Autoimmune risk variants in ERAP2 are associated with gene-expression levels in thymus

Area of Science:

• Immunogenetics
• Molecular Biology
• Human Genetics

Background:

• Genetic polymorphisms in endoplasmic reticulum aminopeptidase (ERAP)1 and ERAP2 are linked to autoimmune diseases (AIDs).
• Understanding the regulatory mechanisms of these genetic associations is crucial for elucidating AID pathogenesis.

Purpose of the Study:

• To investigate if fine-mapped autoimmune disease single-nucleotide polymorphisms (SNPs) in the ERAP region influence ERAP1 and ERAP2 gene expression in the thymus.
• To identify potential causal regulatory variants underlying the association between ERAP gene polymorphisms and AIDs.

Main Methods:

• Performed a cis expression quantitative trait locus (eQTL) screen in human thymus tissue.
• Analyzed seven fine-mapped AID SNPs within the ERAP region.
• Assessed the overlap between eQTL signals and known AID risk loci.

Main Results:

• Identified six significant thymic eQTLs for ERAP1 and ERAP2.
• Both ERAP1 and ERAP2 exhibited highly significant and independent eQTL signals in the thymus.
• The strongest eQTL signals for ERAP2 strongly overlapped with known AID risk loci.
• Six top eQTL SNPs for ERAP2 were located within transcription factor motifs in a thymic enhancer region.

Conclusions:

• Fine-mapped autoimmune disease risk variants function as eQTLs for ERAP2 in the thymus.
• These findings highlight potential causal regulatory variants influencing ERAP2 expression and contributing to autoimmune disease susceptibility.