The genetic basis of spondyloarthritis

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Ann Rheum Dis 2011;70(Suppl 1):i44–i50. doi:10.1136/ard.2010.140574i44

Accepted 1 November 2010

ABSTRACT Modern technological innovations have advanced our

understanding of the genetic basis of spondyloarthritis.

In ankylosing spondylitis (AS), where the major

histocompatibility complex (MHC) accounts for nearly

half of the predisposition, most comes from HLA-B27, for

which 65 subtypes are now recognised, although other

genes are also at work including HLA-B60 ( B*40:01 ).

Other genes have been identifi ed, including those involved

in peptide editing for loading onto class I MHC molecules

(ERAP1) and cytokine genes such as interleukin 1A (IL-

1A) and those involved in the Th17 network (IL-23R, an

association seen primarily in Caucasians) and others. In

acute anterior uveitis, these associations are also seen

as well as a region on chromosome 9p and genes whose

confi rmation is under way. Psoriasis and psoriatic arthritis

fall into this disease spectrum, with the largest region of

susceptibility coming from the MHC (most likely HLA-C,

ie, C*06:02 although additional infl uences are also being

implicated), and most of the other genetic susceptibility

coming from genes involved in cytokine production,

specifi cally genes in the Th17 pathway (IL-12B, IL-23A

and IL-23R, the latter, like in AS, not seen in Asians),

genes in the nuclear factor B pathway (TNFAIP3 and

TNIP1) and genes in the Th2 pathway (IL-4 and IL-13).

Given that more than half of patients with AS have

evidence on colonoscopy of at least occult infl ammatory

bowel disease (IBD), it is not surprising that shared

genetic infl uences are operative. In IBD, genes important

in the innate immune response (NOD2), autophagy

(ATG6L1) and regulation of the IL-23 pathway (IL-23R)

play a role in disease susceptibility.

INTRODUCTION Recent years have witnessed rapid advances in our understanding of the genetic basis of spondylo-arthritis and related diseases (ankylosing spondylitis (AS), acute anterior uveitis (AAU), psoriasis and psoriatic arthritis (PsA) and infl ammatory bowel disease (IBD)). From HLA and other candidate gene studies, genetic methodologies have progressed through family studies with microsatellite marker to more recent dense explorations of the genome through computer-based gene chip technologies. This review will explore the more recent fi ndings in spondyloarthritis and related disease susceptibility.

GENETICS OF ANKYLOSING SPONDYLITIS Studies of disease concordance in twins and fami-lies of patients with AS indicate that the suscepti-bility to the disease is largely due to genetic factors and that several loci are likely to be involved. Twin studies have shown that the MZ twin concordance rate is 63% compared with the DZ concordance rate of 12.5%. 1 Genetic variance modelling has

indicated that genetic factors contribute over 90% to overall susceptibility, with the rest due to ran-dom environmental effects. 2 The environmental trigger(s) are therefore likely to be widespread (such as gut fl ora) and do not contribute signifi cantly to the overall causation of the disease.

ROLE OF HLA-B27 For nearly 40 years it has been known HLA-B27 formed the most signifi cant association with AS, as well as with other types of spondyloarthritis (SpA), especially reactive arthritis (70% in white people), psoriatic spondylitis (60–70%), the spondylitis associated with IBD (50–60%) and AAU (50%). Other types of SpA show a much lower associa-tion (eg, peripheral PsA about 25% compared with a frequency of 6–8% in controls) or no association at all (eg, peripheral enteropathic arthritis). 3

