age at disease onset, could be used to in a model to predict radiographic
severity of AS. The predictive model had an area under the receiver operator curve
of 0.76 (95% confidence interval, 0.71–0.80); this dropped to 0.68 (96% confidence
interval, 0.63–0.73) when the SNPs were removed from the model. The MHC genes
were in or near the classical alleles HLA-DRB1,HLA-B, and HLA-DQA1.NELL1 is
expressed in bone and promotes bone formation in animal models.
ADRB1 is the
gene that encodes the b1 adrenergic receptor. b-blockers have effects on bone
mineral density and fracture risk, which supports this finding.
These data have
not been replicated.
In contrast to the previously described studies, which examined the patient’s radio-
graphic progression over time, Ward and colleagues
examined the genetic predic-
tors of the ratio of BASRI of the spine to disease duration as an indicator of disease
progression in patients with disease duration of 20 years or more. They found
HLA-B*4100 (OR 512), HLA-DRB1*0804 (OR 512), HLA-DQA1*0401 (OR 55),
HLA-DQB1*0603 (OR 53), and HLA-DPB1*0202 (OR 523) associated with more
progressive disease. In this study HLA-DRB1*0801 was associated with protection
from radiographic progression with an OR of 0.03.
In contrast to its important effects in disease onset HLA-B27 has not been associ-
ated with radiographic change in multiple studies.
The continuing development of genomics offers further potential for genetic discov-
eries in AS. Study design features likely to lead to further progress include the
1. Increase in sample sizes: Thus far the largest genetic study in AS involved a GWAS
of 3023 cases, far fewer than have been studied for other autoimmune diseases of
Table 3
HLA-B27 carriage rates in ankylosing spondylitis and axial spondyloarthritis patient cohorts
Cohort SpA Definition AS Definition
Rate %
Rate %
Modified ESSG mNY 74.7 82.2
Modified ESSG mNY 72.6 84.3
Kiltz et al,
2012 ASAS ASpA mNY 86.4 89.1
58.4 —
Haibel et al,
MRI arm used solely because of the HLA-B27 arm of the study being affected by ascertainment
bias, because HLA-B27 is part of the entry criteria for this part of the study.
To be included patients had to have low back pain for greater than 3 months and a symptom
onset before the age of 50 years and at least three of the following six criteria and at least two
of criteria 1 to 3: 1. Inflammatory back pain; 2. Carry HLA-B27; 3. Active inflammation in the spine
or sacroiliac joints demonstrated on MRI; 4. Good response to nonsteroidal anti-inflammatory
drugs; 5. Current or past anterior uveitis, peripheral arthritis, or enthesitis; 6. A family history of
spondyloarthritis. Patients who met the modified New York criteria for AS were excluded.
The Genetics of Ankylosing Spondylitis 547
similar population frequency, such as multiple sclerosis,
or even rheumatic
diseases of much lower population frequency than AS, such as systemic lupus er-
ythematosus. There is a clear link between sample size and productivity.
larger studies in AS are clearly indicated, and are likely to flow from international
collaborative studies, such as the International Genetics of AS Consortium Immu-
nochip study.
2. Transethnic studies: Most studies to date of AS genetics have been performed in
white European populations, and little data are available about other important
ethnic groups including east Asians and Indian Asians. These studies are likely to
be beneficial particularly in localizing genetic effects, using differences in the
linkage disequilibrium structure of the various populations studied.
3. Low-frequency and rare-variant studies: Early sequencing studies and studies
using microarray genotyping targeting low-frequency variants have already been
productive in AS-related diseases, notably in IBD.
These variants are not well
detected by current GWAS microarrays, which target common variants. Although
they will take large studies to identify, sequencing and low-frequency targeted
microarray studies are likely to be productive in such diseases as AS, where
a significant fraction of the disease’s heritability remains unaccounted for.
4. Genetic studies of AS-disease manifestations: Very little is known about the
genetics of disease severity in AS, or of associated features, such as the develop-
ment of acute anterior uveitis. These are likely to have genetic determinants, and to
be addressable by GWAS and other genetic studies.
The use of genetic prediction of those at risk of AS is likely to be one of the earliest
genetic screens adopted for common conditions, because the high heritability of the
disease suggests that genetic risk prediction will be informative. At this stage,
however, more evidence regarding the benefit of early intervention is required before
this approach can be recommended.
