Background/Purpose: Psoriatic arthritis (PsA) is a complex genetic disorder with a prevalence of up to 1% in the general population. The association of PsA with psoriasis has been demonstrated in the overlap of clinical features as well as the susceptibility loci identified from genetic studies. However, there are very few specific PsA risk loci that have been found.  The strong heritability of this disease in comparison to psoriasis suggests that there are more specific PsA susceptibility loci that remain to be discovered.

Methods: Dense genotyping of known autoimmune susceptibility loci was carried out with a custom Illumina array (Immunochip) in a total of 1,960 Caucasian PsA patients and 8923 Caucasian healthy controls. Expression quantitative trait loci (eQTL) analysis of the 5q31 region was performed using publically available data. The regulatory role of the region was characterised and potential functional variants were identified with data sourced from the encyclopaedia of DNA elements (ENCODE) project.

Results: A significant association was detected to the SNP rs715285 on chromosome 5q31 (P = 3.06×10^-10, OR = 1.25). This peak of association encompasses the genes P4HA2, PDLIM4 and SLC22A4, and is independent from an association signal previously identified in the region with variants of the IL13 gene. Bioinformatic analysis of the region identified potential eQTLs that influence the expression of P4HA2, SLC22A4 and SLC22A5. Differential expression of P4HA2 was found in lymphoblastoid cell lines, while SLC22A4 and SLC22A5 were differentially expressed in monocytes indicating the potential for cell specific effects. Functional variants that could affect the regulatory role of the region were identified, including rs10065787, rs721121, rs708455 and rs27437. These SNPs lie within gene enhancers, regions of open chromatin and transcription factor binding sites, including that of BATF. This transcription factor regulates the function of interleukin 17 – a pro-inflammatory cytokine involved in the pathogenesis of PsA. 

Conclusion: We have identified a novel association on chromosome 5q31 in a region previously suggested to be specific for PsA. A number of interesting candidate genes in the region have been implicated which encode proteins involved in collagen synthesis and bone development – processes which are affected in PsA. Bioinformatics analysis supports evidence for functional SNPs in the region which now need to be validated in the laboratory. These findings can aid in further understanding of the underlying pathogenic pathways that are specific to PsA. This in turn could potentially enable the identification of a novel therapeutic target to provide more effective treatment therapies to patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/investigating-a-novel-locus-for-psoriatic-arthritis/