Félicie Costantino1, Alice Talpin2, Irini Evnouchidou3, Amir Kadi2, Ariane Leboime4, Roula Said-Nahal4, Nelly Bonilla2, Franck Letourneur5, Tifenn Leturcq2, Zeyna Ka2, Peter van Endert3, Henri-Jean Garchon1, Gilles Chiocchia2, Maxime Breban1. 1. INSERM U1173, Université de Versailles St. Quentin-en-Yvelines, and Laboratoire d'Excellence INFLAMEX, Paris, France and Hôpital Ambroise Paré, AP-HP, Boulogne-Billancourt, France. 2. INSERM U1173, Université de Versailles St. Quentin-en-Yvelines, and Laboratoire d'Excellence INFLAMEX, Paris, France. 3. INSERM U1151, CNRS (UMR 8253), Université Paris Descartes, Sorbonne Paris Cité, Paris, France. 4. Hôpital Ambroise Paré, AP-HP, Boulogne-Billancourt, France. 5. Institut Cochin, INSERM U1016, CNRS (UMR8104) and Université Paris Descartes, Paris, France.
Abstract
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.
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.
Authors: Eilon Barnea; Dganit Melamed Kadosh; Yael Haimovich; Nimman Satumtira; Martha L Dorris; Mylinh T Nguyen; Robert E Hammer; Tri M Tran; Robert A Colbert; Joel D Taurog; Arie Admon Journal: Mol Cell Proteomics Date: 2017-02-10 Impact factor: 5.911
Authors: Carlos Alvarez-Navarro; Adrian Martín-Esteban; Eilon Barnea; Arie Admon; José A López de Castro Journal: Mol Cell Proteomics Date: 2015-04-19 Impact factor: 5.911
Authors: Alejandro Sanz-Bravo; Carlos Alvarez-Navarro; Adrian Martín-Esteban; Eilon Barnea; Arie Admon; José A López de Castro Journal: Mol Cell Proteomics Date: 2018-04-09 Impact factor: 5.911