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.

Relationship of common expression quantitative trait loci genes to the immune system

“…Some research has found that a variety of HLA-B gene subtypes is related to the progression of HIV infection (Gao et al, 2001;Carrington and O'Brien, 2003). We also confirmed that loci rs9268853 and rs9271100, which are associated with ulcerative colitis (Pereyra et al, 2010) and systemic lupus erythematosus (Han et al, 2009;Alcina et al, 2012), affect the expression of HLA class II, DR beta 1 (HLA-DRB1) in lymphoid cell lines (Montgomery et al, 2010). The results showed that the eQTL genes shared among tissues are consistent with disease risk genes and loci in GWAS.…”

From Markers to Molecular Mechanisms: Type 1 Diabetes in the Post-GWAS Era

“…This finding therefore suggests that the linked causal variants in these regions are likely to be expression quantitative trait loci (eQTL), at which polymorphism affects the expression of one or more transcripts. Indeed, the data obtained on candidate genes for several autoimmune diseases strongly support the hypothesis that most of the genetically encoded risk of disease is conferred by eQTL [38,71,103,[156][157][158][159][160][161][162][163].…”

The CIITA genetic polymorphism rs4774*C in combination with the HLA-DRB1*15:01 allele as a putative susceptibility factor to multiple sclerosis in Brazilian females

“…In particular, the association between HLA-class II genes and the relative risk for MS has been investigated in several populations 1,6,9 , and a link between HLA-DRB1* and MS susceptibility in Brazilian patients has already been reported 19 .…”

“…The genetic components of MS pathogenesis are quite complex 6 , and the human leukocyte antigen (HLA) class II genes (6p21.3) appear to play an important role in determining the risk for MS. For example, the HLA-DRB1*15:01 allele is consistently associated with MS 6 . Studies performed on North American and European populations revealed an association between the HLA-DRB1*15:01, -DQA1*01:02 and -DQB1*06:02 alleles and the development of MS 7 , and these alleles have also been linked to MS in the Brazilian population 8,9,10 .…”