Genetic discoveries in AS have identified associated pathways previously not consid-
ered important. These discoveries have enabled direct translation to clinical practice
as agents to target the pathways have been developed with other uses in mind but are
now being turned to treat AS. This is the exciting future for the genetics of AS, from the
laboratory to the clinic, and in doing so improving the lives of patients.
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... Таким образом, на уровне транслируемого белка существует 160 известных Патогенная роль HLA-B27 в развитии спондилоартритов до конца неизвестна. Однако существует несколько гипотез, объясняющих роль HLA-B27 в развитии заболеваний суставов [51][52][53]: гипотеза артритогенных пептидов; гипотеза неправильного свертывания HLA-B27; гипотеза гомодимеров. ...
... Гипотеза неправильного свертывания основана на накоплении тяжелых цепей HLA-B27 в эндоплазматическом ретикулуме (ЭР), что приводит к синтезу медиаторов воспаления, участвующих в развитии заболеваний суставов [51][52][53]. Тяжелые цепи молекулы HLA-B27 синтезируются в ЭР, где они связываются c легкой цепью β2m и пептидом. Пептиды для загрузки в пептидзагружающий комплекс появляются благодаря процессу расщепления белка бактерий аминопептидазами. ...
... Гипотеза гомодимеров основана на способности тяжелых цепей HLA-B27 образовывать гомодимеры, приобретая неканоническую конформацию HLA-B27 и возможность связываться с NK-клетками -естественными киллерами и CD4+ Т-лимфоцитами, вызывая синтез провоспалительных медиаторов [51][52][53]. Так, в результате неправильной укладки HLA-B27 появляются молекулы, не содержащие в себе β2-микроглобулин и презентируемый пептид -гомодимеры В27 2 . Активация Т-и NK-клеток приводит к развитию воспалительной реакции. ...
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The literature review presents the characteristics of the human leukocyte antigen (HLA)-B27 as a factor contributing to the development of psoriatic arthritis. HLA-B27 is a class I surface antigen encoded by the major histocompatibility complex (MHC) B locus located on chromosome 6. The main function is to present antigenic peptides to the CD8+ T-cells. HLA-B27 is the most important genetic biomarker for psoriatic arthritis, as it provides phenotypic differentiation in the patient population. The prevalence of HLA-B27 in various population groups are presented. The structural features of the HLA-B27 molecule are described. The characteristics of methods for detecting HLA-B27 status and determining its subtypes are given. The main mechanisms of the HLA-B27 polymorphism influence on the development of psoriatic arthritis are considered, and hypotheses are analyzed that explain the pathogenic effect of HLA-B27: the arthritogenic peptide hypothesis, the misfolding hypothesis, the HLA-B27 heavy chain homodimer formation hypothesis. The features of the clinical manifestations and course of HLA-B27-positive psoriatic arthritis are presented, allowing the use of HLA-B27 to predict the development of psoriatic joint damage.
... Furthermore, targeting the IL-23/IL-17 signalling pathway with medication has shown improvement in patients with axSpA [42••, 45]. While genomewide associations have uncovered multiple proteins (including ERAP and IL-23 receptor) associated with axSpA, the strongest genetic association with ankylosing spondylitis and psoriatic arthritis is HLA-B27 [50,51]. Interestingly, HLA-B27 may cause the presentation of arthritogenic peptides on the cell surface [52]. ...
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Purpose of Review Psoriatic arthritis and ankylosing spondylitis belong to a family of rheumatological diseases that lead to painful joint inflammation that impacts on patient function and quality of life. Recent studies have shown that the pro-inflammatory cytokine IL-17 is involved in the inflammatory joint changes in spondyloarthritides. We will review the pathophysiology of IL-17 and review the biological therapies targeting IL-17. Recent Findings IL-17 is produced and released from T cells and is dependent on multiple upstream cytokines, which include IL-23. There are six members of the IL-17 family that are secreted from multiple populations of T cells. The initial biologic medications have been developed against IL-17A, which is the best-studied member of this family. These medications appear to be effective in controlling joint inflammation, improving patient quality of life, and are generally well tolerated. More recently, medications have been developed that target both IL-17A and IL-17F. In addition, brodalumab, an antibody targeting the IL-17 receptor, has had a resurgence after initial concerns for an increased risk of suicide. Summary IL-17 is an inflammatory cytokine that is critical in the pathobiology of axial spondyloarthritides. Recent biological therapies targeting IL-17A are effective and well tolerated in patients with axial spondyloarthritis. Specific targeting of the Il-17A/F heterodimer is also effective and provides another viable option in the clinician’s armamentarium.
