title: A genome-wide association study identifies SLC8A3 as a susceptibility locus for ACPA-positive rheumatoid arthritis.
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.
authors.affiliation: Vall d'Hebron Hospital Research Institute, Rheumatology Research Group, Barcelona.
authors.forename: Antonio
authors.initials: A
authors.lastname: Julià
authors.affiliation: Rheumatology Department, Hospital Universitario La Princesa. IIS La Princesa, Madrid.
authors.forename: Isidoro
authors.initials: I
authors.lastname: González
authors.affiliation: UGC Reumatología, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga.
authors.forename: Antonio
authors.initials: A
authors.lastname: Fernández-Nebro
authors.affiliation: Rheumatology Department, INIBIC-Hospital Universitario A Coruña, A Coruña.
authors.forename: Francisco
authors.initials: F
authors.lastname: Blanco
authors.affiliation: Rheumatology Department, Hospital Clínico San Carlos, Madrid, Madrid.
authors.forename: Luis
authors.initials: L
authors.lastname: Rodriguez
authors.affiliation: Instituto de Investigación Sanitaria-Hospital Clínico Universitario de Santiago, Rheumatology Unit, Santiago de Compostela.
authors.forename: Antonio
authors.initials: A
authors.lastname: González
authors.affiliation: Rheumatology Department, Hospital Clínic de Barcelona, Barcelona.
authors.forename: Juan D
authors.initials: JD
authors.lastname: Cañete
authors.affiliation: Rheumatology Department, Hospital del Mar, Barcelona, Barcelona.
authors.forename: Joan
authors.initials: J
authors.lastname: Maymó
authors.affiliation: Rheumatology Department, Hospital Universitario Central de Asturias, Oviedo.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Alperi-López
authors.affiliation: Rheumatology Department, Hospital Universitari Germans Trias i Pujol.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Olivé
authors.affiliation: Rheumatology Department, Hospital Moisès Broggi, Barcelona.
authors.forename: Héctor
authors.initials: H
authors.lastname: Corominas
authors.affiliation: Rheumatology Department, Hospital Universitario Marqués de Valdecilla, Cantabria.
authors.forename: Víctor
authors.initials: V
authors.lastname: Martínez-Taboada
authors.affiliation: Rheumatology Department, Hospital Sant Rafael, Barcelona.
authors.forename: Alba
authors.initials: A
authors.lastname: Erra
authors.affiliation: Rheumatology Department, Hospital General La Mancha Centro, Ciudad Real.
authors.forename: Simón
authors.initials: S
authors.lastname: Sánchez-Fernández
authors.affiliation: Vall d'Hebron Hospital Research Institute, Rheumatology Research Group, Barcelona.
authors.forename: Arnald
authors.initials: A
authors.lastname: Alonso
authors.affiliation: Vall d'Hebron Hospital Research Institute, Rheumatology Research Group, Barcelona.
authors.forename: Maria
authors.initials: M
authors.lastname: Lopez-Lasanta
authors.affiliation: Vall d'Hebron Hospital Research Institute, Rheumatology Research Group, Barcelona.
authors.forename: Raül
authors.initials: R
authors.lastname: Tortosa
authors.affiliation: Life Sciences, Barcelona Supercomputing Centre Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona.
authors.forename: Laia
authors.initials: L
authors.lastname: Codó
authors.affiliation: Life Sciences, Barcelona Supercomputing Centre Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona.
authors.forename: Josep Lluis
authors.initials: JL
authors.lastname: Gelpi
authors.affiliation: Banco Nacional de ADN Carlos III, University of Salamanca, Salamanca.
authors.forename: Andres C
authors.initials: AC
authors.lastname: García-Montero
authors.affiliation: Nacional Genotyping Centre (CeGen), Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Jaume
authors.initials: J
authors.lastname: Bertranpetit
authors.affiliation: Hudson Alpha Institute for Biotechnology, Abshers lab, Huntsville.
authors.forename: Devin
authors.initials: D
authors.lastname: Absher
authors.affiliation: Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham.
authors.forename: S Louis
authors.initials: SL
authors.lastname: Bridges
authors.affiliation: Hudson Alpha Institute for Biotechnology, Myers lab, Huntsville, AL, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Myers
authors.affiliation: Rheumatology Department, Hospital Universitario De Guadalajara, Guadalajara, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Tornero
authors.affiliation: Vall d'Hebron Hospital Research Institute, Rheumatology Research Group, Barcelona sara.marsal@vhir.org.
authors.forename: Sara
authors.initials: S
authors.lastname: Marsal
mesh_terms: D000328:Adult; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000235:genetics* / Q000276:immunology; D001323:Autoantibodies / Q000097:blood* / Q000276:immunology; D016022:Case-Control Studies; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D019831:Sodium-Calcium Exchanger / Q000097:blood / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D001323:Autoantibodies; D010456:Peptides, Cyclic; C101832:SLC38A3 protein, human; D019831:Sodium-Calcium Exchanger; C487763:cyclic citrullinated peptide
keywords: anti-citrullinated protein antibodies; genetic risk; genome-wide association study; joint erosions; rheumatoid arthritis