Article Published in the Author Account of

John Bowes

The Genetics of Psoriatic Arthritis: Lessons from Genome-wide Association Studies

Abstract: Psoriatic arthritis (PsA) occurs in approximately 30% of psoriasis patients. Understanding the similarities and differences in the etiology of these related diseases may highlight pathways for intervention and allow risk prediction in the future. Both are complex diseases in which environmental susceptibility factors trigger disease in genetically susceptible individuals. In recent years, genome-wide association studies have been highly successful in identifying genetic susceptibility factors for psoriasis. Most of the psoriasis loci tested so far are also associated with PsA. For example, associations of HLA-Cw*06 and the IL12B and IL23R genes are well-established with both conditions. More recently, analysis of psoriasis genome-wide association studies in a PsA subgroup has also implicated IL23A, TNFAIP3, and TNIP1 genetic variants as conferring risk to PsA. One study has suggested that late cornified envelope (LCE) gene polymorphisms are associated with psoriasis but not PsA. However, this finding was not confirmed by a second study. Similarly, association of the 5q31 gene region encompassing the IL13 gene has been reported with PsA but not psoriasis by one group, but this awaits confirmation in other series. Dedicated genome-wide association studies of PsA are underway and are likely to reveal further insights into why some patients with psoriasis develop arthritis whilst the majority do not.



Psoriatic Arthritis

Psoriatic arthritis (PsA) is defined as “an inflammatory arthritis in the presence of psoriasis in which patients are usually negative for rheumatoid factor.” Almost all patients have co-existing plaque psoriasis or a family history of psoriasis although the appearance of psoriasis does not always pre-date the arthritis (Gladman et al., 2005). Family studies suggest a strong genetic component to both psoriasis and PsA. For PsA, examination of recurrence risks in subjects with variable degrees of relatedness to the index cases from the Icelandic genealogical database suggests that PsA has a multiplicative genetic component with first-degree relatives at nearly 40-fold increased risk of disease (Karason et al., 2009). Estimates of familial recurrence risks in psoriasis are lower suggesting that patients with PsA harbor additional risk variants over and above the contribution to psoriasis (Chandran et al., 2009). Understanding the similarities and differences between genetic risk factors for psoriasis and PsA could lead to the development of more effective therapies for both conditions. It would also raise the possibility of screening psoriasis subjects to identify those at high risk of PsA, who could then be closely monitored in order to introduce treatment at the earliest signs of joint involvement. A number of candidate gene studies have been undertaken over the years but the most robust findings have emerged largely (but not exclusively) since the advent of genome-wide association studies (GWAS). This review will focus on what we can learn about the genetic susceptibility to PsA from GWAS in PsA, psoriasis, and other related diseases.

Genome-wide Association Studies

In a GWAS, up to a million genetic single nucleotide polymorphisms (SNP) and other genetic markers are simultaneously surveyed and allele frequencies compared between cases and controls. It is now firmly established as the dominant method in genetic epidemiology and its application has greatly accelerated the identification of loci associated with common disease susceptibility and many other complex quantitative traits. The National Human Genome Research Institute’s catalogue of published GWAS currently lists approximately 3,000 associated SNPs (Hindorff et al., 2009). The GWAS approach succeeds not only because of the large number of SNPs that can be simultaneously tested but also because the selection of these SNPs is unbiased by prior hypotheses regarding involvement with the study trait. The foundation of this success is based on the maturation of population-based reference panels of genetic variation and the rapid advance in the technology that allows the affordable genotyping of up to one million SNPs (Hardy and Singleton, 2009).

Prior to the advent of GWAS only a single genetic risk locus, the major histocompatibility complex (MHC) on chromosome 6p21, had been robustly associated with susceptibility to PsA. Evidence to implicate this region in susceptibility to psoriatic disease was first discovered in psoriasis, where the association was limited to early onset psoriasis (type 1; onset ≤ 40 years of age) (Allen et al., 2005; Nair et al., 2006). This was later confirmed in PsA with the strongest association mapping to the MHC class I molecule HLA-Cw6, in particular the HLA-Cw*0602 allele (Gladman et al., 1999). All subsequent GWAS have confirmed that this remains the strongest association signal but have also identified non-MHC risk loci.

