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Genetic Analysis with the Immunochip Platform in Behçet Disease. Identification of Residues Associated in the HLA Class I Region and New Susceptibility Loci

2016; Public Library of Science; Volume: 11; Issue: 8 Linguagem: Inglês

10.1371/journal.pone.0161305

1932-6203

Lourdes Ortiz‐Fernández, F. David Carmona, Marco-Antonio Montes-Cano, José-Raúl Garcı́a-Lozano, Marta Conde‐Jaldón, Norberto Ortego‐Centeno, María J. Castillo, Gerard Espinosa, Jenaro Graña Gil, Juan Sánchez‐Bursón, María Rosa Juliá, Roser Solans, Ricardo Blanco, Ana-Celia Barnosi-Marín, Ricardo Gómez de la Torre, P. Fanlo, Mónica Rodríguez‐Carballeira, Luis Rodríguez‐Rodríguez, Teresa Camps, Santos Castañeda, Juan José Alegre Sancho, Javier Martı́n, María Francisca González‐Escribano,

Autoimmune and Inflammatory Disorders Research

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.