Antonio Julià1, Francisco Blanco2, Benjamín Fernández-Gutierrez3, Antonio González4, Juan D Cañete5, Joan Maymó6, Mercedes Alperi-López7, Alex Olivè8, Héctor Corominas9, Víctor Martínez-Taboada10, Isidoro González-Álvaro11, Antonio Fernandez-Nebro12, Alba Erra13, Simón Sánchez-Fernández14, Arnald Alonso1, María López-Lasanta1, Raül Tortosa1, Laia Codó15, Josep Lluis Gelpi15, Andrés C García-Montero16, Jaume Bertranpetit17, Devin Absher18, Richard M Myers18, Jesús Tornero19, Sara Marsal1. 1. Vall d'Hebron Hospital Research Institute, Barcelona, Spain. 2. Instituto de Investigación Biomédica de A Coruña-Hospital Universitario A Coruña, A Coruña, Spain. 3. Hospital Clínico San Carlos, Madrid, Spain. 4. Instituto de Investigación Sanitaria and Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain. 5. Hospital Clínic de Barcelona, Barcelona, Spain. 6. Hospital del Mar, Barcelona, Barcelona, Spain. 7. Hospital Universitario Central de Asturias, Oviedo, Spain. 8. Hospital Universitari Germans Trias i Pujol, Barcelona, Spain. 9. Hospital Moisès Broggi, Barcelona, Spain. 10. Hospital Universitario Marqués de Valdecilla, Santander, Spain. 11. Hospital Universitario La Princesa, IIS Princesa, Madrid, Spain. 12. Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga, and Universidad de Málaga, Málaga, Spain. 13. Hospital Sant Rafael, Barcelona, Spain. 14. Hospital General La Mancha Centro, Ciudad Real, Spain. 15. Barcelona Supercomputing Center, Barcelona, Spain. 16. National DNA Bank Carlos III and University of Salamanca, Salamanca, Spain. 17. National Genotyping Center and Pompeu Fabra University, Barcelona, Spain. 18. HudsonAlpha Institute for Biotechnology, Huntsville, Alabama. 19. Hospital Universitario de Guadalajara, Guadalajara, Spain.
Abstract
OBJECTIVE: Rheumatoid factor (RF) is a well-established diagnostic and prognostic biomarker in rheumatoid arthritis (RA). However, ∼20% of RA patients are negative for this anti-IgG antibody. To date, only variation at the HLA-DRB1 gene has been associated with the presence of RF. This study was undertaken to identify additional genetic variants associated with RF positivity. METHODS: A genome-wide association study (GWAS) for RF positivity was performed using an Illumina Quad610 genotyping platform. A total of 937 RF-positive and 323 RF-negative RA patients were genotyped for >550,000 single-nucleotide polymorphisms (SNPs). Association testing was performed using an allelic chi-square test implemented in Plink software. An independent cohort of 472 RF-positive and 190 RF-negative RA patients was used to validate the most significant findings. RESULTS: In the discovery stage, a SNP in the IRX1 locus on chromosome 5p15.3 (SNP rs1502644) showed a genome-wide significant association with RF positivity (P = 4.13 × 10(-8) , odds ratio [OR] 0.37 [95% confidence interval (95% CI) 0.26-0.53]). In the validation stage, the association of IRX1 with RF was replicated in an independent group of RA patients (P = 0.034, OR 0.58 [95% CI 0.35-0.97] and combined P = 1.14 × 10(-8) , OR 0.43 [95% CI 0.32-0.58]). CONCLUSION: To our knowledge, this is the first GWAS of RF positivity in RA. Variation at the IRX1 locus on chromosome 5p15.3 is associated with the presence of RF. Our findings indicate that IRX1 and HLA-DRB1 are the strongest genetic factors for RF production in RA.
OBJECTIVE:Rheumatoid factor (RF) is a well-established diagnostic and prognostic biomarker in rheumatoid arthritis (RA). However, ∼20% of RApatients are negative for this anti-IgG antibody. To date, only variation at the HLA-DRB1 gene has been associated with the presence of RF. This study was undertaken to identify additional genetic variants associated with RF positivity. METHODS: A genome-wide association study (GWAS) for RF positivity was performed using an Illumina Quad610 genotyping platform. A total of 937 RF-positive and 323 RF-negative RApatients were genotyped for >550,000 single-nucleotide polymorphisms (SNPs). Association testing was performed using an allelic chi-square test implemented in Plink software. An independent cohort of 472 RF-positive and 190 RF-negative RApatients was used to validate the most significant findings. RESULTS: In the discovery stage, a SNP in the IRX1 locus on chromosome 5p15.3 (SNP rs1502644) showed a genome-wide significant association with RF positivity (P = 4.13 × 10(-8) , odds ratio [OR] 0.37 [95% confidence interval (95% CI) 0.26-0.53]). In the validation stage, the association of IRX1 with RF was replicated in an independent group of RApatients (P = 0.034, OR 0.58 [95% CI 0.35-0.97] and combined P = 1.14 × 10(-8) , OR 0.43 [95% CI 0.32-0.58]). CONCLUSION: To our knowledge, this is the first GWAS of RF positivity in RA. Variation at the IRX1 locus on chromosome 5p15.3 is associated with the presence of RF. Our findings indicate that IRX1 and HLA-DRB1 are the strongest genetic factors for RF production in RA.
Authors: Philippa M Wells; Frances M K Williams; M L Matey-Hernandez; Cristina Menni; Claire J Steves Journal: J Autoimmun Date: 2019-03-05 Impact factor: 7.094
Authors: Pedro P Perrotti; Adrià Aterido; Antonio Fernández-Nebro; Juan D Cañete; Carlos Ferrándiz; Jesús Tornero; Javier P Gisbert; Eugeni Domènech; Benjamín Fernández-Gutiérrez; Fernando Gomollón; Esther García-Planella; Emilia Fernández; Raimon Sanmartí; Jordi Gratacós; Víctor Manuel Martínez-Taboada; Luís Rodríguez-Rodríguez; Núria Palau; Raül Tortosa; Mireia L Corbeto; María L Lasanta; Sara Marsal; Antonio Julià Journal: PLoS One Date: 2017-10-05 Impact factor: 3.240