... HLA-B27 is present in 8-10% of the general Caucasian population and a lower prevalence in other ethnicities such as Asian, African, and Middle Eastern populations [22,23]. The prevalence of radiographic axSpA in those who are HLA-B27 positive is only 1-5%. ...
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Purpose of Review This review examines axial spondyloarthritis (axSpA) and the wider field of rheumatology through a value-based healthcare (VBHC) lens. VBHC is focused on ensuring patients receive high quality care to improve outcomes and reduce unnecessary costs. Recent Findings There are many opportunities to apply the principles of VBHC in axSpA. These include the appropriate utilization of diagnostic investigations, such as HLA-B27 and magnetic resonance imaging, assessing outcomes meaningful to patients, and optimizing care pathways. Multidisciplinary care may improve value, and reduced specialist review and medication tapering may be appropriate. Summary Increasing the value of the care we provide to patients can occur across domains and directly and indirectly improves patient outcomes. Taking the time to integrate principles of VBHC into our practice will allow us to justifiably gain and maintain access to diagnostic and therapeutic advances for the benefit of all our patients.
... STAT3 is a major signaling molecule within the Th17 lymphocyte differentiation pathway. IL-23 signals through its receptor IL-23R and induces STAT3 phosphorylation [57]. This stimulates Th17 cells to produce proinflammatory cytokines such as TNF, IL-1B and IL-17, leading to joint and bowel inflammation [54]. ...
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Emerging evidence suggests there is a gut-joint axis in spondyloarthritis (SpA). In a study, subclinical gut inflammation occurred in nearly 50% of SpA. Chronic gut inflammation also correlated with disease activity in SpA. Trillions of microorganisms reside in the human gut and interact with the human immune system. Dysbiosis affects gut immune homeostasis and triggers different autoimmune diseases including SpA. The absence of arthritis in HLA-B27 germ-free mice and the development of arthritis after the introduction of commensal bacteria to HLA-B27 germ-free mice proved to be the important role of gut bacteria in shaping SpA, other than the genetic factor. The recent advance in gene sequencing technology promotes the identification of microorganisms. In this review, we highlighted current evidence supporting the link between gut and axial SpA (axSpA). We also summarized available findings of gut microbiota and its interaction with the immune system in axSpA. Future research may explore the way to modulate gut microorganisms in axSpA and bring gut microbiome discoveries towards application.
... Growing evidence indicates that AS is caused by genetic and environmental factors. And genetic factors play the leading role in the onset of AS [6,7]. Moreover, with the development of molecular biology and modern genetics many AS-associated genes have been discovered, such as pentraxin3 gene (PTX3), protein tyrosine phosphatase non-receptor type 22 (PTPN22) and IL-23R [8][9][10]. ...
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Background The aim of this study was to investigate whether thymocyte-expressed, positive selection-associated 1 (TESPA1) gene polymorphisms were associated with increased risk of developing ankylosing spondylitis(AS) in a Chinese Han population. Methods A total of 99 AS patients were recruited as case group and 96 healthy individuals were collected as control group. TESPA1 polymorphisms were genotyped by polymerase chain reaction (PCR) and sequencing methods. The genotype distribution of TESPA1 gene rs4758993 and rs4758994 polymorphism was detected by Hardy-Weinberg equilibrium (HWE). The genotype and allele distributions of each polymorphism were also compared between groups. Moreover, odds ratios (OR) with 95% confidence intervals (95%CI) were calculated using the χ² test to evaluate the association between AS susceptibility and TESPA1 polymorphisms. Results rs4758993 and rs4758994 polymorphisms were conformed to be in HWE in genotypes distribution of the control group (P > 0.05 for both). A remarkable decrease trend of rs4758993 AG genotype and A allele were detected in AS patients than in healthy controls (P = 0.01 and 0.02, respectively), indicating that they obviously decreased the risk of AS in a Chinese Han population (OR = 0.303, 95%CI = 0.144–0.637; OR = 0.002, 95%CI = 0.173–0.703). However, No significant differences were detected for TESPA1 gene rs4758994 polymorphism in both genotype and allele distributions between case and control groups (P > 0.05). Conclusions Our findings suggest that TESPA1 gene rs4758993 polymorphism was significantly associated with AS susceptibility in the Chinese Han population and the mutant A allele severed as a protect factor for the development of AS.
