title: Multiple sclerosis risk variant HLA-DRB1*1501 associates with high expression of DRB1 gene in different human populations.
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.
authors.affiliation: Instituto de Parasitología y Biomedicina "López Neyra", Consejo Superior de Investigaciones Científicas (IPBLN-CSIC), Granada, Spain. pulgoso@ipb.csic.es
authors.forename: Antonio
authors.initials: A
authors.lastname: Alcina
authors.forename: María Del Mar
authors.initials: Mdel M
authors.lastname: Abad-Grau
authors.forename: María
authors.initials: M
authors.lastname: Fedetz
authors.forename: Guillermo
authors.initials: G
authors.lastname: Izquierdo
authors.forename: Miguel
authors.initials: M
authors.lastname: Lucas
authors.forename: Oscar
authors.initials: O
authors.lastname: Fernández
authors.forename: Dorothy
authors.initials: D
authors.lastname: Ndagire
authors.forename: Antonio
authors.initials: A
authors.lastname: Catalá-Rabasa
authors.forename: Agustín
authors.initials: A
authors.lastname: Ruiz
authors.forename: Javier
authors.initials: J
authors.lastname: Gayán
authors.forename: Concepción
authors.initials: C
authors.lastname: Delgado
authors.forename: Carmen
authors.initials: C
authors.lastname: Arnal
authors.forename: Fuencisla
authors.initials: F
authors.lastname: Matesanz
mesh_terms: D000328:Adult; D000483:Alleles; D005260:Female; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population; D055106:Genome-Wide Association Study; D059866:HLA-DQ beta-Chains / Q000235:genetics; D059811:HLA-DRB1 Chains / Q000235:genetics*; D059847:HLA-DRB5 Chains / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D016015:Logistic Models; D008297:Male; D009103:Multiple Sclerosis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics; D012307:Risk Factors; D044465:White People / Q000235:genetics
chemical_list: D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D059811:HLA-DRB1 Chains; C489631:HLA-DRB1*15:01 antigen; D059847:HLA-DRB5 Chains