Best Practice & Research Clinical Rheumatology 24 (2010) 579–588

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Best Practice & Research ClinicalRheumatology

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1

Update on the genetics of spondyloarthritis – ankylosingspondylitis and psoriatic arthritis

Vinod Chandran, MBBS, MD, DM, Clinical Research Fellow, Division ofRheumatology, Department of Medicine a, Proton Rahman, MD, MSc, FRCPC,Professor of Medicine (Rheumatology) b,*aUniversity of Toronto, Toronto, ON, CanadabMemorial University of Newfoundland, St. John’s, NL, Canada

Keywords:PsoriasisMajor histocompatibility complexHuman leukocyte antigen genesGenetic linkageGenetic associationEndoplasmic reticulum (ER)-associatedaminopeptidase 1Interleukin 23 receptorGene deserts

* Corresponding author. 154 Le Marchant Rd, St.5736. Fax: þ1 (709) 777 5212.

E-mail address: prahman@mun.ca (P. Rahman)

1521-6942/$ – see front matter � 2010 Elsevier Ltdoi:10.1016/j.berh.2010.05.006

Spondyloarthritis refers to a group of inflammatory rheumaticdiseases that share common clinical and genetic characteristics.Due to the rapid advances in technology and computationalgenetics, there is now an increasing list of well-validated genes inspondyloarthritis. The newest genetic associations are of modestmagnitude and have been identified as a result of analysingthousands of samples, using genome-wide association scans ortargeted candidate-gene association studies. In this article, we willhighlight the genes associated with spondyloarthritis, with anemphasis on the recent candidate genes that have been identifiedin ankylosing spondylitis and psoriatic arthritis. If applicable, wewill also discuss their potential relevance to the clinicalrheumatologist.

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Spondyloarthritis

Spondyloarthritis (SpA) is an inflammatory disease that is best characterised by inflammation ofsacroiliac joints and the apophyseal joints of the spine. The prevalence of SpA approaches that ofrheumatoid arthritis (1%) and the disability and economic impact of these two chronic diseases iscomparable. The four major diseases that comprise SpA are ankylosing spondylitis (AS), psoriaticarthritis (PsA), reactive arthritis (ReA) and enteropathic arthritis (EA). The aetiology of SpA is stilllargely unknown. The pathogenesis is likely to be a result of genetic, immunological and environmental

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factors. There is convincing evidence for the genetic basis of SpA from genetic epidemiological studiesthat document high familial aggregation and some robust candidate genes that have reached genome-wide significance.

Genetics of AS

Genetic epidemiology

For over four decades, AS has been known to run in families. The recurrence risk ratio for AS insiblings of probands with AS ranges from 50 to 80 and the heritability from twin studies is estimated tobe over 90% (as reviewed in ref. 1). This ranks among the highest heritability of any complex rheumaticdisease. AS does not demonstrate a clear Mendelian pattern of inheritance (dominant or recessive), butrather an oligogenic model, where genes interact in a multiplicative fashion[2]. The recurrence risk infamilies has been shown to differ between genders of the probands with increased risk of AS inrelatives of young female probands[3]. Approximately, 20% of HLA-B27 positive relatives of AS patientsdevelop SpA[4]. Genetic factors also appear to play a role in disease expression in AS, as cross-sectionalstudies have demonstrated that disease severity and radiological damage appear to be heritable[5].Due to the strong heritability of AS, the treating physician must inquire about a family history of SpAwhen assessing AS patients.

Major histocompatibility complex (MHC) region and AS

Themajor histocompatibility complex (MHC) region on chromosome 6 is about four megabases andis associated with disease susceptibility in most complex auto-immune diseases. The MHC is a gene-dense region that comprises of three clusters: class I, II and III. The MHC region is characterised byextreme linkage disequilibrium (LD), which has resulted in amajor impediment for the identification ofthe actual or causative allele in this region.

