title: Genetic Analysis with the Immunochip Platform in Behçet Disease. Identification of Residues Associated in the HLA Class I Region and New Susceptibility Loci.
abstract: Behcet's disease (BD) is an immuno-mediated vasculitis in which knowledge of its etiology and genetic basis is limited. To improve the current knowledge, a genetic analysis performed with the Immunochip platform was carried out in a population from Spain. A discovery cohort comprising 278 BD cases and 1,517 unaffected controls were genotyped using the Immunochip platform. The validation step was performed on an independent replication cohort composed of 130 BD cases and 600 additional controls. The strongest association signals were observed in the HLA class I region, being HLA-B*51 the highest peak (overall P = 6.82E-32, OR = 3.82). A step-wise conditional logistic regression with classical alleles identified HLA-B*57 and HLA-A*03 as additional independent markers. The amino acid model that best explained the association, includes the position 97 of the HLA-B molecule and the position 66 of the HLA-A. Among the non-HLA loci, the most significant in the discovery analysis were: IL23R (rs10889664: P = 3.81E-12, OR = 2.00), the JRKL/CNTN5 region (rs2848479: P = 5.00E-08, OR = 1.68) and IL12A (rs1874886: P = 6.67E-08, OR = 1.72), which were confirmed in the validation phase (JRKL/CNTN5 rs2848479: P = 3.29E-10, OR = 1.66; IL12A rs1874886: P = 1.62E-08, OR = 1.61). Our results confirm HLA-B*51 as a primary-association marker in predisposition to BD and suggest additional independent signals within the class I region, specifically in the genes HLA-A and HLA-B. Regarding the non-HLA genes, in addition to IL-23R, previously reported in our population; IL12A, described in other populations, was found to be a BD susceptibility factor also in Spaniards; finally, a new associated locus was found in the JRKL/CNTN5 region.
authors.affiliation: Department of Immunology, Hospital Universitario Virgen del Rocío (IBiS, CSIC, US), Sevilla, 41013, Spain.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Ortiz-Fernández
authors.affiliation: Instituto de Parasitología y Biomedicina "López-Neyra", CSIC, PTS Granada, Granada, 18016, Spain.
authors.forename: Francisco-David
authors.initials: FD
authors.lastname: Carmona
authors.affiliation: Department of Immunology, Hospital Universitario Virgen del Rocío (IBiS, CSIC, US), Sevilla, 41013, Spain.
authors.forename: Marco-Antonio
authors.initials: MA
authors.lastname: Montes-Cano
authors.affiliation: Department of Immunology, Hospital Universitario Virgen del Rocío (IBiS, CSIC, US), Sevilla, 41013, Spain.
authors.forename: José-Raúl
authors.initials: JR
authors.lastname: García-Lozano
authors.affiliation: Department of Immunology, Hospital Universitario Virgen del Rocío (IBiS, CSIC, US), Sevilla, 41013, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Conde-Jaldón
authors.affiliation: Department of Internal Medicine, Hospital Clínico San Cecilio, Granada, 18003, Spain.
authors.forename: Norberto
authors.initials: N
authors.lastname: Ortego-Centeno
authors.affiliation: Department of Internal Medicine, Hospital Universitario Virgen del Rocío, Sevilla, 41003, Spain.
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Castillo
authors.affiliation: Department Autoimmune Diseases, Hospital Universitari Clínic, Barcelona, 08036, Spain.
authors.forename: Gerard
authors.identifier: http://orcid.org/0000-0003-1336-0163
authors.initials: G
authors.lastname: Espinosa
authors.affiliation: Department of Rheumatology, Complejo Hospitalario Universitario A Coruña, A Coruña, 15006, Spain.
authors.forename: Genaro
authors.identifier: http://orcid.org/0000-0001-9041-8117
authors.initials: G
authors.lastname: Graña-Gil
authors.affiliation: Department of Rheumatology, Hospital Universitario de Valme, Sevilla, 41014, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Sánchez-Bursón
authors.affiliation: Department of Immunology, Hospital Universitari Son Espases, Palma de Mallorca, 07120, Spain.
authors.forename: María Rosa
authors.initials: MR
authors.lastname: Juliá
authors.affiliation: Department of Internal Medicine, Autoimmune Systemic Diseases Unit, Hospital Vall d'Hebron, Universidad Autonoma de Barcelona, Barcelona, 08035, Spain.
authors.forename: Roser
authors.initials: R
authors.lastname: Solans
authors.affiliation: Department of Rheumatology, Hospital Universitario Marqués de Valdecilla, Santander, 39008, Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Blanco
authors.affiliation: Department of Internal Medicine, Complejo Hospitalario Torrecárdenas, Almería, 04009, Spain.
authors.forename: Ana-Celia
authors.initials: AC
authors.lastname: Barnosi-Marín
authors.affiliation: Department of Internal Medicine, Hospital Universitario Central de Asturias, Asturias, 33011, Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Gómez de la Torre
authors.affiliation: Department of Internal Medicine, Hospital Virgen del Camino, Pamplona, 31008, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Fanlo
authors.affiliation: Deparment of Internal Medicine, Hospital Universitari Mútua Terrassa, Terrassa, 08221, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: Rodríguez-Carballeira
authors.affiliation: Department of Rheumatology, Hospital Clínico San Carlos, Madrid, 28040, Spain.
authors.forename: Luis
authors.identifier: http://orcid.org/0000-0002-2869-7861
authors.initials: L
authors.lastname: Rodríguez-Rodríguez
authors.affiliation: Department of Internal Medicine, Hospital Regional Universitario de Málaga, Málaga, 29010, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Camps
authors.affiliation: Department of Rheumatology, Hospital de la Princesa, IIS-Princesa, Madrid, 28006, Spain.
authors.forename: Santos
authors.initials: S
authors.lastname: Castañeda
authors.affiliation: Department of Rheumatology, Hospital Universitario Doctor Peset, Valencia, 46017, Spain.
authors.forename: Juan-Jose
authors.initials: JJ
authors.lastname: Alegre-Sancho
authors.affiliation: Instituto de Parasitología y Biomedicina "López-Neyra", CSIC, PTS Granada, Granada, 18016, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Martín
authors.affiliation: Department of Immunology, Hospital Universitario Virgen del Rocío (IBiS, CSIC, US), Sevilla, 41013, Spain.
authors.forename: María Francisca
authors.initials: MF
authors.lastname: González-Escribano
mesh_terms: D000483:Alleles; D001528:Behcet Syndrome / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D016022:Case-Control Studies; D058966:Contactins / Q000235:genetics* / Q000276:immunology; D005787:Gene Frequency; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D015791:HLA-A3 Antigen / Q000235:genetics / Q000276:immunology; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology; D059949:HLA-B51 Antigen / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007118:Immunoassay; D053765:Interleukin-12 Subunit p35 / Q000235:genetics* / Q000276:immunology; D016015:Logistic Models; D046228:Microarray Analysis; D008958:Models, Molecular; D018123:Receptors, Interleukin / Q000235:genetics* / Q000276:immunology; D013030:Spain
chemical_list: C000595918:CNTN5 protein, human; D058966:Contactins; D015791:HLA-A3 Antigen; D015235:HLA-B Antigens; D059949:HLA-B51 Antigen; C103707:HLA-B57 antigen; C508858:IL12A protein, human; C515500:IL23R protein, human; D053765:Interleukin-12 Subunit p35; D018123:Receptors, Interleukin