Over 69 subtypes of HLA-B27 have now been recognised, 4 whose evolution from the parent B27 allele B*27:05 has largely followed geographi-cal grounds refl ecting human migrations ( table 1 ). The overwhelming majority of HLA-B27 alleles in Western European Caucasians comprise HLA-B*27:05 (about 90%) and HLA-B*27:02 (about 10%). In patients from Eastern Asia, HLA-B*27:04 and B*27:05 are most commonly encountered, especially in patients with AS, and in Southern Asia HLA-B*27:07 is found. Two subtypes— HLA-B*27:06 (encountered in South-east Asia) and B*27:09 (found largely in Sardinia)—appear to have lost their associ-ation with AS for reasons that are as yet still unclear. Other B27 subtypes are very rare and are mostly reported in only single individuals or families, although HLA-B*27:01 and B*27:14 have also been reported in patients with spondylitis. Molecular folding of HLA-B27 protein subtypes is determined by the global effect of polymorphic residues and shows incomplete correspondence to AS. 5

The association of HLA-B27 with AS is found in nearly all ethnic groups, although it is least strong in those of sub-Saharan African ancestry. Older studies from Africa reported AS to be rare, with a very low frequency of HLA-B27 in patients with AS. 6 7 This was attributed, as least in part, to a ‘protective’ West African B27 subtype ( B*27:03 ), 7 although subsequent studies reported an associa-tion of this subtype with AS in Africans. 8 The only previous study of HLA alleles in African Americans with AS suggested that only about 50% of patients are HLA-B27 positive; instead, HLA-B27-negative patients have been shown to be more likely to have the HLA-B7 cross-reactive group antigens ( B*7, B*40, B*42 , B*55 or B*56 ). 9 Recent studies from West Africa have implicated HLA-B*14:03 in susceptibility to AS. 10 This association has also extended to undifferentiated spondyloarthritis and

Correspondence to John D Reveille, The University of Texas–Houston Health Science Center, MSB 5.270, 6431 Fannin, Houston, TX 77030, USA; [email protected]

The genetic basis of spondyloarthritis John D Reveille

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Ann Rheum Dis 2011;70(Suppl 1):i44–i50. doi:10.1136/ard.2010.140574 i45

the overall risk for SpA. The entire effect of the MHC, on the other hand, is about 50%. This suggests that other genetic infl u-ences are operative in the MHC in addition to HLA-B27.

OTHER GENES IMPLICATED IN SUSCEPTIBILITY TO AS The serological specifi city of HLA-B60 (known as HLA-B*40:01 by DNA typing) was shown to be increased in B27-positive patients with AS in fi ve independent data sets in 1989 but not increased in B27-negative patients with AS, increasing the risk for AS threefold ( table 2 ). 13 This association was subsequently confi rmed in 284 UK patients with AS, 14 as well as in HLA-B27-negative Taiwanese patients with AS 15 and in African American patients with AS (Zhang et al , unpublished data). However, it was not seen in Mexican Mestizos with SpA. 16 Other MHC alleles have also been implicated, but defi nitive associations with these have been confounded by linkage to HLA-B27.

Other than the MHC, a number of genetic infl uences have been implicated in susceptibility to AS in small cohorts that could not subsequently be replicated. The fi rst gene cluster for which independent confi rmation could be established was the inter-leukin-1 (IL-1) locus on chromosome 2q15. Initial microsatellite data implicated IL-1 receptor antagonist (IL-1RN), although this was not subsequently confi rmed. After a larger study instead suggested IL-B, a collaborative study was undertaken of nine single nucleotide polymorphisms (SNPs) in the IL-1 gene cluster, including members IL-1A, IL-1B, IL-1F10 and IL-1RN, in 2675 cases of AS and 2592 healthy controls recruited in 12 different centres in 10 countries, which confi rmed that IL-1A is associ-ated with susceptibility to AS (although association of the other IL-1 gene complex members could not be excluded in specifi c populations). 17

reactive arthritis in the setting of HIV infection where an asso-ciation is also seen with HLA-B*57:03. 10

Several theories have been put forward to explain the associa-tion of HLA-B27 and SpA. 3 The arthritogenic peptide hypoth-esis suggests that disease results from the ability of HLA-B27 to bind a unique peptide or a set of antigenic peptides. However, identifi cation of such an ‘arthritogenic peptide’ has been elusive. That said, the current genetic models favour this hypothesis.

