ERAP1 Gene Expression Is Influenced by Nonsynonymous Polymorphisms Associated With Predisposition to Spondyloarthritis.
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.


CONCLUSIONS
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.
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.
Félicie
F
Costantino
INSERM U1173, Université de Versailles St. Quentin-en-Yvelines, and Laboratoire d'Excellence INFLAMEX, Paris, France.
Alice
A
Talpin
INSERM U1151, CNRS (UMR 8253), Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Irini
I
Evnouchidou
INSERM U1173, Université de Versailles St. Quentin-en-Yvelines, and Laboratoire d'Excellence INFLAMEX, Paris, France.
Amir
A
Kadi
Hôpital Ambroise Paré, AP-HP, Boulogne-Billancourt, France.
Ariane
A
Leboime
Hôpital Ambroise Paré, AP-HP, Boulogne-Billancourt, France.
Roula
R
Said-Nahal
INSERM U1173, Université de Versailles St. Quentin-en-Yvelines, and Laboratoire d'Excellence INFLAMEX, Paris, France.
Nelly
N
Bonilla
Institut Cochin, INSERM U1016, CNRS (UMR8104) and Université Paris Descartes, Paris, France.
Franck
F
Letourneur
INSERM U1173, Université de Versailles St. Quentin-en-Yvelines, and Laboratoire d'Excellence INFLAMEX, Paris, France.
Tifenn
T
Leturcq
INSERM U1173, Université de Versailles St. Quentin-en-Yvelines, and Laboratoire d'Excellence INFLAMEX, Paris, France.
Zeyna
Z
Ka
INSERM U1151, CNRS (UMR 8253), Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Peter
P
van Endert
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.
Henri-Jean
HJ
Garchon
INSERM U1173, Université de Versailles St. Quentin-en-Yvelines, and Laboratoire d'Excellence INFLAMEX, Paris, France.
Gilles
G
Chiocchia
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.
Maxime
M
Breban
D000328:Adult; D000626:Aminopeptidases / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D016022:Case-Control Studies; D015331:Cohort Studies; D003713:Dendritic Cells / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D065840:Protective Factors; D012333:RNA, Messenger / Q000378:metabolism*; D025242:Spondylarthropathies / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D013167:Spondylitis, Ankylosing / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism
D015778:Minor Histocompatibility Antigens; D012333:RNA, Messenger; D000626:Aminopeptidases; C464841:ERAP1 protein, human