... Other genetic links have also been suggested, e.g. polymorphisms of the interleukin-23 (IL- 23) receptor gene and endoplasmic reticulum aminopeptidase 1 (ERAP-1) gene [4,33,41]. ERAP encodes for an aminopeptidase and is involved in preparing peptides for MHC class 1 presentation to immune effector cells. The IL-23 R activates T-helper cells [33,42]. ...
... Excellent review has been published on a large number of gene variants involved in SpA and AS [170,176]. Which genes are the cause and which are the effect still remains challenge in understanding the disease. ...
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This review summarizes the genetic alterations and knockdown approaches published in the literature to assess the role of key proteoglycans and glycoproteins in the structural development, function, and repair of tendon, ligament, and enthesis. The information was collected from (i) genetically altered mice, (ii) in vitro knockdown studies, (iii) genetic variants predisposition to injury, and (iv) human genetic diseases. The genes reviewed are for small leucine-rich proteoglycans (lumican, fibromodulin, biglycan, decorin, and asporin); dermatan sulfate epimerase (Dse) that alters structure of glycosaminoglycan and hence the function of small leucine-rich proteoglycans by converting glucuronic to iduronic acid; matricellular proteins (thrombospondin 2, secreted phosphoprotein 1 (Spp1), secreted protein acidic and rich in cysteine (Sparc), periostin, and tenascin X) including human tenascin C variants; and others, such as tenomodulin, leukocyte cell derived chemotaxin 1 (chondromodulin-I, ChM-I), CD44 antigen (Cd44), lubricin (Prg4), and aggrecan degrading gene, a disintegrin-like and metallopeptidase (reprolysin type) with thrombospondin type 1 motif, 5 (Adamts5). Understanding these genes represents drug targets for disrupting pathological mechanisms that lead to tendinopathy, ligamentopathy, enthesopathy, enthesitis and tendon/ ligament injury, that is, osteoarthritis and ankylosing spondylitis.
... Excellent review has been published on a large number of gene variants involved in SpA and AS [170,176]. Which genes are the cause and which are the effect still remains challenge in understanding the disease. ...
Introduction: Ankylosing spondylitis, also known as radiographic axial spondyloarthritis, is a complex, immune-mediated inflammatory disorder most commonly involving the spine including the sacroiliac joints. Areas covered: Complex pathogenesis of axial spondyloarthritis involving genetic, environmental, and both innate and adaptive immune systems. Treatment options for ankylosing spondylitis. Pharmacologic properties, efficacy, and safety of tofacitinib, a JAK inhibitor. Data regarding efficacy of approved JAK inhibitors in the treatment of ankylosing spondylitis, including tofacitinib, upadacitinib, and filgotinib. Expert opinion: Current treatment options of ankylosing spondylitis include NSAIDs, TNFi, and IL-17i. JAK inhibitors present a new class of therapy that has shown efficacy in the treatment of active ankylosing spondylitis in adults. While it has not been directly compared to alternate therapies, tofacitinib has been shown to be effective in both phase II and phase III trials for the treatment of ankylosing spondylitis. While these trials did not show any significant difference from placebo in terms of safety, the ORAL Surveillance study showed tofacitinib to be inferior to TNFi when comparing adverse events. Thus, tofacitinib presents a viable treatment option for the management of AS, however shared decision making regarding risks and benefits will be important.
Objective: To compare the distribution of HLA-B*27 subtypes in healthy controls and in ankylosing spondylitis (AS) patients of different ethnic groups from Pakistan. Study design: Descriptive study. Place and duration of study: Armed Forces Institute of Pathology, Rawalpindi, Pakistan, from April 2016 to October 2017. Methodology: Forty-nine HLA-B*27 positive, unrelated AS patients and 18 HLA-B*27 positive healthy BMT/renal transplant donors were selected for this study. Typing of the HLA-B27 alleles was performed by the polymerase chain reaction-sequence-specific primer (PCR-SSP). Results: There was a wide number of HLA-B*27 subtypes and an elevated frequency of the B*2707 allele in the AS patients. The allele B*2706 seems to have a protective role in the population studied because it was found only in the healthy controls. HLA-B*27:03 and 07 were found predominant subtypes in Punjabis and Pathans, respectively. Conclusion: There were no significant differences for the distribution of B*27 subtypes between patients and controls (p >0.05).