Another theory rests on the propensity for HLA-B27 heavy chains to self-associate or form homodimers due to the pres-ence of Cys67 residue (unique to HLA-B27) in their extracellular α1 domain. HLA-B27 heavy chains would then misfold in the endoplasmic reticulum, are retained there by BiP and give rise to a proinfl ammatory unfolded protein response. Also, HLA-B27 homodimers are expressed on the cell surface and are ligands for a number of natural killer and related cell surface receptors. The fact that most HLA-B27-positive individuals do not develop SpA suggests that this theory is not adequate by itself to explain susceptibility to AS.

A third theory deals with alteration of intracellular invasion/killing of microorganisms. HLA-B27-positive individuals are more effi cient at handling certain viral infections (HIV, hepatitis C, infl uenza) and less able to combat other intracellular bacte-rial infections ( Salmonella , Shigella , Chlamydia , etc). Inability to eliminate these microorganisms contributes to susceptibility to SpA, further suggested by older data demonstrating the pres-ence of bacterial antigens or DNA in the synovium of patients with reactive arthritis. 11

Less than 5% of HLA-B27-positive people in the general population develop SpA. On the other hand, 20% of HLA-B27-positive relatives of patients with AS will develop SpA. 12 Family studies have suggested that HLA-B27 forms only about 40% of

Table 1 HLA-B27 subtype frequencies (%) in different world populations Population 27:01 27:02 27:03 27:04 27:05 27:06 27:07 27:08 27:09 27:13 27:14

Northern Europe 10 90 Denmark 10 90 Southern Europe 20 80 Spain (Galicia) 18 80 3 Northern Spain 7 91 1 1 Azores 7 86 7 Italy 30 65 2 3 Sardinia 3 77 20 Greece 34 8 50 8 Cyprus 52 32 17 Turkey 7 30 43 14 5 Lebanon 24 12 35 30 Jewish 48 3 38 13 Siberia 14 84 2North India 33 61 6 West India 34 34 18 12 2Japan 82 18 Chinese 2 66 31 2 Taiwan 0.05 0.5 87 4 7 2 0.02 Taiwan (Han) 3 94 6 Taiwan Aborigines 100 Chinese Indonesian 38 62 Native Indonesian 6 6 89 Malays 19 6 72 3 Thailand 42 5 53 Maoris 36 64 Brazil 10 6 80 3 North Africa 50 50 West Africa 32 68

Only fi rst more common B27 subtypes are shown.



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In a follow-up study of 2300 British, US and Australian cases of AS of white European descent examining 370 000 SNPs using Illumina HumHap300 microarray genotyping slides, the ERAP1 and IL-23R associations were extended and additional regions were implicated in AS susceptibility, including gene deserts at chromosome 2p15 and 21q22 and additional candidate genes IL-1 receptor 2 ( IL-1R2 ) and anthraxin receptor 2 ( ANTXR2 ) 32 ( fi gure 1 ).

The gene desert at 2p15 has not previously been associated with any other disease and there are no other genes in the immediate vicinity. The gene desert at 21q22 has previously been associated with paediatric IBD, 33 although the associa-tion in our dataset did not change with exclusion of clinical IBD cases. As with 2p15, there are no genes in the immediate vicinity.

Another gene implicated in this study was IL-1R2 , which is not associated with any other disease. It acts as a decoy recep-tor, interfering with the binding of IL-1 to IL-1R1. It may be acted upon by ERAP1 in cleavage. IL-1R2 is not differentially expressed in AS, and the association may refl ect linkage with IL-1R1 located nearby.

The fourth new gene implicated in this genome-wide associa-tion study (GWAS) was ANTXR2 . The ANTXR2 gene encodes ANTXR2 (capillary morphogenesis protein-2). The protein binds to collagen IV and laminin, suggesting that it may be involved in extracellular matrix adhesion. Mutations of this gene cause juvenile hyaline fi bromatosis and infantile systemic hyalinosis. 34 It is not known to be associated with any other disease and is not differentially expressed in AS.

