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Genetic variation at the glycosaminoglycan metabolism pathway contributes to the risk of psoriatic arthritis but not psoriasis
  1. Adrià Aterido1,2,
  2. Juan D Cañete3,
  3. Jesús Tornero4,
  4. Carlos Ferrándiz5,
  5. José Antonio Pinto6,
  6. Jordi Gratacós7,
  7. Rubén Queiró8,
  8. Carlos Montilla9,
  9. Juan Carlos Torre-Alonso10,
  10. José J Pérez-Venegas11,
  11. Antonio Fernández Nebro12,
  12. Santiago Muñoz-Fernández13,
  13. Carlos M González14,
  14. Daniel Roig15,
  15. Pedro Zarco16,
  16. Alba Erra17,
  17. Jesús Rodríguez18,
  18. Santos Castañeda19,
  19. Esteban Rubio20,
  20. Georgina Salvador21,
  21. Cesar Díaz-Torné22,
  22. Ricardo Blanco23,
  23. Alfredo Willisch Domínguez24,
  24. José Antonio Mosquera25,
  25. Paloma Vela26,
  26. Simon Angel Sánchez-Fernández27,
  27. Héctor Corominas22,28,
  28. Julio Ramírez3,
  29. Pablo de la Cueva29,
  30. Eduardo Fonseca30,
  31. Emilia Fernández31,
  32. Lluis Puig32,
  33. Esteban Dauden33,
  34. José Luís Sánchez-Carazo34,
  35. José Luís López-Estebaranz35,
  36. David Moreno36,
  37. Francisco Vanaclocha37,
  38. Enrique Herrera38,
  39. Francisco Blanco39,
  40. Benjamín Fernández‐Gutiérrez40,
  41. Antonio González41,
  42. Carolina Pérez-García42,
  43. Mercedes Alperi‐López8,
  44. Alejandro Olivé Marques43,
  45. Víctor Martínez‐Taboada23,
  46. Isidoro González-Álvaro19,
  47. Raimon Sanmartí3,
  48. Carlos Tomás Roura44,
  49. Andrés C García-Montero45,
  50. Sílvia Bonàs-Guarch46,
  51. Josep Maria Mercader46,
  52. David Torrents46,47,
  53. Laia Codó48,
  54. Josep Lluís Gelpí48,
  55. Mireia López-Corbeto1,
  56. Andrea Pluma1,
  57. Maria López-Lasanta1,
  58. Raül Tortosa1,
  59. Nuria Palau1,
  60. Devin Absher49,
  61. Richard Myers49,
  62. Sara Marsal1,
  63. Antonio Julià1
  1. 1 Rheumatology Research Group, Vall d'Hebron Research Institute, Barcelona, Spain
  2. 2 Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
  3. 3 Rheumatology Department, Hospital Clínic de Barcelona and IDIBAPS, Barcelona, Spain
  4. 4 Rheumatology Department, Hospital Universitario Guadalajara, Guadalajara, Spain
  5. 5 Dermatology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
  6. 6 Rheumatology Department, Complejo Hospitalario Juan Canalejo, A Coruña, Spain
  7. 7 Rheumatology Department, Hospital Parc Taulí, Sabadell, Spain
  8. 8 Rheumatology Department, Hospital Universitario Central de Asturias, Oviedo, Spain
  9. 9 Rheumatology Department, Hospital Virgen de la Vega, Salamanca, Spain
  10. 10 Rheumatology Department, Hospital Monte Naranco, Oviedo, Spain
  11. 11 Rheumatology Department, Hospital de Jerez de la Frontera, Cádiz, Spain
  12. 12 Rheumatology Department, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga, Málaga, Spain
  13. 13 Rheumatology Department, Hospital Universitario Infanta Sofía, Universidad Europea, Madrid, Spain
  14. 14 Rheumatology Department, Hospital Universitario Gregorio Marañón, Madrid, Spain
  15. 15 Rheumatology Department, Hospital Moisès Broggi, Barcelona, Spain
  16. 16 Rheumatology Department, Hospital Universitario Fundación Alcorcón, Madrid, Spain
  17. 17 Rheumatology Department, Hospital Sant Rafael, Barcelona, Spain
  18. 18 Rheumatology Department, Hospital Universitari de Bellvitge, Barcelona, Spain
  19. 19 Rheumatology Department, Hospital Universitario La Princesa, IIS La Princesa, Madrid, Spain