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Proteolytic cleavage of TNF receptor 1 (TNFR1) generates soluble receptors that regulate TNF bioactivity. We hypothesized that the mechanism of TNFR1 shedding might involve interactions with regulatory ectoproteins. Using a yeast two-hybrid approach, we identified ARTS-1 (aminopeptidase regulator of TNFR1 shedding) as a type II integral membrane protein that binds to the TNFR1 extracellular domain. In vivo binding of membrane-associated ARTS-1 to TNFR1 was confirmed by coimmunoprecipitation experiments using human pulmonary epithelial and umbilical vein endothelial cells. A direct relationship exists between membrane-associated ARTS-1 protein levels and concordant changes in TNFR1 shedding. Cells overexpressing ARTS-1 demonstrated increased TNFR1 shedding and decreased membrane-associated TNFR1, while cells expressing antisense ARTS-1 mRNA demonstrated decreased membrane-associated ARTS-1, decreased TNFR1 shedding, and increased membrane-associated TNFR1. ARTS-1 neither bound to TNFR2 nor altered its shedding, suggesting specificity for TNFR1. Although a recombinant ARTS-1 protein demonstrated selective aminopeptidase activity toward nonpolar amino acids, multiple lines of negative evidence suggest that ARTS-1 does not possess TNFR1 sheddase activity. These data indicate that ARTS-1 is a multifunctional ectoprotein capable of binding to and promoting TNFR1 shedding. We propose that formation of a TNFR1–ARTS-1 molecular complex represents a novel mechanism by which TNFR1 shedding is regulated.
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We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10⁻⁸). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.
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Association between ankylosing spondylitis (AS) and two genes, ERAP1 and IL23R, has recently been reported in North American and British populations. The population attributable risk fraction for ERAP1 in this study was 25%, and for IL23R, 9%. Confirmation of these findings to ERAP1 in other ethnic groups has not yet been demonstrated. We sought to test the association between single nucleotide polymorphisms (SNPs) in these genes and susceptibility to AS among a Portuguese population. We also investigated the role of these genes in clinical manifestations of AS, including age of symptom onset, the Bath Ankylosing Spondylitis Disease Activity, Metrology and Functional Indices, and the modified Stoke Ankylosing Spondylitis Spinal Score. The study was conducted on 358 AS cases and 285 ethnically matched Portuguese healthy controls. AS was defined according to the modified New York Criteria. Genotyping of IL23R and ERAP1 allelic variants was carried out with TaqMan allelic discrimination assays. Association analysis was performed using the Cochrane-Armitage and linear regression tests of genotypes as implemented in PLINK for dichotomous and quantitative variables respectively. A meta-analysis for Portuguese and previously published Spanish IL23R data was performed using the StatsDirect Statistical tools, by fixed and random effects models. A total of 14 nsSNPs markers (8 for IL23R, 5 for ERAP1, 1 for LN-PEP) were analysed. Three markers (2 for IL23R and 1 for ERAP1) showed significant single-locus disease associations, confirming that the association of these genes with AS in the Portuguese population. The strongest associated SNP in IL23R was rs1004819 (OR=1.4, p=0.0049), and in ERAP1 was rs30187 (OR=1.26, p=0.035). The population attributable risk fractions in the Portuguese population for these SNPs are 11% and 9.7% respectively. No association was seen with any SNP in LN-PEP, which flanks ERAP1 and was associated with AS in the British population. No association was seen with clinical manifestations of AS. These results show that IL23R and ERAP1 genes are also associated with susceptibility to AS in the Portuguese population, and that they contribute a significant proportion of the population risk for this disease.
To identify new susceptibility loci for psoriasis, we undertook a genome-wide association study of 594,224 SNPs in 2,622 individuals with psoriasis and 5,667 controls. We identified associations at eight previously unreported genomic loci. Seven loci harbored genes with recognized immune functions (IL28RA, REL, IFIH1, ERAP1, TRAF3IP2, NFKBIA and TYK2). These associations were replicated in 9,079 European samples (six loci with a combined P < 5 x 10(-8) and two loci with a combined P < 5 x 10(-7)). We also report compelling evidence for an interaction between the HLA-C and ERAP1 loci (combined P = 6.95 x 10(-6)). ERAP1 plays an important role in MHC class I peptide processing. ERAP1 variants only influenced psoriasis susceptibility in individuals carrying the HLA-C risk allele. Our findings implicate pathways that integrate epidermal barrier dysfunction with innate and adaptive immune dysregulation in psoriasis pathogenesis.
Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.