More recent studies using computer-automated chip genotyp-ing have allowed denser examination of the genome. A study of British and US patients with AS (the Australo-Anglo-American Spondylitis Consortium or TASC, in collaboration with the Wellcome Trust Case Control Consortium) identifi ed an asso-ciation with a non-MHC gene encoding an endoplasmic reticu-lum aminopeptidase, ERAP1 18 (previously known as ARTS-1 ). This has been subsequently confi rmed in an independent cohort from the UK, as well as in additional patients from the USA, Canada, Portugal, Hungary and China. 19 – 23

ERAP1 has two known functions, either of which may explain its association with AS. Within the endoplasmic reticu-lum, ERAP1 is involved in trimming peptides to the optimal length for MHC class I presentation. 24 This would suggest that antigen presentation is crucial in the pathogenesis of AS. The second known function of ERAP1 is that it cleaves cell surface receptors for the proinfl ammatory cytokines IL-1 (IL-1R2), IL-6 (IL-6Rα) and TNF (TNFR1), thereby downregulating their signalling. 25

Based on the observation that the IL-23 receptor (IL-23R) locus was associated with IBD 26 and subsequently psoriasis, 27 an analy sis was performed of seven SNPs in the IL-23R gene in 532 UK and 903 North American patients with AS. The most signifi cant association was with the same SNP found in IBD, rs11209026. This SNP was associated as part of an extended hap-lotype and not independently. The association of IL-23R with AS has subsequently been confi rmed in studies from Canada, Spain, Portugal and Hungary, although it was not associated with AS in Koreans and inconsistently in two studies from China. 21 23 28 – 31

Table 2 MHC and non-MHC genes associated with ankylosing spondylitis (updated from Reveille 3 ) Genes defi nitely associated with AS Chromosome Function Comment

HLA-B27 6p21.3 Presents endogenously processed antigens to T cells Perhaps the best example of a disease association with a hereditary marker

HLA-B60 ( B*4001 ) 6p21.3 Presents endogenously processed antigens to T cells Replicated in Caucasians and non-CaucasiansERAP1 5q15 Trims intracellular peptides to the optimal length for

loading onto MHC class I moleculesReplicated in two different studies, likely a real association

IL-23R 1p31.3 Promotes the differentiation of naïve CD4 T cells into helper Th17 T cells (Th17)

Replicated in studies from Spain, the UK and Canada. Association not seen in Koreans or Chinese

Kinesin family 21B (KIF21B) 1q31 A plus end-directed kinesin motor protein used to transport essential cellular components along axonal and dendritic microtubules

Seen in recent GWAS Caucasian IBD and AS patients; additional replication pending

IL-1R2 2q11-12 Acts as a decoy receptor, interfering with the binding of IL-1 to IL-1R1

Seen and independently confi rmed in one study. Confi rmation in other cohorts pending

Anthraxin receptor 2 (ANTXR2) 4q21 Binds to collagen IV and laminin, possibly involved in extracellular matrix adhesion

Seen and independently confi rmed in one study. Confi rmation in other cohorts pending

Signal transducer and activator of transcription 3 (STAT3)

17q21 A cytoplasmic transcription factor that is activated by IL-5, IL-6, IL-11, among others

Seen in European, US and Chinese AS and IBD patients

Genes replicated but not consistently associated with AS CYP2D6 22q13.1 Involved in the metabolism of xenobiotics Limited to North European Caucasians, not seen in recent

GWASIL-1 genes (primarily IL-1A) 2q12.1 Important modulators of the Th1 response Replicated in most ethnic groups, not seen in recent

GWASANKH 5p15.2 Exports inorganic pyrophosphate from intracellular to

extracellular compartments. Regulates tissue calcifi cationSeen in a relatively small North American and marginally in a Japanese AS cohort. Not replicated in a large UK AS cohort – a disease severity gene

TLR4 9q32-33 A pattern recognition receptor in innate immunity for lipopolysaccharide

