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Ann Rheum Dis. 2018 Dec 14. pii: annrheumdis-2018-214158. doi: 10.1136/annrheumdis-2018-214158. [Epub ahead of print]

Genetic variation at the glycosaminoglycan metabolism pathway contributes to the risk of psoriatic arthritis but not psoriasis.

Author information

1
Rheumatology Research Group, Vall d'Hebron Research Institute, Barcelona, Spain.
2
Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
3
Rheumatology Department, Hospital Clínic de Barcelona and IDIBAPS, Barcelona, Spain toni.julia@vhir.org sara.marsal@vhir.org jcanete@clinic.ub.es.
4
Rheumatology Department, Hospital Universitario Guadalajara, Guadalajara, Spain.
5
Dermatology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.
6
Rheumatology Department, Complejo Hospitalario Juan Canalejo, A Coruña, Spain.
7
Rheumatology Department, Hospital Parc Taulí, Sabadell, Spain.
8
Rheumatology Department, Hospital Universitario Central de Asturias, Oviedo, Spain.
9
Rheumatology Department, Hospital Virgen de la Vega, Salamanca, Spain.
10
Rheumatology Department, Hospital Monte Naranco, Oviedo, Spain.
11
Rheumatology Department, Hospital de Jerez de la Frontera, Cádiz, Spain.
12
Rheumatology Department, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga, Málaga, Spain.
13
Rheumatology Department, Hospital Universitario Infanta Sofía, Universidad Europea, Madrid, Spain.
14
Rheumatology Department, Hospital Universitario Gregorio Marañón, Madrid, Spain.
15
Rheumatology Department, Hospital Moisès Broggi, Barcelona, Spain.
16
Rheumatology Department, Hospital Universitario Fundación Alcorcón, Madrid, Spain.
17
Rheumatology Department, Hospital Sant Rafael, Barcelona, Spain.
18
Rheumatology Department, Hospital Universitari de Bellvitge, Barcelona, Spain.
19
Rheumatology Department, Hospital Universitario La Princesa, IIS La Princesa, Madrid, Spain.
20
Rheumatology Department, Centro de Salud Virgen de los Reyes, Sevilla, Spain.
21
Rheumatology Department, Hospital Universitario Mútua de Terrassa, Terrassa, Spain.
22
Rheumatology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
23
Rheumatology Department, Hospital Universitario Marqués de Valdecilla, Santander, Spain.
24
Rheumatology Department, Complexo Hospitalario de Ourense, Ourense, Spain.
25
Rheumatology Department, Complejo Hospitalario Hospital Provincial de Pontevedra, Pontevedra, Spain.
26
Rheumatology Department, Hospital General Universitario de Alicante, Alicante, Spain.
27
Rheumatology Department, Hospital La Mancha Centro, Alcázar de San Juan, Spain.
28
Rheumatology Department, Hospital Dos de Maig, Barcelona, Spain.
29
Rheumatology Department, Hospital Clínic de Barcelona and IDIBAPS, Barcelona, Spain.
30
Dermatology Department, Hospital Universitario Infanta Leonor, Madrid, Spain.
31
Dermatology Department, Complejo Hospitalario Universitario de A Coruña, A Coruña, Spain.
32
Dermatology Department, Hospital Universitario de Salamanca, Salamanca, Spain.
33
Dermatology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
34
Dermatology Department, Hospital Universitario La Princesa, IIS La Princesa, Madrid, Spain.
35
Dermatology Department, Hospital General Universitario de Valencia, Valencia, Spain.
36
Dermatology Department, Hospital Universitario Fundación Alcorcón, Madrid, Spain.
37
Dermatology Department, Hospital Virgen Macarena, Sevilla, Spain.
38
Dermatology Department, Hospital Universitario 12 de Octubre, Madrid, Spain.
39
Dermatology Department, Hospital Universitario Virgen de la Victoria, Málaga, Spain.
40
Rheumatology Department, INIBIC-Hospital Universitario A Coruña, A Coruña, Spain.
41
Rheumatology Department, Hospital Clínico San Carlos, IDISSC, Madrid, Spain.
42
Instituto de Investigación Sanitaria Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain.
43
Rheumatology Department, Parc de Salut Mar Barcelona, Barcelona, Spain.
44
Rheumatology Department, Hospital Universitari Germans Trias i Pujol, Barcelona, Spain.
45
Rheumatology Department, Hospital Comarcal d'Amposta, Tarragona, Spain.
46
Banco Nacional de ADN Carlos III, University of Salamanca, Salamanca, Spain.
47
Barcelona Supercomputing Centre (BSC), Joint BSC-CRG-IRB Research Program in Computational Biology, Barcelona, Spain.
48
Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
49
Life Sciences Department, Barcelona Supercomputing Centre, Barcelona, Spain.
50
HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA.
51
Rheumatology Research Group, Vall d'Hebron Research Institute, Barcelona, Spain toni.julia@vhir.org sara.marsal@vhir.org jcanete@clinic.ub.es.

Abstract

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.

KEYWORDS:

drug repurposing; genetics; genome-wide association study; glycosaminoglycan; psoriatic arthritis

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