Autoimmune risk variants in ERAP2 are associated with gene-expression levels in thymus.
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 × 10-15and 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.
Department of Medical Genetics, University of Oslo and Oslo University Hospital, Oslo, Norway.|K. G. Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway.
I S M
IS
Gabrielsen
Department of Medical Genetics, University of Oslo and Oslo University Hospital, Oslo, Norway.|Department of Immunology, Oslo University Hospital and University of Oslo, Oslo, Norway.
M K
MK
Viken
Department of Medical Genetics, University of Oslo and Oslo University Hospital, Oslo, Norway.
S S
SS
Amundsen
Department of Medical Genetics, University of Oslo and Oslo University Hospital, Oslo, Norway.|K. G. Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway.
H
H
Helgeland
Norwegian PSC Research Center, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Oslo, Norway.
K
K
Holm
Department of Medical Genetics, University of Oslo and Oslo University Hospital, Oslo, Norway.|K. G. Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway.
S T
ST
Flåm
Department of Medical Genetics, University of Oslo and Oslo University Hospital, Oslo, Norway.|K. G. Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway.
B A
BA
Lie
D000626:Aminopeptidases / Q000235:genetics*; D001327:Autoimmune Diseases / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D015870:Gene Expression; D006239:Haplotypes; D006801:Humans; D007223:Infant; D015810:Linkage Disequilibrium; D008297:Male; D015778:Minor Histocompatibility Antigens / Q000235:genetics; D009928:Organ Specificity; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012307:Risk Factors; D013950:Thymus Gland / Q000378:metabolism*
D015778:Minor Histocompatibility Antigens; D000626:Aminopeptidases; C464841:ERAP1 protein, human; C503944:ERAP2 protein, human