The association of HLA-B27 and AS was noted in the early 1970s and continues to be one of thestrongest disease associations for an auto-immune disease[1]. HLA-B27 is present in over 90% of ASpatients and in up to 50% in patients with other types of spondyloarthritis (PsA, EA and ReA). However,less than 5% of HLA-B27-positive individuals in the general population develop AS. The overallcontribution of HLA-B27 to AS is considerable and is estimated to be between 16% and 30%, based onlinkage and association studies within the MHC region[1]. There are now at least 57 coding variantsreported of HLA-B27 (as reviewed in ref. 6). These subtypes differ from the parent and predominantsubtype (B*2705) by 1–12 residues[2]. Other common subtypes such as B*2702, B*2704 and B*2707 arealso implicated in disease susceptibility. Exceptions to this rule include the B*2706 subtype (found innative Indonesians) and B*2709 (found in Sardinia and parts of mainland Italy)[2].

There is also substantial evidence that HLA-B27 is not the sole susceptibility factor within the MHCregion in AS. The entire genetic contribution of theMHC region in AS is estimated to be 33%, ofwhich theHLA-B27 accounts for about 16%[1]. This has led to a plethora of association studies, searching forcandidate geneswithin theMHC region.However, onlya fewhavebeen consistently replicated, themostnotable of which is HLA-B60[7]. Associations with MHC Class II alleles and AS have been reported forsusceptibility and disease expression. However, these associations have not been widely replicated[8].

Multiple non-HLA-B27 genes within the MHC region have also been proposed to be associated withAS. These include TAP alleles, low molecular weight proteosome (LMP), tumour necrosis factor (TNF)-a and Hsp-70 (as summarised in 2). LMP-2 has been implicated in juvenile AS[9] and in AS patientswith uveitis[10]. Whether these genes represent additional genetic effects above and beyond HLA-B27is not clear due to the extensive LD in this region.

From a clinical perspective, HLA-B27 has recently become an important factor in the diagnosis ofaxial SpA[11]. Presently, axial SpA is classified on the basis of sacroiliitis (via radiography or magneticresonance imaging (MRI)) along with one clinical SpA feature or presence of HLA-B27 and two clinicalSpA features. HLA-B27 also appears to be important in prognosticating radiographic damage in AS, asa cross-sectional study has shown that HLA-B27 patients appear to have a higher spinal damage score[12].

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Linkage studies and AS

Threegenome-wide linkage studies (fromtheUnitedKingdom,NorthAmericaandFrance) havebeencompleted in AS[13–15]. Laval et al.,[13] assessed 255 affected AS sibling pairs form 185 British families.The strongest logarithm of odds (LOD) score was in the MHC region (15.6). The most significant linkageoutside the MHC region was noted in chromosome 16q (extending from 99 to 106 cM from the p-telomere). Suggestive LOD scores were noted in chromosomes 2q, 9q,10q and 19q. The North AmericanSpondylitis Consortium (NASC) cohort assessed 244 sibling pairs from 180 families[14]. Linkage wasnoted at the MHC region and suggestive linkage at 6q and chromosome 11. The French Task Force forgenetic research on spondyloarthropathies performed a genome-wide linkage on 151 affected siblingpairs from65multiplex families[15]. Significant linkagewas found inMHCregion and suggestive linkagein chromosomes 5q, 9q,13q and 17q. The patient population from the French linkage studywas differentfrom the other two genome-wide linkage scans. The French Task Force included patients with SpA asdefined by the Amor and/or the European Spondyloarthropathy Study Group (ESSG) criteria, while theBritish and North American studies assessed AS patients that satisfied the modified New York criteria.

In general, replication of linkage sites for AS has been difficult due to small effect sizes, inadequatesample sizes, poor marker density, computational challenges and differences in study design. TheInternational Genetics of Ankylosing Spondylitis Consortium (IGAS) combined data from the threewhole genome linkage scans for AS[16]. Other than the convincing linkage at the MHC region,suggestive linkage was noted on chromosomes 10q and 16q and nominal linkage was noted onchromosomes 1q, 3q, 5q, 6q, 9q, 17q and 19q.

A smaller linkage study has been completed in 76 affected sibling pairs with acute anterioruveitis.[17]Strong linkage was seen at a region on chromosome 9p21–9p24, with an LOD score of 3.7.When the authors compared the acute anterior uveitis sibling pairs with a companion cohort of ASfamilies, the linkage at this regionwas found in associationwith acute anterior uveitis, but not with AS.

