Objective Psoriatic arthritis (PsA) is a chronic inflammatory arthritis affecting up to 30% of patients with psoriasis (Ps). To date, most of the known risk loci for PsA are shared with Ps, and identifying disease-specific variation has proven very challenging. The objective of the present study was to identify genetic variation specific for PsA.
Methods We performed a genome-wide association study in a cohort of 835 patients with PsA and 1558 controls from Spain. Genetic association was tested at the single marker level and at the pathway level. Meta-analysis was performed with a case–control cohort of 2847 individuals from North America. To confirm the specificity of the genetic associations with PsA, we tested the associated variation using a purely cutaneous psoriasis cohort (PsC, n=614) and a rheumatoid arthritis cohort (RA, n=1191). Using network and drug-repurposing analyses, we further investigated the potential of the PsA-specific associations to guide the development of new drugs in PsA.
Results We identified a new PsA risk single-nucleotide polymorphism at B3GNT2 locus (p=1.10e-08). At the pathway level, we found 14 genetic pathways significantly associated with PsA (pFDR<0.05). From these, the glycosaminoglycan (GAG) metabolism pathway was confirmed to be disease-specific after comparing the PsA cohort with the cohorts of patients with PsC and RA. Finally, we identified candidate drug targets in the GAG metabolism pathway as well as new PsA indications for approved drugs.
Conclusion These findings provide insights into the biological mechanisms that are specific for PsA and could contribute to develop more effective therapies.
- psoriatic arthritis
- genome-wide association study
- drug repurposing
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Handling editor Josef S Smolen
Contributors AA, JDC, SM and AJ conducted the study design and data interpretation. JT, CF, JAP, JG, RQ, CM, JCT-A, JJP-V, AFN, SM-F, CMG, DR, PZ, AE, JR, SC, ER, GS, CD-T, RB, AWD, JAM, PV, SAS-F, HC, JR, PdlC, EdF, EmF, LP, ED, JLS-C, JLL-E, DM, FV, EH, FB, BF-G, AG, CP-G, MA-L, AOM, VM-T, IG-A, RS, CTR, ML-C, AP, ML-L, RT, NP and SM were involved in sample collection. AA, AJ, SB-G, JMM, DT, LC, HLG, DA and RM performed genetic analyses. AA and AJ performed functional and drug-repurposing analyses. AA, JDC, SM and AJ wrote the manuscript. All authors revised the manuscript and gave final approval for its submission.
Funding This study was funded by the Spanish Ministry of Economy and Competitiveness (grant numbers: PSE-010000-2006-6 and IPT-010000-2010-36, cofunded by the European Regional Development Fund). This work was also sponsored by the 'Agència de Gestió d’Ajuts Universitaris i de Recerca' (AGAUR, FI-DGR2016, grant number: 00587), which is supported by the 'Secretaria d’Universitats i Recerca' (Economy and Knowledge Department, Generalitat de Catalunya) and cofunded by the European Social Fund. The obtention of the GWAS data from the PsA case-control cohort from North American population was supported by grants from the NIH, the Canadian Institutes of Health Research, the Krembil Foundation, the Babcock Memorial Trust, the Barbara and Neal Henschel Charitable Foundation and the Ann Arbor Veterans Affairs Hospital. The study sponsors had no role in the collection, analysis or interpretation of the data
Competing interests None declared.
Patient consent Obtained.
Ethics approval The study was approved by Hospital Universitari Vall d'Hebron Clinical Research Ethics Committee. This study was conducted according to the principles of the Declaration of Helsinki. Protocols were reviewed and approved by the local institutional review board of each participating centre.
Provenance and peer review Not commissioned; externally peer reviewed.