Genome-Wide Pathway Analysis Reveals That VEGF Genetic Pathway Is Associated with Oral Ulcers in Systemic Lupus Erythematosus

Antonio Julià¹, Patricia Carreira², Ricardo Blanco³, Victor Martinez Taboada⁴, Luis Carreño⁵, Jose Javier Perez Venegas⁶, Alejandro Olivé⁷, Jose Luis Andreu⁸, Maria Ángeles Aguirre Zamorano⁹, Paloma Vela¹⁰, Joan Miquel Nolla¹¹, José Luis Marenco de la Fuente¹², Antonio Zea¹³, JM Pego-Reigosa¹⁴, Mercedes Freire¹⁵, Elvira Diez Alvarez¹⁶, Adrìa Aterido¹, Arnald Alonso¹, Maria López-Lasanta¹⁷, Mireia López¹⁸, Raül Tortosa¹, Sara Marsal¹⁹ and Antonio Fernandez-Nebro²⁰, ¹Rheumatology Research Group, Vall d'Hebron Hospital Research Institute, Barcelona, Spain, ²Department of Rheumatology, Hospital Universitario 12 de Octubre, Madrid, Spain, ³Rheumatology, Hospital Universitario Marqués de Valdecilla. IDIVAL, Santander, Spain, ⁴Hospital Marqués de Valdecilla., Santander, Spain, ⁵Rheumatology, HGU Gregorio Marañón, Madrid, Spain, ⁶Rheumatology, Hospital de Jerez de la Frontera, Jerez de la Frontera, Spain, ⁷Rheumatology, Hospital Universitario Germans Trias i Pujol, Barcelona, Spain, ⁸Rheumatology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain, ⁹Rheumatology service, IMIBIC/Reina Sofia Hospital/University of Cordoba, Cordoba, Spain, ¹⁰Dpt. Rheumatology, Hospital General Universitario Alicante, Alicante, Spain, ¹¹Rheumatology, Bellvitge University Hospital, Barcelona, Spain, ¹²Rheumatology, Hospital de Valme, Seville, Spain, ¹³Hospital Ramón y Cajal. Madrid, Madrid, Spain, ¹⁴Rheumatology Section, Hospital de Meixoeiro, Pontevedra, Spain, Vigo, Spain, ¹⁵Servicio de Reumatología. Instituto de Investigación Biomédica de A Coruña (INIBIC). Complexo HospitalarioUniversitario de A Coruña (CHUAC), Sergas. Universidade da Coruña (UDC), A Coruña, Spain, ¹⁶Rheumatology, Hospital de León, León, Spain, ¹⁷Vall d'Hebron Hospital Research Institute, Barcelona, Spain, ¹⁸Servicio de Reumatología, Hospital Universitario Vall d´Hebron, Barcelona, Spain, ¹⁹Rheumatology Research Unit, Vall d'Hebron Hospital, Barcelona, Spain, ²⁰Rheumatology, Hospital Universitario Carlos Haya, Malaga, Spain

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: Genetic architecture, GWAS, phenotypes, systemic lupus erythematosus (SLE) and ulcers

Session Information

Date: Tuesday, November 15, 2016

Title: Systemic Lupus Erythematosus – Human Etiology and Pathogenesis - Poster II

Session Type: ACR Poster Session C

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

Background/Purpose: Systemic lupus erythematosus (SLE) is a genetically complex rheumatic disease with heterogeneous clinical manifestations. Recent studies have suggested the existence of a genetic basis for the diverse SLE clinical phenotypes. Also, there is increasing evidence indicating that a substantial part of the genetic variation associated with complex diseases could be explained by small-effect genes from common genetic pathways. The objective of the present study was to identify new genetic variation associated with SLE phenotypes using a genome-wide association study at the pathway level.

Methods: A total of 598,258 SNPs were genotyped in a discovery cohort of n=482 SLE patients of southern European ancestry using the Illumina platform Quad610. After quality control analysis, including ancestry estimation using principal-component analysis, genome-wide pathway analysis was performed. A total of 14 clinically relevant SLE phenotypes were tested for association in n>700 reference genetic pathways. Significantly associated pathways (corrected P-value < 0.05) were subsequently tested for validation in an independent cohort of n=425 SLE patients from the same ancestry. Both discovery and validation cohort patients were Caucasian European and from Spanish origin, and were recruited by n=15 rheumatology departments from Spanish university hospitals. The validated genetic pathways were functionally characterized using in silico analysis on cell types of relevance in SLE pathogenesis.

Results: In the discovery stage, two genetic pathways were significantly associated with the presence of oral ulcers and antinuclear antibodies in SLE (P_FDR<0.05). In the replication stage, we validated the association between oral ulcers and the vascular endothelial growth factor (VEGF) genetic pathway (P=1.3e-2). Analyzing the transcriptional effect of the topical immunotherapies used for the treatment of oral ulcers in SLE, we found a significant differential expression of VEGF pathway genes (P<0.05).

Conclusion: In this work we have performed the first genome-wide association study for clinically relevant SLE phenotype using a pathway-based approach. With this new approach, we have identified and validated the association of VEGF genetic pathway with oral ulcers in SLE. These findings represent an important step towards the characterization of the genetic basis of phenotype heterogeneity in SLE.

Disclosure: A. Julià, None; P. Carreira, None; R. Blanco, None; V. Martinez Taboada, None; L. Carreño, None; J. J. Perez Venegas, None; A. Olivé, None; J. L. Andreu, None; M. Á. Aguirre Zamorano, None; P. Vela, None; J. M. Nolla, None; J. L. Marenco de la Fuente, None; A. Zea, None; J. Pego-Reigosa, None; M. Freire, None; E. Diez Alvarez, None; A. Aterido, None; A. Alonso, None; M. López-Lasanta, None; M. López, None; R. Tortosa, None; S. Marsal, None; A. Fernandez-Nebro, None.

To cite this abstract in AMA style:

Julià A, Carreira P, Blanco R, Martinez Taboada V, Carreño L, Perez Venegas JJ, Olivé A, Andreu JL, Aguirre Zamorano MÁ, Vela P, Nolla JM, Marenco de la Fuente JL, Zea A, Pego-Reigosa J, Freire M, Diez Alvarez E, Aterido A, Alonso A, López-Lasanta M, López M, Tortosa R, Marsal S, Fernandez-Nebro A. Genome-Wide Pathway Analysis Reveals That VEGF Genetic Pathway Is Associated with Oral Ulcers in Systemic Lupus Erythematosus [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/genome-wide-pathway-analysis-reveals-that-vegf-genetic-pathway-is-associated-with-oral-ulcers-in-systemic-lupus-erythematosus/. Accessed .

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