Association-based studies and AS involving non-MHC genes

Technological and computational advances have led to the successful execution of Genome-wideAssociation Scans (GWAS). A genome-wide association study is defined as any study of genetic vari-ation across the entire human genome that is designed to identify genetic associations with observabletraits or the presence or absence of a disease or condition. These studies have led to identification offour non-MHC related loci that have reached genome-wide significance (IL-23R, endoplasmic retic-ulum aminopeptidase (ERAP1) and two gene deserts 2p15 and 21q22). These loci will be discussedalong other genes that have strong evidence for association with AS.

Genome-wide significant association

Endoplasmic reticulum aminopeptidase (ERAP1)A genome-wide association study of 14 500 non-synonymous single-nucleotide polymorphism

(nsSNP) in 1500 Caucasian controls and 1000 Caucasian AS patients[18] identified ERAP1 as a candidategene in AS. ERAP1, also known as aminopeptidase regulating tumour necrosis factor receptor (TNFR)shedding 1 (ARTS-1), is the strongest non-MHC gene associated with AS, with an estimated populationattributable risk of 26%. The association with AS has been found in other Caucasian populations[19] aswell as in Koreans[20]. In humans, there are two known functions of ERAP1. In the endoplasmicreticulum, ERAP1 has the potential to trim peptide antigens to optimal length for binding toMHC class Imolecules[21]. ERAP1 alsomodulates the shedding of interleukin (IL)-1RII, IL-6Ra, and tumour necrosisfactor receptor (TNFR1), thus down-regulating pro-inflammatory cytokines signalling[22]. However,the mechanism of ERAP1 association with AS is yet to be fully elucidated.

Interleukin 23 receptor (IL23R)

The association of IL-23R variants was first noted in the genome-wide pooling study for psoriasis. Inthat study, the common IL-23R haplotype (involving SNPs rs753051 and rs11209026) was associated

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with psoriasis in two replication sample sets and in the combined analysis across all three sample sets[23]. At about the same time, IL-23R variants were also noted to be associatedwith inflammatory boweldisease, as a result of a GWAS[24].

IL-23R was first reported in AS as a result of a combined analysis of the IL-23R gene involving eightSNPs from AS patients in the Wellcome Trust Case Control Consortium (WTCCC) and NASC cohort[25].A peak association in the WTCCC cohort was noted for rs11209032 (p¼ 6�10�6) and in the NorthAmerican cohort the peak was with rs1343151 (p¼ 2�10�5)[25]. The peak association in thecombined data set was with SNP rs11209032 (odds ratio (OR) 1.3; 95% confidence interval (CI) 1.2–1.4;p¼ 3�10�8). This IL-23R association has been confirmed in case-control studies from Canada andSpain[26,27]. Interestingly, there was no association of IL-23R in Korean AS patients when theyexamined similar SNPs to the Canadian study within the IL-23R gene[28].

Gene deserts at chromosome 2p15 and 21q22

The recently published TASC GWAS studied over 2000 AS patients of European descent and 5000ethnically matched controls[29]. The samples were genotyped with approximately 288 000 SNPs fromthe Illumina HumHap370mapping set[29]. A strong associationwas notedwith theMHC and twowell-established AS genes ERAP1 and IL-23R. Genome-wide significance was also noted in two gene deserts2p15 and 21q22. Gene deserts are large tracts of the human genome that are devoid of protein-codinggenes. Regarding 2p15, the closest gene is 100 kb away (B3GNT2) and there is no known diseaseassociation with this gene. Regarding 21q22, the nearest gene to the most strongly associated SNP is82 kb away (PSMG1). The authors report that PSMG1 was not differentially expressed in peripheralblood mononuclear cells (PBMCs) from cases with active AS compared to healthy controls[29].

The significance of the gene deserts is not clear. It has been estimated that approximately a quarterof the human genome consists of gene deserts. Some of the gene deserts appear to be non-essential togenome function as they can be deleted without significant phenotypic effect. However, other genedeserts have been shown to contain regulatory sequences that can act at large distances to controlexpression of neighbouring genes[30].

