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ERAP1 Gene Expression Is Influenced by Nonsynonymous Polymorphisms Associated With Predisposition to Spondyloarthritis
Author(s) -
Costantino Félicie,
Talpin Alice,
Evnouchidou Irini,
Kadi Amir,
Leboime Ariane,
SaidNahal Roula,
Bonilla Nelly,
Letourneur Franck,
Leturcq Tifenn,
Ka Zeyna,
van Endert Peter,
Garchon HenriJean,
Chiocchia Gilles,
Breban Maxime
Publication year - 2015
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.39072
Subject(s) - haplotype , biology , genetics , nonsynonymous substitution , gene , immunology , microbiology and biotechnology , genotype , genome
Objective Several polymorphisms in ERAP1 are strongly associated with susceptibility to spondyloarthritis (SpA). The combination of rs17482078, rs10050860, and rs30187 results in the construction of 3 major haplotypes that are associated with SpA (the “protective” haplotype T/T/C, the “neutral” haplotype C/C/C, and the “susceptibility” haplotype C/C/T). The aim of the present study was to determine whether such haplotypes might affect endoplasmic reticulum aminopeptidase 1 (ERAP‐1) messenger RNA (mRNA) expression, protein level, and/or enzymatic activity in antigen‐presenting cells, a type of cell that is potentially relevant to disease pathogenesis. Methods Monocyte‐derived dendritic cells (DCs) were generated in 2 cohorts (a discovery cohort and a replication cohort) comprising a total of 23 SpA patients and 44 healthy controls. Lymphoblastoid B cell lines were established from individuals who were homozygous for the risk, the neutral, or the protective ERAP1 haplotype, respectively. In those samples, we investigated the relationship between ERAP1 haplotypes and mRNA expression level. We also used Western blot analysis to measure the relative protein expression of ERAP‐1 and a fluorogenic assay to measure its enzymatic activity. Results In monocyte‐derived DCs, there was a strong association between ERAP1 haplotypes and the ERAP‐1 mRNA expression level, with higher levels in subjects harboring the susceptibility haplotype ( P = 0.001 and P = 5.6 × 10 −7 in the discovery and replication cohorts, respectively). In lymphoblastoid B cell lines, we observed a significant correlation between haplotype risk score and ERAP1 transcript or protein level ( P = 0.003, ρ = 0.92 for both). Enzymatic activity followed a similar trend both in monocyte‐derived DCs and in lymphoblastoid B cell lines. Conclusion These data provide strong evidence that SpA‐associated ERAP1 polymorphisms affect the level of gene expression in antigen‐presenting cells. How increased production/activity of ERAP‐1 may influence susceptibility to SpA remains to be determined.