Associated in Finns and Newfoundlanders, not confi rmed in several other studies or GWASs

Killer immunoglobulin-like receptors (KIR) 19q13.4 Regulates activation of NK cells via recognition of HLA class I molecules on target cells

Seen in small cohorts of Spanish and Chinese patients, not replicated in a larger cohort of UK patients

Genes associated with AS in one study but failed replication TGFB1 19q13.1 Mediates infl ammation, fi brosis and bone remodelling Marginal association in one study, two subsequent

studies negativeCD14 5q31.1 Receptor on monocytes important in apoptosis, binds

lipopolysaccharideSeen in one small cohort of Finnish AS patients, not confi rmed elsewhere

TNAP 1p36.1 A phosphoethanolamine and pyridoxal-5′-PO4 acting-ectophosphatase. Degrades PPi

One study showing an association in Caucasians not confi rmed in Asians

AS, ankylosing spondylitis; GWAS, genome-wide association study; IBD, infl ammatory bowel disease; IL, interleukin.



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severe disease. HLA-Cw6 preferentially presented cross-reactive peptides from streptococcal M protein and the hyperprolifera-tive keratin K17 to skin homing CD8 T cells, suggesting that the evolution of guttate into chronic plaque psoriasis might refl ect a transition from a self-limited response to Streptococcus initiated in the tonsils to a sustained response to homologous peptides derived from hyperproliferative skin keratins. 39

Previous family studies using microsatellite markers impli-cated the most important region of psoriasis susceptibility mapped to a 60 kb interval telomeric to HLA-C known as PSORS1. 40 Sequencing of this region has implicated HLA-C itself. 41 Environmental factors such as trauma, stress and infec-tions such as streptococcal pharyngitis have also been impli-cated. GWASs in psoriasis have implicated a number of genes encoding cytokines and cytokine pathways in psoriasis suscep-tibility ( table 3 , fi gure 2 ). 42 43 A recent GWAS in Caucasians has identifi ed genes in the Th17 pathway including IL-12B (the p40 subunit of IL-23 and IL-12), IL-23A (the p19 subunit of IL-23) and IL-23R (encoding a subunit of the IL-23 receptor), as well as genes in the nuclear factor κB (NFκB) pathway (TNFAIP3-TNF-α induced protein 3 and TNIP1-TNFAIP3 interacting protein 1) and genes in the Th2 pathway (IL-4, IL-13). 42 A concomitant study in Chinese patients with psoriasis replicated the MHC and IL-12B associations and identifi ed a new susceptibility locus within the LCE gene cluster on 1q21, 43 which contains multiple conserved genes that encode stratum corneum proteins and are expressed relatively late during fetal assembly of the skin corni-fi ed envelope. Most recently, the Wellcome Trust Case Control Consortium 2 and the Genetic Analysis of Psoriasis Consortium have identifi ed multiple new loci in psoriasis susceptibility. Independent confi rmation will be necessary to better under-stand their role in psoriasis vulgaris and PsA susceptibility. 44

Probably due to phenotypic heterogeneity and case ascertain-ment, the genetics of PsA is not as well defi ned, although asso-ciations with HLA class I alleles (ie, HLA-B38, B39 and B27) have consistently been reported. Studies from the UK and Canada have implicated genes in the IL-1 gene complex 45 46 as well as IL-13, 47 48 and a recent GWAS has identifi ed a region at chromo-some 4q27 that has been implicated in a number of autoimmune diseases. 49

GENES AND IBD SUSCEPTIBILITY Sacroiliitis and spondylitis occur in up to 20% of patients with IBD. Moreover, studies from Europe have shown that 22–69% of patients with AS have microscopic evidence of gut infl amma-tion, although only about 7% develop Crohn’s disease. 50 51

