Associations of ERAP1 coding variants and domain specific interaction with HLA-C∗06 in the early onset psoriasis patients of India

Interferon-γ-induced aminopeptidase ERAP1 trims peptides within the endoplasmic reticulum so that they can be loaded onto MHC class I and presented to the CD8+ T-cells. ERAP1 association and its interaction with HLA-C∗06 is controversial across different populations. We have investigated the association and possible functional role of non-synonymous SNPs at different exons of ERAP1 (rs26653: Arg127Pro, rs30187: Lys528Arg and rs27044: Gln730Glu) and their interactions with HLA-C∗06 in psoriasis. Significant associations of HLA-C∗06 (OR = 5.47, P < 2.2 × 10−16), rs30187 (OR 1.35, P = 7.4 × 10−4) and rs27044 (OR = 1.24, P = 5.8 × 10−3) were observed. All three ERAP1 SNPs showed significant association only for HLA-C∗06 positive patients, while rs30187 and rs27044 showed significant association only for early onset patients (rs30187: OR = 1.47, P = 9.6 × 10−5; rs27044: OR = 1.36, P = 3.3 × 10−4). No differential expression of ERAP1 was observed either between paired uninvolved and involved skin tissues of psoriasis patients or between non-risk and risk variants in the involved skin. Significant epistatic interaction was observed between HLA-C∗06 and the SNP (rs27044) located at the peptide-binding cavity of ERAP1. Evolutionary conservation analysis among mammals showed confinement of Lys528 and Gln730 within highly conserved regions of ERAP1 and suggested the possible detrimental effect of this allele in ERAP1 regulation.