Summary What is known and objective:  Inhaled combination therapy composing of long‐acting β2‐agonist and corticosteroid has been widely applied in the management of asthma, but observed treatment responses vary. The aim of this study was to evaluate the pharmacogenetic effect of the adenylyl cyclase type 9 (ADCY9) gene polymorphism on combination therapy. Materials and methods:  Eighty‐six mild to moderate Korean asthmatics were enrolled in this clinical trial. After the 2‐week ‘run‐in’ period, patients received budesonide (an inhaled corticosteroid) and formoterol (long‐acting β2‐agonist) during the following 12‐week active treatment period. Forced expiratory volume in 1 s (FEV1) and maximum mid‐expiratory flow (MMEF) levels were measured at all visits as primary outcome. ADCY9 (Ile772Met, 150127 C/T, 150130 C/T, 150397 C/T, 150479 C/T, TTTA 5/4) and β2‐adrenergic receptor (ADRB2, Arg16Gly) gene polymorphisms were genotyped. Results:  Significant associations were observed between the ADCY9 single nucleotide polymorphisms and percent changes in FEV1 (Ile772Met T/C, P = 0·030) and MMEF (150397 C/T, P = 0·016) after 8 weeks of combination therapy. Haplotype associations were also observed with respect to percent changes in FEV1 after 8 weeks of therapy (Ht3[TTCC], P = 0·017). Additive therapeutic effect was observed in those with the ADCY9 Ile772Met and ADRB2 Arg16Gly gene polymorphisms in terms of percent change in FEV1 after 8 and 12 weeks of therapy (P = 0·002 and P = 0·027 respectively). What is new and conclusion:  Our results suggest that ADCY9 gene polymorphisms may alone, and in combination with ADRB2 gene polymorphisms, contribute to individual response to combination therapy in mild to moderate asthmatics.

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.