GWAS of PsA

To date only a single GWAS for PsA has been published (Liu et al., 2008). Even that was primarily a study of psoriasis but 91 of the 223 cases were classified as having PsA. The case data were compared against 519 controls, with all samples genotyped for 311,398 SNPs from an Illumina HumanHap300 BeadChip. Validation of putative associations with PsA was undertaken in 576 cases and 480 controls from the U.K. As expected, the strongest signal for association mapped to the HLA region. The SNP, rs10484554, is located approximately 35 kb upstream of HLA-C (p = 6.9×10-11 in the U.K. samples). Association of PsA with the IL12B and IL23R genes was also observed; both genes were known psoriasis susceptibility loci (Cargill et al., 2007). Association was also identified to the 4q27 region which includes the autoimmune genes, IL2 and IL21. This represents a novel risk locus for PsA, but has previously been reported to be associated with a number of autoimmune diseases including rheumatoid arthritis, type I diabetes, and celiac disease, and suggests a region of broad autoimmune importance (van Heel et al., 2007; Zhernakova et al., 2007). However, association of PsA to this region is yet to be independently validated.

Given that the information from PsA GWAS is fairly limited at the present time, we can use information emerging from GWAS performed in other related autoimmune diseases to make inferences about the genetic etiology of PsA.

Psoriasis

Given the clinical overlap and shared genetic risk factors, psoriasis GWAS make for a rich source of potential risk loci for validating in PsA. These GWAS also tend to contain a significant proportion of PsA cases; in some instances, the most associated loci are subsequently analyzed in PsA subgroup separately. The application of the GWAS approach has taken the number of confidently confirmed risk loci for psoriasis from one (HLA-C) to at least 10. These findings have emerged from four GWAS.

Associations to multiple genes in the IL-23 pathway have been identified for both PsA and psoriasis. The first conclusive evidence for the importance of this pathway in psoriasis came from the first genome wide attempt at identifying psoriasis risk loci. This was a large multi-tiered study that genotyped 25,215 gene-centric SNPs in 1,446 psoriasis cases and 1,432 healthy controls (Cargill et al., 2007). This study found association to a SNP (rs3212227) that maps to the 3′-untranslated-region of IL12B, a gene which encodes the IL-12p40 subunit of the heterodimeric IL-23 protein and was the first non-MHC psoriasis risk locus identified.

Upon reseqeuncing the region, a second, independent association (rs6887695) was identified approximately 60 kb upstream of the coding region. In addition, novel association to two non-synonymous SNPs (rs7530511 and rs11209026) in the IL-23 receptor (IL23R) gene, which encodes for one of the two subunits of the IL-23 receptor, was also identified. Subsequently, these associations with psoriasis have been validated by a number of independent research groups (Capon et al., 2007; Smith et al., 2008; Nair et al., 2008). Two studies exploring these associations in PsA identified significant association to both genes (details for all non-MHC association are given in Table 1) (Filer et al., 2008; Huffmeier et al., 2009). Interestingly, association of the IL23A gene that encodes the other subunit, IL-23p19, of IL-23 with psoriasis and PsA has recently been identified (Nair et al., 2009). IL23R is also a risk factor for Crohn’s disease and ankylosing spondylitis but not rheumatoid arthritis, type 1 diabetes, and celiac disease (Duerr et al., 2006; Burton et al., 2007). Hence, PsA seems to be more closely genetically related to the seronegative inflammatory arthritides, which aligns with the clinical classification of these diseases.

