Antonio Julià1, Isidoro González2, Antonio Fernández-Nebro3, Francisco Blanco4, Luis Rodriguez5, Antonio González6, Juan D Cañete7, Joan Maymó8, Mercedes Alperi-López9, Alejandro Olivé10, Héctor Corominas11, Víctor Martínez-Taboada12, Alba Erra13, Simón Sánchez-Fernández14, Arnald Alonso1, Maria Lopez-Lasanta1, Raül Tortosa1, Laia Codó15, Josep Lluis Gelpi15, Andres C García-Montero16, Jaume Bertranpetit17, Devin Absher18, S Louis Bridges19, Richard M Myers20, Jesus Tornero21, Sara Marsal22. 1. Vall d'Hebron Hospital Research Institute, Rheumatology Research Group, Barcelona. 2. Rheumatology Department, Hospital Universitario La Princesa. IIS La Princesa, Madrid. 3. UGC Reumatología, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga. 4. Rheumatology Department, INIBIC-Hospital Universitario A Coruña, A Coruña. 5. Rheumatology Department, Hospital Clínico San Carlos, Madrid, Madrid. 6. Instituto de Investigación Sanitaria-Hospital Clínico Universitario de Santiago, Rheumatology Unit, Santiago de Compostela. 7. Rheumatology Department, Hospital Clínic de Barcelona, Barcelona. 8. Rheumatology Department, Hospital del Mar, Barcelona, Barcelona. 9. Rheumatology Department, Hospital Universitario Central de Asturias, Oviedo. 10. Rheumatology Department, Hospital Universitari Germans Trias i Pujol. 11. Rheumatology Department, Hospital Moisès Broggi, Barcelona. 12. Rheumatology Department, Hospital Universitario Marqués de Valdecilla, Cantabria. 13. Rheumatology Department, Hospital Sant Rafael, Barcelona. 14. Rheumatology Department, Hospital General La Mancha Centro, Ciudad Real. 15. Life Sciences, Barcelona Supercomputing Centre Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona. 16. Banco Nacional de ADN Carlos III, University of Salamanca, Salamanca. 17. Nacional Genotyping Centre (CeGen), Universitat Pompeu Fabra, Barcelona, Spain. 18. Hudson Alpha Institute for Biotechnology, Abshers lab, Huntsville. 19. Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham. 20. Hudson Alpha Institute for Biotechnology, Myers lab, Huntsville, AL, USA. 21. Rheumatology Department, Hospital Universitario De Guadalajara, Guadalajara, Spain. 22. Vall d'Hebron Hospital Research Institute, Rheumatology Research Group, Barcelona sara.marsal@vhir.org.
Abstract
OBJECTIVE: RA patients with serum ACPA have a strong and specific genetic background. The objective of the study was to identify new susceptibility genes for ACPA-positive RA using a genome-wide association approach. METHODS: A total of 924 ACPA-positive RA patients with joint damage in hands and/or feet, and 1524 healthy controls were genotyped in 582 591 single-nucleotide polymorphisms (SNPs) in the discovery phase. In the validation phase, the most significant SNPs in the genome-wide association study representing new candidate loci for RA were tested in an independent cohort of 863 ACPA-positive patients with joint damage and 1152 healthy controls. All individuals from the discovery and validation cohorts were Caucasian and of Southern European ancestry. RESULTS: In the discovery phase, 60 loci not previously associated with RA risk showed evidence for association at P < 5×10(-4) and were tested for replication in the validation cohort. A total of 12 loci were replicated at the nominal level (P < 0.05, same direction of effect as in the discovery phase). When combining the discovery and validation cohorts, an intronic SNP in the Solute Carrier family 8 gene (SLC8A3) was found to be associated with ACPA-positive RA at a genome-wide level of significance RA [odds ratio (95% CI): 1.42 (1.25, 1.6), Pcombined = 3.19×10(-8)]. CONCLUSIONS: SLC8A3 was identified as a new risk locus for ACPA-positive RA. This study demonstrates the advantage of analysing relevant subsets of RA patients to identify new genetic risk variants.
OBJECTIVE:RApatients with serum ACPA have a strong and specific genetic background. The objective of the study was to identify new susceptibility genes for ACPA-positive RA using a genome-wide association approach. METHODS: A total of 924 ACPA-positive RApatients with joint damage in hands and/or feet, and 1524 healthy controls were genotyped in 582 591 single-nucleotide polymorphisms (SNPs) in the discovery phase. In the validation phase, the most significant SNPs in the genome-wide association study representing new candidate loci for RA were tested in an independent cohort of 863 ACPA-positive patients with joint damage and 1152 healthy controls. All individuals from the discovery and validation cohorts were Caucasian and of Southern European ancestry. RESULTS: In the discovery phase, 60 loci not previously associated with RA risk showed evidence for association at P < 5×10(-4) and were tested for replication in the validation cohort. A total of 12 loci were replicated at the nominal level (P < 0.05, same direction of effect as in the discovery phase). When combining the discovery and validation cohorts, an intronic SNP in the Solute Carrier family 8 gene (SLC8A3) was found to be associated with ACPA-positive RA at a genome-wide level of significance RA [odds ratio (95% CI): 1.42 (1.25, 1.6), Pcombined = 3.19×10(-8)]. CONCLUSIONS:SLC8A3 was identified as a new risk locus for ACPA-positive RA. This study demonstrates the advantage of analysing relevant subsets of RApatients to identify new genetic risk variants.
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