Abstract
Genetic polymorphisms in the endoplasmic reticulum aminopeptidase (ERAP)1 and ERAP2 genes have been associated with several autoimmune diseases (AIDs) at a genome-wide significance level. In this study, we performed a cis expression quantitative trait locus (eQTL) screen to investigate whether seven fine-mapped AID single-nucleotide polymorphisms (SNPs) in the ERAP-region influence the gene-expression levels of ERAP1 and ERAP2 in thymus. After quality control, we identified six significant eQTLs. We further assessed the peak eQTL signals, and both genes showed highly significant and independent thymic eQTL signals (P=2.16 × 10-15 and P=8.22 × 10-23, respectively). Interestingly, the peak eQTL signal overlapped with the AID risk loci in ERAP2 (r2>0.94), but were distinct in ERAP1 (r2<0.4). Finally, among the SNPs showing the most significant eQTL associations with ERAP2 (P<3.4 × 10-20), six were located within transcription factor motifs in an enhancer region in thymus. Our study therefore reveals the fine-mapped AID risk variants that act as eQTLs with ERAP2 in thymus, and highlights the potential causal regulatory variants.
Highlights
The endoplasmic reticulum aminopeptidases (ERAP)[1] and ERAP2 have a critical role in the production of final peptides that are presented by human leucocyte antigen class I molecules to the CD8+ T cells
In order to investigate whether autoimmune disease (AID)-associated single-nucleotide polymorphism (SNP) in ERAP1 and ERAP2 influence gene expression in thymic tissue, we performed a cis expression quantitative trait loci (eQTL) screen by correlating genotype data of seven fine-mapped AID-associated SNPs (Supplementary Table S1) with expression levels from all probes within a window of ± 1 Mb (Supplementary Table S2)
We noticed that a large number of SNPs associated with the expression of ERAP2 were situated in the neighboring gene, LNPEP
Summary
The endoplasmic reticulum aminopeptidases (ERAP)[1] and ERAP2 have a critical role in the production of final peptides that are presented by human leucocyte antigen class I molecules to the CD8+ T cells. It has become clear, through genome-wide association studies, that the ERAP1 and ERAP2 genes are implicated in several autoimmune diseases (AIDs).[1,2,3,4,5,6,7] Several of the AID risk variants in ERAP1 and ERAP2 (rs30187, rs27524, rs27434, rs1363907, rs2549794) have been reported as expression quantitative trait loci (eQTL) in multiple tissues.[8,9,10]. In this study, we have performed an eQTL screen with fine-mapped AID SNPs in the ERAP1 and ERAP2 region to investigate if they influence gene-expression levels in thymus
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