Large Scale Genetic Analysis in BehçEt Disease. Identification of Residues Associated in the HLA Class I Region and New Susceptibility Loci

Lourdes Ortiz Fernández¹, Francisco David Carmona², Marco Antonio Montes Cano³, José Raúl García Lozano³, Marta Conde Jaldón⁴, Norberto Ortego Centeno⁵, María Jesús Castillo Palma⁶, Gerard Espinosa⁷, Genaro Graña Gil⁸, Juan Sánchez Bursón Sr.⁹, María Rosa Juliá¹⁰, Roser Solans¹¹, Ricardo Blanco Alonso¹², Ana Celia Barnosi Marín¹³, Ricardo Gómez de la Torre¹⁴, Patricia Fanlo Mateo¹⁵, Mónica Rodriguez Carballeira¹⁶, Luis Rodriguez-Rodriguez¹⁷, Teresa Camps¹⁸, Santos Castañeda¹⁹, Juanjo J Alegre Sancho²⁰, Javier Martín² and María Francisca Gonzalez Escribano²¹, ¹Instituto de Parasitología y Biomedicina "López-Neyra", CSIC, Granada, Spain, ²Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, PTS-Granada, Granada, Spain, ³Departament of Immunology, Hospital Universitario Virgen del Rocío (IBiS,CSIC,US), Sevilla, Spain, ⁴Immunology, Hospital Universitario Virgen del Rocío, Sevilla, Spain, ⁵Systemic Autoimmune Diseases Unit, Hospital Universitario San Cecilio, Granada, Spain, ⁶Department of Internal Medicine, Hospital Universitario Virgen del Rocío, Sevilla, Spain, ⁷Department of Autoimmune Diseases, Hospital Clinic, Barcelona, Spain, ⁸Rheumatology Division, INIBIC-Complejo Hospitalario Universitario A Coruña (CHUAC), A Coruna, Spain, ⁹Rheumatology, Hospital de Valme., Sevilla, Spain, ¹⁰8Department of Immunology, Hospital Universitari Son Espases, Palma de Mallorca, Spain, ¹¹Autoimmune Systemic Diseases Unit, Department of Internal Medicine, Hospital Vall d'Hebron, Autonomous University of Barcelona, Spain, Barcelona, Spain, ¹²Rheumatology, Hospital Universitario Marqués de Valdecilla. IDIVAL, Santander, Spain, ¹³Department of Internal Medicine, Complejo Hospitalario Torrecárdenas, Almeria, Spain, ¹⁴Departament of Internal Medicine, Hospital Universitario Central de Asturias, Asturias, Spain, ¹⁵Department of Internal Medicine, Hospital Virgen del Camino, Pamplona, Spain, ¹⁶Departament of Internal Medicine, Hospital Universitari Mútua Terrassa, Terrasa, Spain, ¹⁷Rheumatology Service, Hospital Clínico San Carlos, Madrid, Spain, ¹⁸Departament of Internal Medicine, Hospital Regional Universitario de Málaga, Málaga, Spain, ¹⁹Rheumatology, Hospital de la Princesa, IIS-IP, Madrid, Spain, ²⁰Department of Rheumatology, Hospital Universitario Doctor Peset, Valencia, Spain, ²¹Hospital Universitario Virgen del Rocío (IBiS,CSIC,US), Sevilla, Spain

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: Behcet's syndrome and genetics

Session Information

Date: Tuesday, November 15, 2016

Title: Vasculitis - Poster III: Rarer Vasculitides

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: Behçet’s disease (BD) is a complex immune-mediated vasculitis which aetiology remains unknown although some evidences suggest that certain infectious agents and environmental factors may trigger the disease in genetically predisposed individuals. The HLA class I genes are the most important genetic factors in BD although other genes are also involved in the susceptibility to this pathology. To improve the current knowledge of its genetic background, we conducted the first large-scale genetic analysis on Spanish population, with special focus in the HLA region.

Methods: A discovery cohort comprising 278 BD cases and 1,517 unaffected controls were genotyped using the Immunochip platform which is a custom high-density array that allows the analysis of 196,524 genetic variants across 186 known susceptibility loci for autoimmune and autoinflammatory disorders. We also imputed HLA data with a previously validated imputation method to perform a more comprehensive analysis of this genomic region. The validation step was performed on an independent replication cohort composed of 130 BD cases and 600 additional controls.

Results: 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. Interestingly, these class I positions are located in the binding groove of their corresponding molecules. 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).

Conclusion: 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.

Disclosure: L. Ortiz Fernández, None; F. D. Carmona, None; M. A. Montes Cano, None; J. R. García Lozano, None; M. Conde Jaldón, None; N. Ortego Centeno, None; M. J. Castillo Palma, None; G. Espinosa, None; G. Graña Gil, None; J. Sánchez Bursón Sr., None; M. R. Juliá, None; R. Solans, None; R. Blanco Alonso, None; A. C. Barnosi Marín, None; R. Gómez de la Torre, None; P. Fanlo Mateo, None; M. Rodriguez Carballeira, None; L. Rodriguez-Rodriguez, None; T. Camps, None; S. Castañeda, None; J. J. Alegre Sancho, None; J. Martín, None; M. F. Gonzalez Escribano, None.

To cite this abstract in AMA style:

Ortiz Fernández L, Carmona FD, Montes Cano MA, García Lozano JR, Conde Jaldón M, Ortego Centeno N, Castillo Palma MJ, Espinosa G, Graña Gil G, Sánchez Bursón J Sr., Juliá MR, Solans R, Blanco Alonso R, Barnosi Marín AC, Gómez de la Torre R, Fanlo Mateo P, Rodriguez Carballeira M, Rodriguez-Rodriguez L, Camps T, Castañeda S, Alegre Sancho JJ, Martín J, Gonzalez Escribano MF. Large Scale Genetic Analysis in BehçEt Disease. Identification of Residues Associated in the HLA Class I Region and New Susceptibility Loci [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/large-scale-genetic-analysis-in-behcet-disease-identification-of-residues-associated-in-the-hla-class-i-region-and-new-susceptibility-loci/. Accessed .

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