Candidate genes with modest evidence for association with AS

IL-1 gene cluster. British, North American and Taiwanese cohorts have noted significant associationswith the IL-1 gene cluster[31–34]. The IL-1 family gene cluster spans, approximately, 360 kb andcontains the following genes: IL-1A, IL-1B, IL-1F7, IL-1F9, IL-1F6, IL-1F8, IL-1F5, IL-1F10 and IL-1RN. Astrong association and transmission of SNPs and haplotypes broadly within the IL-1 family gene clusterwas first noted in white British families[31]. The most significant associations were noted for markersin the IL1B and IL1F10 genes[31]. Further, fine mapping from the British group suggested that theprimary association in the IL-1B gene may be better explained by its LD with IL-1A[35]. These studieswere followed by a meta-analysis from the IGAS consortium where nine variants within the IL-1 genecluster in 2675 cases and 2592 controls were examined. IL1A was the only consistent genetic associ-ation that was noted and it had a population attributable risk of 4–6% among Caucasians with AS[36].

The recent TASC GWAS has identified additional genes suggestive of association. This includes IL1R2,ANTXR2 and TNFR1. IL1R2 is a decoy receptor interfering impeding the binding of IL-1 to IL-1R1[6].Regarding ANTXR2, this maps to chromosome 4q21 and mutations in this gene have been associatedwith juvenile hyaline fibromatosis and infantile systemic hyalinosis[37,38]. The significance of thesetwo genes with respect to AS is unclear at present. Meanwhile, TNFR1 encodes TNF 1 and it has beenproposed that TNFR1–ERAP1 molecular complex represents a novel mechanism by which TNFR1shedding is regulated[39].

Other candidate genes that have been previously reported but still require larger replicationstudies include ANKH and CYP2D6. ANKH has been implicated in AS and familial autosomal dominantchondrocalcinosis. With respect to AS, two novel genetic variants, one in the 50 non-coding regionand the other in the promoter region of ANKH, were found to be associated with AS[40]. However,Timms et al. were unable to replicate the association between ANKH and AS with respect tosusceptibility or clinical manifestations[41]. Two independent case-control studies from the UK have

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reported an association between homozygosity for CYP2D6*4 and AS[42,43]. However, the biologicaland clinical significance of this association is not clear and this association was not noted in theFrench population[44].

Genetics of PsA

The genetic factors underlying susceptibility to PsA are closely intertwined with that of cutaneouspsoriasis since almost all patients diagnosed with PsA have either personal or family history ofpsoriasis. Genetics of PsA also overlaps with that of AS since the two diseases have a number ofcommon features and up to 50% of patients with PsA have axial involvement. Moreover, 10–15%patients with AS have concomitant psoriasis.

Genetic epidemiology

The heritability of PsA is higher than that of psoriasis, but not as high as that of AS. The recurrencerisk ratio for PsA in first-degree relatives (FDRs) of probands with PsAwas estimated to range from 30.4to 55, while that for affected siblings (ls) of probands with psoriasis is estimated to be between 4 and10 [45]. In a study published in 1973, the prevalence of PsA among FDRs of probands with PsA wasfound to be 5.5% compared with the calculated prevalence in the UK population of 0.1%[46]. Therecurrence risk ratio (l) in FDRs (l1) was 55, according to Risch’s method[47]. In a more recent study,the l1 for PsA was estimated to be 30.4 and the l in siblings (ls) 30.8[48]. Strong heritability was alsodemonstrated in a recent study from Iceland where patients, known to have PsA in Reykjavik, werelinked to the Icelandic genealogy database[49]. FDRs to fourth-degree relatives of patients with PsAhad relative risks of 39, 12, 3.6 and 2.3, respectively (all p-values< 0.0001), reflecting a strong geneticcomponent[49]. The decrease of l -1 more rapidly than by a factor of 2 with the degree of relationshipindicates that multiple genes contribute to susceptibility with some interaction of effects[47]. The onlytwin study in PsA to date confirmed that genes are important for psoriasis but did not have the powerto detect a genetic effect in PsA[50]. Thus, PsA has a strong and complex genetic component.

