Genetic variability of prostaglandin E2 receptor subtype EP4 gene in aspirin-intolerant chronic urticaria

Abstract

Prostaglandin E2 receptor subtype EP4 (PTGER4) is one of the four subtypes of receptors for prostaglandin E2 (PGE2). Overproduction of cysteinyl leukotriene in mast cells may be related with suppression of PGE2 in patients with aspirin hypersensitivity. Considering the association of PTGER4 in mast cells, urticaria-and aspirin-related disease, we hypothesized the genetic variability of PTGER4 may be associated with aspirin-intolerant chronic urticaria (AICU). The case-control study was performed in 141 with AICU, 153 with aspirin-tolerant chronic urticaria (ATCU) and 174 with normal controls (NCs). PTGER4 promoter single-nucleotide polymorphism was genotyped using a primer extension method with the SNAPshot ddNTP primer extension kit. The functional variability of PTGER4 promoter polymorphism was carried out by dual-luciferase system and electrophoretic mobility shift assay (EMSA) in human mast cells (HMC-1). Furthermore, the effect of aspirin was performed for PTGER4 mRNA expression using real-time PCR, and PGE2 production was checked in HMC-1 cells using ELISA. AICU patients carrying GG genotype at À1254 G4A showed significantly higher frequency compared with NC (P ¼ 0.032). Similarly, the minor allele frequency, G allele was significantly higher in AICU compared with NC (P ¼ 0.031). In vitro functional study demonstrated that the À1254 G allele had lower luciferase activity (Po0.001) in HMC-1 cells. EMSA finding showed that PTGER4 À1254 G produced a specific band. Significantly decreased PTGER4 expression (P ¼ 0.008) and PGE2 production by aspirin exposure was confirmed in in vitro HMC cell line model (P ¼ 0.001). The PTGER4 À1254 G allele demonstrated a higher frequency in AICU patients and lower promoter activity with decreased expression of PTGER4 and contributes to the development of AICU.

Genetic variants associated with drugs-induced immediate hypersensitivity reactions: a PRISMA-compliant systematic review

“…The ALOX5 gene encodes a member of the lipoxygenase gene family and plays a dual role in the synthesis of leukotrienes from arachidonic acid. By comparison, the case-control studies performed on NAR to aspirin showed an association with three other genes of the arachidonic acid pathway, LTC4S, TBXA2R, and PTGER4, and only one, ALOX5, which was also associated with NAR to NSAIDs (33,39,41,42). This is consistent with the fact that aspirin and NSAIDs inhibit distinct enzymes of this pathway.…”

“…1). Among the 42 selected studies that reported genetic predictors in association with immediate-type hypersensitivity, 19 were related to BLs (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) (Table 1), 12 to aspirin (31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42) (Table 2), and eight to other NSAIDs (43-50) (Table 3). Three studies reported genetic predictors in association with biologicals, including hypersensitivity to asparaginase (51), EGF receptor inhibitors (52), and infliximab (53) ( Table 4).…”

“…Studies that have assessed the genetic variants potentially associated with immediate-type hypersensitivity to NSAIDs were predominantly conducted in Spain (41)(42)(43)(44)(45)(46)(47)(48). They reported an association with genes belonging to HLA genes (HLA-DRB1, HLA-B44, and HLA-Cw5) (43,44) or to the arachidonic acid pathway (ALOX5, ALOX5AP, ALOX15, TBXAS1, PTGDR, and CYSLTR1) (46, 49) ( Table 3).…”

“…They highlighted the involvement of genes that can be grouped into four pathogenic groups: (i) the membrane-spanning 4A gene family (FCER1A (formerly, FceR1a), MS4A2 (formerly, FceR1b), and FCER1G (formerly, FceR1c); (ii) the histamine production pathway (HNMT) (34,35,38); (iii) the inflammatory cytokines (TGFB1, TNF, and IL18) (36,37,40); and (iv) the arachidonic acid pathway (ALOX5, LTC4S, TBXA2R, and PTGER4) (33,39,41,42) (Table 2 Fig. 3).…”

Update on the Genetic Basis of Drug Hypersensitivity Reactions

“…We previously reported associations for 2 SNPs in PGE1R (rs3810253 and rs3810255) and 1 in PGER2 (rs1254598) [88] in NIUA, neither of which was found in Asian NERD patients [94]. The MAF of PTGER4 -1254G>A was recently found to be higher in NECD patients than in healthy individuals [96]. Finally, the rs8004654 polymorphism in PGDR was shown to be significantly associated with NIUA in 2 independent Spanish populations [88], as well as in American asthmatics [97].…”