This study also found modest association to three SNPs (rs1800925, rs20541, and rs848) mapping within the proximity of the IL13 gene on chromosome 5q31 (results were reported independently of the main study) (Chang et al., 2008). The same research group performed extensive fine-mapping of this chromosomal region and identified an additional association to rs11568506 (mapping to SLC22A4). This association remained significant upon conditioning for the main association to rs1800925 suggesting an independent effect (Li et al., 2008). Intriguingly, when the data from the primary GWAS was analyzed to investigate the contribution of PsA/psoriasis, the effect was restricted to PsA, suggesting the identification of the first PsA specific genetic risk locus (Duffin et al., 2009).

The second reported GWAS, which is the first to use array based technology, was performed by Liu et al. (2008) and confirmed association to the IL12B and IL23R genes for both psoriasis and PsA. In addition, it identified a further signal in the IL23R region to the SNP rs12131065. This SNP, which maps close to the IL12RB2 gene, is not in linkage disequilibrium with previously identified IL23R SNPs, and conditional analysis revealed evidence for an independent effect. A number of novel loci were reported including 13q13, which contains the genes COG6 and LHFP, 15q21, which harbors TNFAIP8L3, 4q27, which contains the genes IL2 and IL21, and finally association to a SNP mapping to the LCE1C gene on chromosome 1q21 (discussed in further detail below). The evidence to support association to the 4q27 region was only replicated in the PsA branch of the study and not validated in the psoriasis follow-up study.

The third published GWAS was conducted in a large population of Chinese Han ancestry using 1,139 psoriasis cases and 1,132 controls (Zhang et al., 2009). Promising signals were then followed up in 5,182 cases and 6,516 controls of Chinese Han ancestry and 539 cases and 824 controls of Chinese Uygur ancestry. The study found very strong evidence for association at two established psoriasis risk loci: HLA-Cw6 and IL12B. In addition, novel disease association to a SNP (rs4085613) mapping to the late cornified envelope (LCE) gene cluster on chromosome 1q21, a region previously identified via linkage studies (PSORS4), was reported. The genes of this region make compelling candidates for psoriatic disease phenotypes as they encode proteins of the stratum corneum which play an important role in epidermal terminal differentiation, disruption of which has been proposed to lead to abnormal differentiation and psoriatic skin lesions (de Cid et al., 2009). Interestingly a study investigating genome wide copy number variation in psoriasis found disease association to a 32 kb deletion (LCE3C_LCE3B-del) encompassing two genes in this cluster: LCE3C and LCE3B (de Cid et al., 2009). This deletion was found to be highly correlated with the SNP rs4112788 (r2 = 0.93) with the major allele (C) tagging LCE3C_LCE3B-del. The SNPs rs4112788 and rs4085613 are in high linkage disequilibrium (r2 > 0.95) but neither SNP is in linkage disequilibrium with rs6701216 reported by Liu et al. (2008). Association to the deletion-correlated SNPs has since been found in a U.K. population of PsA patients but not in a German PsA patient population (Huffmeier et al., 2010; Bowes et al., 2010).

Finally, the most comprehensive psoriasis GWAS in a European population published to date was performed by Nair et al. (2009). This well powered study genotyped 438,670 SNPs in 1,409 cases and 1,436 controls, followed by genotyping of the 21 most associated SNPs from 18 loci in 5,048 cases and 5,041 controls. They found evidence to support disease association to 10 of these loci (P < 0.05 in the follow-up cohort), of which seven had convincing evidence (P < 0.0005 in the follow-up cohort and P < 5×10-8 in the combined sample collection). Association to four previously identified loci, HLA-Cw6, IL13, IL12B, and IL23R, was confirmed. Associations to four novel loci were identified, including an association to IL23A, which, along with IL12B, forms the complete IL-23 molecule. Of particular interest are the associations to two genes of the NFκB pathway — TNF-α induced protein 3 (TNFAIP3) and TNFAIP3 interacting protein 1 (TNIP1) — which further implicate this pathway in general autoimmunity as these have been associated with a number of other diseases including rheumatoid arthritis and systemic lupus erythematosus. Interestingly, the TNFAIP3 psoriasis-associated SNP is not in linkage disequilibrium with either of the two rheumatoid arthritis-associated SNPs (rs6920220 and rs10499194). An especially informative aspect to this study for PsA researchers was the fact that it contained a large proportion of PsA cases in both the discovery and follow-up cohorts (n = 1,755). The authors endeavored to exploit this by investigating potential heterogeneity between psoriasis and PsA with data from their most highly associated signals, but did not find any differences between the two groups as all loci were associated with both diseases. This contrasts with data from Duffin et al. (2009) who found a specific association of IL13 to PsA.

