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.

Figure 1. Association of HapMap III SNPs from the HLA region with expression levels of the HLA DRB1 gene.

The figure shows the strength of association between SNPs and gene expression levels, plotted as −log P-values. Coordinates are in NCBI Build 36. Shown are the CEU, YRI, LWK, MEX, GHI, CHB and JPT HapMap populations .

Figure 2. Location of SNPs associated with DRB1 gene expression in the different human populations.

Image from the UCSC browser showing the HLA Class II region. Vertical bars indicate the location of eQTLs (0.0001 permutation threshold) from all populations. Vertical red bars indicate the common eQTLs among all populations studied.

Figure 3. Association of the MS-risk variant rs9271100 with DRB1 gene expression levels.

In all plots, expression levels are represented for the three genotype groups. (A) Box plots of expression data from normalized results of ILMN_1715169 (DRB1) probe generated by Illumina Human-6 v2 Expression BeadChip (EMBL-EBI database (http://www.ebi.ac.uk/arrayexpress/) ID projects E-MTAB-198). (B) Box plot of expression data from the NM_002124 (DRB1) transcript of 41 CEU individuals obtained from RNA-Seq . P-values are calculated by Kruskal Wallis Test.

Figure 4. Association of risk-variants for different immune-related diseases with expression levels of HLA genes.

Expression data are from CEU individuals obtained from RNA-Seq . The data are from the transcripts DQB1 NM_002123, DQA1 NM_002122, DRB1 NM_002124, DQA2 NM_020056 and DRB5 NM_002125. Underlined are marked the risk alleles.

Figure 5. LD plots of the GWAS- SNPs associated with different immune related disease.

Data are from HapMap III CEU population. (A) Linkage disequilibrium by r². (B) Linkage disequilibrium by D′. Disease abbreviations: Type 1 diabetes (T1D), inflammatory bowel disease (IBD), ulcerative colitis (UC), systemic lupus erythematosus (SLE), asthma and IgA deficiency.