MHC region and PsASince theMHC region on 6 p provides the strongest linkage (psoriasis susceptibility locus (PSORS) 1)

with psoriasis in genome-wide linkage scans, candidate genes in this region have been investigated.This gene dense region codes for a number of genes important in the immune response, including HLAand non-HLA genes. The precise identity of the PSORS1 determinant has remained elusive due to the

Table 1

Type of Study AS PsA

MHC AssociationHLAStrong Association B27 C6; B27 (spondylitis)Moderate Association B60 B7; B38/39

(peripheral arthritis)Non-HLAModerate Association LMP2 MICA, TNFa

Genome-wide Linkage StudiesDefinite Linkage MHC MHCSuggestive Linkage 10q, 16q, 9p21-24

(uveitis)16q

Association StudiesGenome-wide Significance MHC, ERAP-1, IL-23R,

2p15, 21q22MHC

Strong Association IL-1, IL1R2, ANTXR2, TNFR1 KIR2DS1, KIR2DS2IL-23R, IL-12B

Modest Association ANKH, CYP2D6 IL-1

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existence of strong LD within this region, where, at least nine genes with possible biologic significancehave been associated with psoriasis (HLA-B, HLA-C, PSORS1C3, OTF3, HCR, SPR1, SEEK1, corneodesmosin(CDSN) and TNF-a[51]. A detailed analysis of genomic DNA sequences and recombinant haplotypesstrongly suggests that HLA-Cw*0602 is the disease allele at PSORS1[52]. While HLA-Cw6 is associatedwith psoriasis, -B27 and -B7 are specifically associated with PsA[53]. In PsA, HLA Class I allele asso-ciations are stronger with HLA-B thanwith HLA-C alleles. The association of HLA-C with PsAwas foundto be due to association with early onset psoriasis, since no association was found in patients with PsAand late onset psoriasis[54]. HLA alleles also appear to be important in disease expression asHLA-B27 isassociated with axial PsA and -B38 and -B39 with peripheral polyarthritis[53]. In a cross-sectionalstudy, HLA antigens were identified as disease prognostic markers. HLA-B39 alone, HLA-B27 only in thepresence of HLA-DR7, and HLA-DQ3 only in the absence of HLA-DR7, conferred an increased risk fordisease progression[55]. The ‘rheumatoid arthritis (RA) shared epitope’ was found to be associatedwith radiographic erosions[56]. Patients with PsA carrying both HLA-Cw6 and HLA-DRB1*07 alleleshave less severe course of arthritis[54].

Non-HLA genes within the MHC region have also been proposed to be associated with PsA. Theseinclude MHC Class I related (MIC) genes, TNF-a and PSORS1C1[57–63]. The MICA genes, 100 kbcentromeric to the HLA-B locus, have been associated with PsA[57–60]. MICA protein product isexpressed on the cell surface and functions as a stress-induced antigen. MICA is highly polymorphicand, to date, 68 MICA alleles are known. The trinucleotide repeat polymorphism MICA-A9 that corre-sponds to MICA*002 was shown to be associated with PsA independent of HLA Cw*06, MICB or TNF-a.The TNF-a gene, which is located 250 kb centromeric from HLA-B, is a high-priority candidate gene inPsA. Studies show significantly higher levels of TNF-a in the serum, synovial fluid and synovialmembrane of patients with PsA than in those with osteoarthritis or healthy controls. Patients showmarked clinical response to treatment with anti-TNF-a agents. However, genetic association studiesinitially showed conflicting results[61]. Subsequently, a meta-analysis confirmed an associationbetween TNF-a - 238 polymorphism and PsA with an OR of 2.29[61]. The association with PSORS1C1 isprobably due to LD with HLA-Cw*0602[63]. A recent fine mapping of the MHC identified an associationof PsAwith SNP rs1150735 independent of known HLA associations. The SNP resides 1.5 kb upstream ofthe gene ring finger protein 39 that was previously shown to be associated with disease progression inacquired immunodeficiency syndrome (AIDS)[64]. Thus, there are a number of potential candidategenes on 6 p. The extensive LD in this regionmakes identification of the true susceptibility locus or locifor PsA difficult.