  20. 20 Rheumatology Department, Centro de Salud Virgen de los Reyes, Sevilla, Spain
  21. 21 Rheumatology Department, Hospital Universitario Mútua de Terrassa, Terrassa, Spain
  22. 22 Rheumatology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
  23. 23 Rheumatology Department, Hospital Universitario Marqués de Valdecilla, Santander, Spain
  24. 24 Rheumatology Department, Complexo Hospitalario de Ourense, Ourense, Spain
  25. 25 Rheumatology Department, Complejo Hospitalario Hospital Provincial de Pontevedra, Pontevedra, Spain
  26. 26 Rheumatology Department, Hospital General Universitario de Alicante, Alicante, Spain
  27. 27 Rheumatology Department, Hospital La Mancha Centro, Alcázar de San Juan, Spain
  28. 28 Rheumatology Department, Hospital Dos de Maig, Barcelona, Spain
  29. 29 Dermatology Department, Hospital Universitario Infanta Leonor, Madrid, Spain
  30. 30 Dermatology Department, Complejo Hospitalario Universitario de A Coruña, A Coruña, Spain
  31. 31 Dermatology Department, Hospital Universitario de Salamanca, Salamanca, Spain
  32. 32 Dermatology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
  33. 33 Dermatology Department, Hospital Universitario La Princesa, IIS La Princesa, Madrid, Spain
  34. 34 Dermatology Department, Hospital General Universitario de Valencia, Valencia, Spain
  35. 35 Dermatology Department, Hospital Universitario Fundación Alcorcón, Madrid, Spain
  36. 36 Dermatology Department, Hospital Virgen Macarena, Sevilla, Spain
  37. 37 Dermatology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
  38. 38 Dermatology Department, Hospital Universitario Virgen de la Victoria, Málaga, Spain
  39. 39 Rheumatology Department, INIBIC-Hospital Universitario A Coruña, A Coruña, Spain
  40. 40 Rheumatology Department, Hospital Clínico San Carlos, IDISSC, Madrid, Spain
  41. 41 Instituto de Investigación Sanitaria Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain
  42. 42 Rheumatology Department, Parc de Salut Mar Barcelona, Barcelona, Spain
  43. 43 Rheumatology Department, Hospital Universitari Germans Trias i Pujol, Barcelona, Spain
  44. 44 Rheumatology Department, Hospital Comarcal d’Amposta, Tarragona, Spain
  45. 45 Banco Nacional de ADN Carlos III, University of Salamanca, Salamanca, Spain
  46. 46 Barcelona Supercomputing Centre (BSC), Joint BSC-CRG-IRB Research Program in Computational Biology, Barcelona, Spain
  47. 47 Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
  48. 48 Life Sciences Department, Barcelona Supercomputing Centre, Barcelona, Spain
  49. 49 HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA
  1. Correspondence to Antonio Julià, Rheumatology Research Group, Vall d’Hebron Research Institute, Barcelona 08035, Spain; toni.julia{at}vhir.org; Sara Marsal, Rheumatology Research Group, Vall d’Hebron Research Institute, Barcelona 08035, Spain; sara.marsal{at}vhir.org; Juan D Cañete, Rheumatology Department, Hospital Clínic de Barcelona and IDIBAPS, Barcelona 08036, Spain; jcanete{at}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.

  • psoriatic arthritis
  • genetics
  • genome-wide association study
  • glycosaminoglycan
  • drug repurposing
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Footnotes

  • 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.

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