Other SNPs that were increased in frequency but did not achieve genome-wide signifi cance in the TASC study included the gene encoding tumour necrosis factor receptor 1 ( TNFR1 ), which was seen in the discovery set but not in the confi rma-tion set, although it was also seen in a subsequent study in Han Chinese patients with AS. TNFR1 is differentially expressed in AS, and TNF overexpression signals via TNFR1 in mice led to spondyloarthritis. Other SNPs implicated included those in the TNF-associated death domain ( TRADD ) gene, which was found and confi rmed in the UK patients but not North American patients, as well as in CARD9 and STAT3 . In a subsequent study of 775 Han Chinese patients with AS and 1587 controls from Shanghai and Nanjing, the associations with ERAP1 , STAT3 , TNFR1 and the gene desert on 2p15 were further confi rmed 35 and, in another study examining genes implicated in suscep-tibility to IBD, associations with KIF21B and CDKAL1 were established. 36

GENETIC SUSCEPTIBILITY IN AAU AAU affects approximately 40% of patients with AS over time and can occur in patients with no evidence of SpA. Over 90% of patients with B27-associated AAU have SpA. Although iritis rarely precedes the clinical onset of AS, it is often the fi rst clue to the recognition that low back pain is infl ammatory. Half of patients with anterior uveitis have HLA-B27. A study of micro-satellite markers in 76 affected sibpairs with AAU found strong linkage to a region on chromosome 9p21–9p24 and, when com-pared with a companion cohort of AS families without AAU, the linkage at this region was found in association with AAU but not with AS. 37 In addition to this, a GWAS from this group has implicated ERAP1 and IL-23R as well as novel genes whose confi rmation is pending.

GENETICS OF PSORIASIS AND PSA PsA is another disease encountered in the spectrum of SpA and is associated with spondylitis. The prevalence of psoriasis is much higher among fi rst-degree relatives of probands with PsA than in the general population. Moreover, in one recent study, the recurrence risk ratio for fi rst-degree relatives (λ 1 ) for PsA was 30.4 and that for psoriasis was 7.6, suggesting a stronger heritability for PsA than psoriasis per se. 38 Early studies impli-cated HLA-B13, B37 and B57, which subsequently were found to be in linkage disequilibrium with HLA-Cw6. The HLA-Cw6 association is specifi cally seen in those with plaque and guttate (although not with palmoplantar) psoriasis and indicates higher risk for younger age at onset, familial aggregation and more

Figure 1 Innate immunity, antigen presentation and the Th17 pathway all implicated in susceptibility to ankylosing spondylitis (AS).



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GWASs have also implicated genes in the Th17 pathway such as IL-23R on chromosome 1p31, a fi nding that has been reproduced extensively in replication cohorts of patients with Crohn’s disease or ulcerative colitis, 26 and others such as STAT3 . More recently, an intergenic region on chromosome 10q21.1 and a coding variant in ATG16L1 (2q37), which is expressed in intestinal epithelial cell lines, have been implicated and repli-cated in IBD susceptibility. 55 56 Functional knockdown of this gene abrogates autophagy of Salmonella typhimurium . 56 Dendritic cells (DCs) from patients with Crohn’s disease with susceptibil-ity variants in NOD2 or ATG16L1 are defi cient in autophagy induction, suggesting that NOD2 infl uences bacterial degra-dation and interacts with the MHC class II antigen presenta-tion machinery within DCs, and that ATG16L1 and NOD2 are linked within a functional pathway. 57 Also reported were strong associations with independent replication to variation in the genomic regions encoding PHOX2B, NCF4 and a predicted gene on 16q24.1 ( FAM92B ) ( fi gure 3 ). Most recently, a number

The most consistent region for IBD susceptibility on genome-wide screens has been found on chromosome 16q12 (IBD1) at NOD2/ CARD15, 52 53 whose product serves as an intracellular receptor for bacterial products in monocytes and transduces sig-nals leading to NFκB activation. Mutant alleles of NOD2 have been associated with susceptibility to Crohn’s disease in most ethnic groups; 10–30% of patients with Crohn’s disease are hetero zygotes and 3–15% are homozygotes for one of three NOD2 mutations compared with 8–15% and 0–1% of controls, respectively. NOD2 explains about 20% of the overall genetic susceptibility.

