Association analysis of formyl peptide receptor 2 (FPR2) polymorphisms and Aspirin exacerbated respiratory diseases

Abstract

Aspirin-exacerbated respiratory diseases (AERD) are associated with the metabolism of arachidonic acid. FPR2 (formyl peptide receptor2) is a high-affinity ligand receptor for potent anti-inflammatory lipid metabolites: lipoxins. Thus, functional alterations of the FPR2 may contribute to AERD. We investigated the relationship between single-nucleotide polymorphisms (SNPs) in the FPR2 and AERD. Asthmatics were categorized into AERD o15% decreases in forced expiratory volume in one second (FEV 1 ), and/or naso-ocular reactions after oral aspirin challenge (n¼170) and aspirin-tolerant asthma (ATA, n¼268). In all, 11 SNPs were genotyped. FPR2 protein expressions on CD14-positive monocytes in peripheral blood were measured using flow cytometric analysis. We performed RT-PCR of the FPR2 mRNA expressed by peripheral blood mononuclear cells. Logistic regression analysis showed that the minor allele frequency of FPR2 À4209T4G (rs1769490) in intron 2 was significantly lower in the AERD group (n¼170) than in the ATA group (n¼268) (P¼0.006, P corr ¼0.04, recessive model). The decline of FEV 1 after aspirin challenge was significantly lower in the subjects with GG homozygotes of FPR2 À4209T4G than those with the other genotypes (P¼0.0002). Asthmatic homozygotes for FPR2 À4209T4G minor allele exhibited significantly higher FPR2 protein expression in CD14-positive monocytes than did those with the common allele of FPR2 À4209T4G allele (P¼0.01). There was no difference in the expression of the wild form and the exon 2 deleted variant form of FPR2 gene according to the genotypes of FPR2 À4209T4G. The minor allele at FPR2 À4209T4G may have a protective role against the development of AERD, via increase of FPR2 protein expression in inflammatory cells.

The common promoter polymorphism rs11666254 downregulates FPR2/ALX expression and increases risk of sepsis in patients with severe trauma

“…Taken together, the three SNPs (rs11666254, rs17695052, and rs17695064) selected in this study for genotyping might capture most of the genetic variation of the entire FPR2/ALX gene and might represent potential biological significance of the FPR2/ALX genetic variations. Three SNPs in our study (rs11666254 [−1010G/A], rs7248161 [−1160G/G], and rs7256993 [398 T/T]) were not included in Kim et al’s study [37]. The reason may be the relatively low MAF of the three SNPs in their study population.…”

“…Gwinn et al found that two SNPs (F110S and C126W), which were located in the open reading frame of FPR2/ALX , were associated with juvenile periodontitis [36]. Kim et al observed that an intronic SNP (4209 T/G) was associated with the risk of asthma disease [37]. These three SNPs (F110S and C126W, 4209 T/G) along with 220A/G variants (data in the study by Simiele et al [29]) were not analyzed in the present study.…”

Genetic basis of hypersensitivity reactions to nonsteroidal anti-inflammatory drugs

“…Functional N-acetyltransferase and CYP2C polymorphisms have recently been analyzed in relation to metamizole metabolic profile [85 && ]. Associations with NERD have been also reported for SNPs in formyl peptide receptor 2, a high-affinity ligand receptor for lipoxins [86], heat shock protein 70 [87], and members of the rat sarcoma viral (RAS) oncogene family [88].…”

Enemy attraction: bacterial agonists for leukocyte chemotaxis receptors

“…The fact that PSM levels correspond to staphylococcal virulence 74 suggests that PSMs are true PAMPs that enable the innate immune system to initiate appropriate immune responses via FPR2. Mast cell degranulation can be elicited by δ-toxin, an α-type PSM 83 , and polymorphisms in FPR2 are associated with urticaria 84 and asthma 85,86 , which suggests that PSM-FPR2 interactions may also be important co-triggers of allergies. who are hospitalized and immunocompromised 87 .…”