Multiple Sclerosis Risk Variant HLA-DRB1*1501 Associates with High Expression of DRB1 Gene in Different Human Populations

• DOI: 10.1371/journal.pone.0029819
• Publication Date: 2012-01-13T21:52:56Z
• Authors: Antonio Alcina; María del Mar Aba...; María Fedetz; Guillermo Izquierdo; Miguel Lucas; Óscar Fernández; Dorothy Ndagire; Antonio Catalá-Ra...; Agustín Ruiz; Javier Gayán; Concepción Delgado; Carmen Arnal; Fuencisla Matesanz
• Keywords: Adult; Male; 0301 basic medicine; Multiple Sclerosis; Science; Quantitative Trait Loci; Genome-wide association studies; Polymorphism, Single Nucleotide; Inflammatory bowel disease; Linkage Disequilibrium; Multiple sclerosis; 03 medical and health sciences; Systemic lupus erythematosus; Risk Factors; HLA-DQ beta-Chains; Humans; Genetic Predisposition to Disease; Variant genotypes; Alleles; Genetic Association Studies; Q; R; 3. Good health; HLA-DRB5 Chains; African americans; Genetics, Population; Logistic Models; Gene Expression Regulation; Haplotypes; Medicine; Female; Gene expression; Research Article; Genome-Wide Association Study; HLA-DRB1 Chains

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.