Linkage studies and PsAAlthough a number of linkage studies have been conducted in psoriasis, only one genome-wide

linkage scan has been conducted in PsA[51,65]. This study was conducted in Iceland, where 178patients with PsA were identified from 906 patients included in a genetic study of psoriasis. A total of100 out of the 178 patients with PsA were connected into 39 families using a genealogy database. Alinkage with an LOD score of 2.17 was observed on 16q. When the linkage analysis was conditioned onpaternal transmission to affected individuals, an LOD score of 4.19 was obtained, whereas an LOD scoreof only 1.03 was obtained when conditioned on maternal transmission, thus providing evidence ofimprinting that was first suggested by Rahman et al[66]. This locus is close to the PSORS8 locusidentified for psoriasis[65].

Association studies in PsA involving non-MHC genesAssociation studies in PsA have identified a number of genes outside chromosome 6 p. Those that

have been replicated include IL-1 gene cluster (chromosome 2q), Killer-cell immunoglobulin-likereceptor (KIR) genes (chromosome 19q) and IL-23R (chromosome 1 p)[67–69]. An association with theIL-1a-889 SNP variant was first reported in 2004[70]. Subsequently, a study using 29 SNPs at the IL-1cluster revealed two regions contributing independently to risk of PsA: a region spanned by markersrs3783547, rs3783543 and rs17561 in IL1A, and a region near the end of IL1B, through IL1F7, IL1F8 andinto IL1F10[68]. The activating KIR, KIR2DS1 and KIR2DS2, are associated with PsA, particularly in theabsence of the HLA ligands for the corresponding inhibitory KIRs (KIR2DL1 and KIR2DL2/3)[69,71].Later, it was shown that the susceptibility to PsAmay be determined by the overall balance of activating

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and inhibitory composite KIR-HLA genotypes[69]. As mentioned previously, the common IL-23Rhaplotype involving SNPs rs753051 and rs11209026 was first noted in the genome-wide pooling studyfor psoriasis[23]. The associationwas subsequently confirmed in the Collaborative Association Study ofPsoriasis[72]. Association between Arg381Gln SNP (rs11209026) and haplotypes encoding this variantin the IL23R receptor gene and PsA have been confirmed[67,73]. Association with two IL12B SNPs(rs3212227 and rs6887695) with PsA (and psoriasis) was reported and replicated[73,74]. The IL12Bgene encodes the common IL-12p40 subunit of two heterodimeric cytokines, IL-12 and IL-23, andIL23R encodes a subunit of the receptor for IL23A/IL23. These cytokines belong to the TH17 pathway ofeffector CD4þ T helper cells produced directly from naive CD4 T cells and reflect the important role ofthis pathway in the pathogenesis of psoriasis and PsA. The effect sizes of the associations observed inpatients with PsA are, however, similar to or smaller than those reported in patients with psoriasis,suggesting that the primary association is with psoriasis susceptibility. Associations between highergenomic copy number for beta-defensin genes on chromosome 8, and LCE3B and LCE3Cmembers of thelate cornified envelope (LCE) gene cluster on 1q21 and psoriasis have been demonstrated[75,76].Interestingly, the deletion of LCE3C and LCE3B genes did not contribute to susceptibility to PsA[77].

