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.
Highlights
Multiple sclerosis (MS) is a common inflammatory disorder of the central nervous system characterized by demyelination with axonal and neuronal degeneration [1]
At the 0.0001 permutation threshold (PT), we discovered 21 CEU, 6 CHB, 33 GIH, 40 LWK, 7 Mexican ancestry in Los Angeles (MEX), 7 JPT and 14 YRI SNPs that were significantly cis-associated with DRB1 expression
Our results indicate that the SNPs that have been extensively determined to be the main multiple sclerosis (MS) association signals, in the human leukocyte antigen (HLA) Class II region, correlate with higher expression levels of DRB5, DRB1 and DQB1 genes
Summary
Multiple sclerosis (MS) is a common inflammatory disorder of the central nervous system characterized by demyelination with axonal and neuronal degeneration [1]. The remarkably strong linkage disequilibrium (LD) across the HLA region has hampered the unequivocal ascertainment of the primary disease-risk HLA gene. This Class II association has been mapped to the DRB5*0101DRB1*1501-DQA1*0102- DQB1*0602 haplotype in the North European population [5]. The mechanism for the strong LD in these HLA haplotypes has been shown to be consistent with a functional epistatic interaction between DRB1*1501 and DRB5*0101 alleles. This functional epistasis is associated with a milder form of experimental autoimmune encephalomyelitis (EAE) in mice [6]
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