More recently, genes located in a functional haplotype in the susceptibility region IBD5 on chromosome 5, including the genes prolyl 4-hydroxylase through interferon regulatory fac-tor 1 and including the organic cation transporter ( OCTN ) gene cluster has been identifi ed and confi rmed. 54 Although the pre-cise mechanism is not known, mutations in NOD2/CARD15 or OCTNI/II may affect the host’s ability to combat bacteria that gain entry to the host through the gut.

Table 3 MHC and non-MHC genes associated with psoriasis and psoriatic arthritis (updated from Reveille 3 ) Genes defi nitely associated with psoriasis and/or psoriatic arthritis Chromosome Function Comment

HLA-C*06:02 6p21.3 Presents endogenously processed bacterial, viral, tumour or self-derived peptides to α:β T cell receptor on CB8 positive T lymphocytes

Extensively replicated, most highly seen with earlier age onset disease

HLA-B alleles 6p21.3 Presents endogenously processed bacterial, viral, tumour or self-derived peptides to α:β T cell receptor on CB8 positive T lymphocytes

Associations with HLA-B*13, B*37, B*57, B*58 with PsV likely represent linkage with HLA-C*06:02, whereas B*38, B*39 primary PsA association

IL-23 receptor 1p31 Constitutive association of IL-23R with JAK2 and ligand-dependent association with STAT3, as well as IL-23-dependent tyrosine phosphorylation of IL-23R

Not relevant in Eastern Asians

IL-12B 5q31 The IL-12 p40 subunit, or IL-12B, heterodimerises with the IL-12 p35 subunit to form IL-12 and, with the IL-23 p19 subunit, to form IL-23. In addition, IL-12 p40 exists as a monomer and as a homodimer (IL-12 p80). Important in both the Th1 and Th17 responses

Extensively replicated in Caucasian and Asian PsV patients

Genes replicated but not consistently associated with psoriasis and/or psoriatic arthritis IL-13/IL-4 5q31 Critical cytokines in the Th2 response, key in asthma

and anti-parasitic responses; also profi broticIL-13 associated with PsA in two case–control studies. Extensively described in Caucasians, not seen in one Chinese GWAS study

Late cornifi ed envelope (LCE) genes 1q21 The LCE cluster contains multiple conserved genes that encode stratum corneum proteins

A gene deletion has been described in Chinese and West European patients in both PsV and PsA, but not in Germany

Chromosome 4q27 gene cluster 4q27 This region harbours the IL-2 and IL-21 genes (both critical in the Th2 response). IL-21 has been implicated in the epidermal hyperplasia of psoriasis

Associated with four autoimmune diseases (celiac disease, type 1 diabetes, Grave’s disease and rheumatoid arthritis)

CDKAL1 6p22.3 Function unknown, highest expression in skeletal muscle and brain cells

Associated with multiple autoimmune diseases and PsV in the UK and USA, seen in case: control studies though not confi rmed in GWASs

MICA 6p21.3 Stimulates NK and T cell effector functions by engagement of NKG2D, enhances cytokine release from T effector cells

Associated with PsV in Chinese and Thai patients and MICA-A9 with PsA in Italian, Croat, Spanish, Jewish patients

IL-1 gene complex (IL-1A, IL-1B, IL-1RN) 2q12.1 Important modulators of the Th1 response Associated primarily with psoriatic arthritis in two case–control studies from the UK and Canada. Not seen on PsV GWASs

ADAM33 20p13 A member of the disintegrin and metalloproteinase domain family of proteins

Associated in UK, US, French, Chinese case: control studies but not GWASs

Genes associated with psoriasis and/or psoriatic arthritis in one study, independent replication pending TNFα-induced protein 3 (TNFAIP3) 6q23 Downregulates NFκB signalling through the

cooperative activity of its two ubiquitin-editing domains

Not seen in a GWAS of Chinese PsV patients

TNFAIP3-interacting protein 1 (TNIP1 or NAF1) 5q32 Increases cell surface expression of CD4; attenuates activated ERK2 signalling