An adequately powered GWAS on PsA has not yet been done. However, such studies in psoriasishave been reported and, in a couple of studies, a subset of patients was known to also have PsA. Thus,the authors were able to investigate association with PsA and the differences between PsA andpsoriasis alone. In the Collaborative Association Study of Psoriasis, a GWAS analysis using 438 670autosomal SNPs and 2.5 million imputed SNPs was conducted and 21 SNPs in 18 loci were selected forreplication[72]. The study had a discovery cohort of 1409 psoriasis cases and 1436 controls. Thereplication study was done in a cohort consisting of 5048 cases and 5051 healthy controls. Evidence ofassociation was found at 10 of these 18 loci and was particularly compelling at seven loci (combined pvalue <5�10�8). Initial comparison of case-control allele frequencies confirmed association at thefollowing established psoriasis susceptibility loci: HLA-C (rs12191877, p¼ 4�10�53), IL12B (rs2082412,p¼ 5�10�10) and IL23R (rs2201841, p¼ 3�10�7). Other loci with confirmed association includedIL23A, TNF-a induced protein 3 (TNAIP3), TNFAIP3 interacting protein 1 (TNIP1), IL4 and IL13. Thus, inaddition to HLA-C, three pathways of psoriasis susceptibility were identified: TH17 pathway (IL12B,IL23A, and IL23R), NFkB pathway (TNFAIP3, TNIP1) and TH2 pathway (IL-4, IL-13). In this study, 1755cases were known to have psoriasis with PsA and 3523 had psoriasis alone. In a secondary analysis,three loci were associated with PsA when compared with normal controls (HLA-C, IL12B and TNIP1).There was a statistically significant difference between PsA and psoriasis alone at three loci (HLA-C,IL12B and IL23R). HLA-C and IL23R were more strongly associated with psoriasis alone, and IL12B withPsA[72].

In another smaller GWAS, 223 psoriasis cases (91 with PSA) were genotyped with 311398 SNPs, andresults were compared with those from 519 controls. Replications were performed with independentcohorts of 577 psoriasis cases and 737 controls, and 576 PsA patients and 480 controls[74]. This studyreplicated previously reported associations with IL23R and IL12B as well as with the MHC region (mosthighly associated SNP was rs10484554, which lies 34.7 kb upstream from HLA-C). The gene rs2395029encoding the G2 V polymorphismwithin the class I gene HCP5 had the highest ORs with both psoriasisand PsA (4.1 and 3.2, respectively). This variant is associated with low viral set point following humanimmunodeficiency virus (HIV) infection and its effect is independent of rs10484554. The study alsoidentified a novel PsA (and potentially psoriasis) locus on chromosome 4q27 that harbours the IL2 andIL21 genes. A formal GWAS on PsA is currently being undertaken.

Conclusions

Thus, there have been major advances in understanding the genetic epidemiology and genetics ofAS and PsA. A number of susceptibility loci for AS and PsA have been discovered and the pace ofdiscovery has accelerated as a result of GWAS (Table 1). However, these loci explain only a fraction ofthe heritability estimates as the genotype relative risk for most variants is very modest and account foronly a small proportion of the genetic risk. To validate new SNPsmuch larger sample sizes are required.

It is also important to assess the impact of copy number variations (CNVs) to obtain a more thor-ough understanding of genetic susceptibility in complex disease. A CNV is a common type of genomic

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variation ranging in size from 1 kb to several megabases and covers at least 25% of the genome[78]. Inthe human genome, a single CNV can have different forms (i.e., duplication, deletion and invertion)among individuals. Recently, CNVs have been recognised as important for both normal variability anddisease susceptibility.

Finally, as the DNA sequencing technology is progressing very rapidly, high-quality sequencing datawill soon become readily available and hence, detailed phenotypes will become the major hurdle forgene identification of complex diseases[79]. For these future studies, detailed clinical characterisationis required along with sophisticated genetic analysis, due to the extensive data that will be generatedfrom testing of numerous clinical and environmental variables. This includes pharmacogenetic studiesas there appears to be increasing a priori knowledge of pharmacogenetic mechanisms due to theemergence of anti-cytokine therapy including TNF-a and IL-23.

Practice points

� There is a high heritability for AS and PsA.� The MHC region is the major contributor to genetic risk for AS and PsA.� Multiple genes outside the MHC region have been identified for AS and PsA.� Each of the non-MHC genes identified to date exert a modest effect on disease risk in AS andPsA.

Research agenda for AS and PsA

� Identification of additional genetic loci including rare variants and copy number variants.� Identification of markers for disease severity and expression.� More comprehensive pharmacogenetic studies.� Better characterisation of gene–environment and gene–gene interactions.� Assess the clinical utility of validated genes in disease susceptibility, progression, pharma-cotherapy and pharmacogenetics.

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