Multiple Sclerosis Risk Variant HLA-DRB1*1501 Associates with High Expression of DRB1 Gene in Different Human Populations Alcina Madueño, Antonio Abad Grau, María Del Mar Fedetz, María Izquierdo, Guillermo Lucas, Miguel Fernández, Óscar Ndagire, Dorothy Catalá-Rabasa, Antonio Ruiz, Agustín Gayán, Javier Delgado, Concepción Arnal, Carmen Matesanz, Fuencisla African americans Gene expression Genome-wide association studies Haplotypes Inflammatory bowel disease Multiple sclerosis Systemic lupus erythematosus Variant genotypes 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. 2014-03-28T11:30:32Z 2014-03-28T11:30:32Z 2012 info:eu-repo/semantics/article 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] 1932-6203 doi: 10.1371/journal.pone.0029819 http://hdl.handle.net/10481/31148 eng http://creativecommons.org/licenses/by-nc-nd/3.0/ info:eu-repo/semantics/openAccess Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License Public Library of Science (PLOS)