Other Autoimmune Diseases

Many examples of overlapping genetic risk factors are now documented that support shared pathways across related autoimmune diseases (Zhernakova et al., 2007). In addition to psoriasis, the clinical features of PsA also overlap with rheumatoid arthritis, ankylosing spondylitis, and Crohn’s disease. Identified genetic risk loci in these diseases could provide insight into the genetics of PsA. However, very little work has been done to explore this overlap as yet.

Rheumatoid arthritis

There is no consistent evidence to support association between the two strongest rheumatoid arthritis risk loci, HLA-DRB1 and PTPN22, and susceptibility to PsA (Hinks et al., 2005; Butt et al., 2006; Huffmeier et al., 2006; Ho et al., 2008). In addition to these two well known rheumatoid arthritis risk loci, GWAS have revealed a number of additional loci. However, to date there is only limited evidence to support a genetic overlap between the two diseases. The 6q23 region, harboring the TNFAIP3 gene, has recently become a well established rheumatoid arthritis risk locus (Thomson et al., 2007; Plenge et al., 2007). Nair et al. (2009) identified an association to rs610604, which maps to the 6q23 region, with susceptibility to both psoriasis and PsA; however this SNP is not correlated with either of the reported rheumatoid arthritis SNPs. Additional loci with suggestive evidence for overlap include SNPs at the AFF3 and IL2/IL21 gene regions (Liu et al., 2008; Barton et al., 2009), but confirmation in further independent datasets is required. We might have expected to see more overlap given that both diseases cause inflammation in synovial joints and respond to similar treatments. However, the genetic studies suggest that the two diseases are distinct. A comprehensive assessment of all the confirmed rheumatoid arthritis risk loci has yet to be published.

Ankylosing spondylitis

PsA clinically shows overlap with ankylosing spondylitis. Approximately 10% of patients with PsA present with spinal involvement and sacroiliitis although radiographic studies suggest that the incidence of sub-clinical disease may be even higher. HLA-B27 is known to be associated with both conditions (Battistone et al., 1999). GWAS of ankylosing spondylitis have revealed a number of non-MHC associated variants (Brown, 2010). In particular, a non-synonymous SNP mapping to the ERAP1 gene is strongly associated with ankylosing spondylitis (Burton et al., 2007). We have also found it to be associated with PsA (Castelino et al., manuscript submitted).

Conclusion

Despite the current lack of dedicated PsA GWAS, significant advances have been made in the understanding of the underlying genetics from GWAS in closely related autoimmune diseases. This information has led to the identification of multiple non-MHC risk factors for PsA and highlighted the importance of the NF-κB and IL-23 pathways in the susceptibility to multiple autoimmune diseases including PsA. Dedicated PsA GWAS are now underway and the real hope of these studies is that they provide insights into the unique etiology of PsA by identifying genetic risk factors not shared with other autoimmune diseases, thus revealing PsA specific genetic susceptibility pathways, which could be targeted for treatment.

Disclosure

The authors report no conflicts of interest.

(Corresponding author: Anne Barton, M.D., Ph.D., Arthritis Research UK Epidemiology Unit, Manchester Academic Health Science Centre, The University of Manchester, Manchester M13 9PT, United Kingdom and The Kellgren Centre for Rheumatology, Central Manchester Foundation Trust, NIHR Manchester Biomedical Research Centre, Manchester M13 9WL, United Kingdom.)

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[Discovery Medicine; ISSN: 1539-6509; Discov Med 10(52):177-183, September 2010.]

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