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Please use this identifier to cite or link to this item: http://hdl.handle.net/10481/31148

Title: Multiple Sclerosis Risk Variant HLA-DRB1*1501 Associates with High Expression of DRB1 Gene in Different Human Populations
Authors: Alcina Madueño, Antonio
Abad-Grau, María M.
Fedetz, María
Izquierdo, Guillermo
Lucas, Miguel
Fernández, Óscar
Ndagire, Dorothy
Catalá-Rabasa, Antonio
Ruiz, Agustín
Gayán, Javier
Delgado, Concepción
Arnal, Carmen
Matesanz, Fuencisla
Issue Date: 2012
Abstract: The human leukocyte antigen (HLA) DRB1*1501 has been consistently associated with multiple sclerosis (MS) in nearly all populations tested. This points to a specific antigen presentation as the pathogenic mechanism though this does not fully explain the disease association. The identification of expression quantitative trait loci (eQTL) for genes in the HLA locus poses the question of the role of gene expression in MS susceptibility. We analyzed the eQTLs in the HLA region with respect to MS-associated HLA-variants obtained from genome-wide association studies (GWAS). We found that the Tag of DRB1*1501, rs3135388 A allele, correlated with high expression of DRB1, DRB5 and DQB1 genes in a Caucasian population. In quantitative terms, the MS-risk AA genotype carriers of rs3135388 were associated with 15.7-, 5.2- and 8.3-fold higher expression of DQB1, DRB5 and DRB1, respectively, than the non-risk GG carriers. The haplotype analysis of expression-associated variants in a Spanish MS cohort revealed that high expression of DRB1 and DQB1 alone did not contribute to the disease. However, in Caucasian, Asian and African American populations, the DRB1*1501 allele was always highly expressed. In other immune related diseases such as type 1 diabetes, inflammatory bowel disease, ulcerative colitis, asthma and IgA deficiency, the best GWAS-associated HLA SNPs were also eQTLs for different HLA Class II genes. Our data suggest that the DR/DQ expression levels, together with specific structural properties of alleles, seem to be the causal effect in MS and in other immunopathologies rather than specific antigen presentation alone.
Sponsorship: This work was supported by the Ministerio de Ciencia e Innovación - Fondos Feder [PN-SAF2009-11491 to AA], Junta de Andalucía [P07-CVI-02551 to AA], and Fondo de Investigación Sanitaria [FIS PI081636, CP10/00526 to FM]. MF and DN are holders of a fellowship from Fundación Española de Esclerosis Múltple (FEDEM).
Publisher: Public Library of Science (PLOS)
Keywords: African americans
Gene expression
Genome-wide association studies
Haplotypes
Inflammatory bowel disease
Multiple sclerosis
Systemic lupus erythematosus
Variant genotypes
URI: http://hdl.handle.net/10481/31148
ISSN: 1932-6203
Rights : Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License
Citation: Alcina, A.; et al. Multiple Sclerosis Risk Variant HLA-DRB1*1501 Associates with High Expression of DRB1 Gene in Different Human Populations. Plos One, 7(1): e29819 (2012). [http://hdl.handle.net/10481/31148]
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