Influence of Leukotriene Pathway Polymorphisms (Arachidonate 5-Lipoxygenase ALOX5, Leukotriene A4hydrolase LTA4H) on Response to Montelukast in A Sample of Asthmatic Iraqi Patients

Abstract

Background: Montelukast, which is safe, and efficacious cysteinyl leukotriene receptor 1 antagonist used in asthma, which is a chronic inflammatory disease, imposes a large burden on society since large proportion of morbidity, mortality and healthcare costs associated with asthma. objective: To determine associations between polymorphisms in leukotriene pathway candidate gene with lung function outcomes in Iraqi patients with asthma receiving montelukast for one month in order to determine the interpatient variability in response to montelukast. Method: This study conducted in a study group of Iraqi patients and healthy subjects from Baghdad. Two hundred participants (men, women) recruited as healthy subjects (80) and patients with bronchial asthma (120) fulfill entry criteria and classified into three groups, first group contained 40 asthmatic patients taking montelukast for 4 weeks at a dose of 10 mg once a day before bed time, second group contained 40 asthmatic patients taking inhaled short acting beta agonist salbutamol at a dose of four buffs daily (0.1mg/dose) for 4 weeks, third group contain 40 asthmatic patients taking budesonide/formoterol inhalation powder(160/4.5mcg/dose) at a dose of two buffs daily for 4 weeks. Results: The allelic varients of ALOX5 and LT4H were found in Iraqi population. A allele frequency of ALOX5(rs2115819) was (0.59), G allele frequency was (0.40). The G allele frequency of LT4H(rs2660845) was (0.58), A allele frequency was (0.42). G allele frequency of ALOX5 for healthy individuals was (0.21%) while A allele frequency was (0.79). A allele frequency of LTA4H for healthy individuals was (0.71) while G allele frequency was (0.29). For ALOX5 SNP, there was non-significant difference in percentage change in % predicted FEV1 over baseline and percentage change in % predicted PEF over baseline in patients montelukast intake. For LTA4H (rs2660845) SNP of our study, the values of % change in % predicted PEF in patients with the AA genotype were improved after montelukast intake compared with those who carried the G allele, while percentage change in % predicted FEV1 over baseline showed significance improvement in patients with the G allele carriers compared with those who carried AA genotype. For salbutamol patients’ group, A significant association observed in the carriers of G allele of LTA4H (rs2660845) SNP compared to AA genotype carriers who were on salbutamol treatment and the % change in % predicted FEV1 showed non-significant associations between GG genotype and A allele carriers of ALOX5 (rs2115819) in participants taking inhaled salbutamol.

For budesonide/formoterol inhalation powder patients’ group, A significant association observed in the carriers of AA genotype of LTA4H (rs2660845) SNP compared to G allele carriers with the % change in % predicted FEV1 with non-significant associations were observed between % change in % predicted FEV1 with ALOX5 (rs2115819). Conclusion: Our study results concluded that genetic variation in leukotriene pathway candidate genes contributed to variability in clinical responses to montelukast in Iraqi asthmatic patients from Baghdad who received montelukast for one month.