تأثير تعدد النمط الجيني ل Transporter OAT2B1و CYP2C8 Metabolizing Enzyme على استجابة علاج المونتيلوكاست لدى الأطفال المصابين بالربو

Effects of Genetic Polymorphisms of OATP2B1 Transporter and CYP2C8 Metabolizing Enzyme on Montelukast Therapy Response in Asthmatic Children in Kerbela Province

Abstract:
Background: Montelukast, a cysteinyl leukotriene 1 receptor antagonist, approved for both acute and chronic therapy of asthma in adults and children.
A nonsynonymous single nucleotide polymorphism (SNP) in the organic anion transporting polypeptide 2B1 (OATP2B1), (rs12422149) c.935G>A, and CYP2C8*1B (rs7909236) g.-271 enzyme have been associated with reduced plasma concentrations of montelukast in patients with asthma.
Aims of the study:
The study aims to investigate the effects of genetic polymorphisms of OATP2B1 c.935G>A (rs12422149) transporter and CYP2C8*1B (rs7909236) metabolizing enzyme polymorphism on montelukast therapy response in asthmatic children.
Patients and methods: This cross-sectional observational study is done on Respiratory clinic center of Karbala hospital of children, from end of October 2022 to the end of September 2023. One hundred male and female, aged between 6 to 15 years old and taken montelukast as maintenance therapy daily for at least one month, were enrolled in the study. Pulmonary Function test (PFT), Asthma Control Test (ACT), and total serum Immunoglobulin E were measured. Allele specific polymerase chain reaction (AS-PCR) had been done to detect different patients’ genotypes after DNA extraction.
Results: The results of this study show that the distribution of OATP2B1 transporter gene c.935G>A polymorphism was 48(48%) for wild homozygous GG, 45(45%) for mutant heterozygous GA, and 7 (7%) for mutant homozygous AA. This polymorphism was estimated to have a significant association with montelukast therapy response and the patients who have wild homozygous GG genotype, show better response to montelukast therapy that indicated by improvement in pulmonary function test, reduction of serum total Ig E level, and improvement of asthma symptom in asthma control test (score ≥20) when compared with mutant genotypes (GA and AA).
Regarding to CYP2C8*1B g.-271C>A gene polymorphism, the result of current study shows no significant association of CYP2C8*1B polymorphism with montelukast therapy response. The distribution of CYP2C8*1B g.-271C>A gene was as follows; 74(74%) for CC homozygous wild type, 22 (22%) for CA heterogeneous mutant and 4 (4%) for AA homozygous mutant types.
Conclusions: The polymorphism of OATP2B1 transporter affects the response of asthmatic children to montelukast therapy and asthmatic children having wild GG genotype showed better improvement in lung function and clinical condition (reduction of serum total IgE level and ≥20 score of asthma control test) after treatment in comparison with those having mutant AA and GA genotypes in mild to moderate asthma.
The CYP2C8*1B g.-271C>A genetic polymorphism was not significantly associated with montelukast therapy responses despite its existence in Iraqi asthmatic patients.