Not seen in a GWAS of Chinese PsV patients

Novel GWAS associations pending independent replication ERAP1, IL-28RA, REL, IF1H1, TRAF31P2, NFKB1A, TYK2 Multiple genes with important impact on immunologic

functionRecently identifi ed in WTCCC2 dataset, ERAP1 interacts with HLA-C*06:02. Needs replication elsewhere

Genes associated with psoriasis and/or psoriatic arthritis in one study, not replicated Protein tyrosine phosphatase, PTPN22, MTHFR, VEGF, small proline rich (SPRR) and peptidoglycan recognition protein (PGLYRP), vascular endothelial growth factor (VEGF), SPRR and PGLYRP, IL-20RA and RB, ZNF313/RNF114, fi laggrin, serotonin receptor 2A, CTLA4, ACEI, vitamin D receptor genes, LMP and TAP, TNF, CYP2S1, retinoid X receptor, HLA-DRB1

GWAS, genome-wide association study; IL, interleukin; PsA, psoriatic arthritis; PsV, PsV, psoriasis vulgaris; TNF, tumour necrosis factor.



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However, apart from the MHC genes, the individual contribu-tions of individual non-MHC genes or SNPs is quite small, the causal variants are yet to be identifi ed, and much of the genetic variance is still unexplained. Hence, the use of genetic testing outside HLA-B27 is premature.

Funding This study was supported by grant P01-052915-01.

Competing interests None.

Provenance and peer review Not commissioned; externally peer reviewed.

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J Rheumatol 2008 ; 35 : 2236 – 40 .

of new genes have been identifi ed in Crohn’s disease and UC susceptibility by GWAS and meta-analysis approaches, bringing the total of IBD susceptibility loci up to 71 58 – 60 ; their complete delineation is outside the scope of this review. However, only 25% of the genetic variance for IBD is explained by the genes ascertained thus far, suggesting a need for future studies to iden-tify rare variants and recessive traits not easily identifi able by GWAS approaches.

CONCLUSIONS AND FUTURE DIRECTIONS Signifi cant advances have been made recently in elucidating the genetic basis of SpA. In AS, along with recent studies confi rm-ing other MHC (ie, B*40:01 ) and non-MHC (IL-1A) infl uences in addition to HLA-B27, GWASs have shown an important impact of other genes such as ERAP1, IL-23R as well as other genes and genetic regions (gene deserts on chromosomes 2 and 21, IL-1R2, ANTXR2 and STAT3, TNFR1, TRADD, CARD9). In psoriasis and PsA, the MHC component has also been dissected and is likely to include at least HLA-C and possibly other MHC infl u-ences. In addition, TH17 cytokine genes in common with AS (IL-23R) and unique to Ps (IL-12, IL-23A), as well as TH2 cyto-kines (IL-4, IL-13) and NFκB pathway genes (TNFAIP3, TNIP1), have been implicated. In IBD, genes important in the innate immune response (NOD2), autophagy (ATG6L1) and regulation of the IL-23 pathway (IL-23R) play a role in disease susceptibil-ity. These data suggest that genetic markers in susceptibility to AS, psoriasis and IBD are both disease-specifi c and class-specifi c, suggesting common mechanisms of susceptibility and patho-genesis. There is also the possibility that these markers could be used along with HLA testing (particularly B27) in diagnosis.

Figure 2 Innate immunity, antigen presentation and the Th17 pathway all implicated in susceptibility to psoriasis and psoriatic arthritis.

Figure 3 Innate immunity, autophagy and the Th17 pathway all implicated in Crohn’s disease.



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doi: 10.1136/ard.2010.140574 2011 70: i44-i50Ann Rheum Dis

John D Reveille The genetic basis of spondyloarthritis

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