β(2) -adrenoreceptor polymorphisms in asthmatic and non-asthmatic schoolchildren from colombia and their relationship to treatment response

Asthma is a chronic and recurrent disease. Its high prevalence around the world is the result of a complex interaction between genetic and environmental factors. The genetic aspects of susceptibility, severity, and response to treatment in asthma are of great scientific interest. The purpose of the study was to establish the relationship between the Gln27Glu and Arg16Gly alleles of the β(2) -adrenergic receptor (ADRB2) gene with respect to the susceptibility to and severity of asthma, as well as the response to treatment in mestizo schoolchildren. 109 schoolchildren with asthma diagnosis and 137 asymptomatic controls were genotyped for the Arg16Gly and Gln27Glu alleles of the ADRB2 gene by minisequencing. Allele, genotype, and haplotype frequencies of the ADRB2 gene between asthmatic and non-asthmatic as well as demographic, clinical, and spirometric variables among asthmatic patients according to their genotype were compared. ADRB2 gene expression was determined by real-time quantitative PCR. No statistical differences were found in allele, genotype, and haplotype frequencies of the ADRB2 gene between cases and controls. We did not find differences between asthmatic patients classified according to their ADRB2 genotypes and haplotypes when evaluating demographic, clinical, and spirometric variables. The ADRB2 genotype and haplotype are not associated with spirometric responses or ADRB2 gene expression after administration of a β-(2) agonist plus a glucocorticoid. These results suggest that in the group of mestizo schoolchildren studied, the Arg16Gly and Gln27Glu polymorphisms are not markers of susceptibility or severity of asthma and do not affect ADRB2 gene expression during the rescue therapy.     

Cytochrome P450 2B6 516G→T is associated with plasma concentrations of nevirapine at both 200 mg twice daily and 400 mg once daily in an ethnically diverse population

Objectives

The aim of the study was to characterize the impact of the cytochrome P450 2B6 (CYP2B6), CYP3A4, CYP3A5 and ATP‐binding cassette sub‐family B member 1 (ABCB1) polymorphisms on nevirapine plasma concentrations.

Methods

A total of 104 patients (82% male; 26% non‐Caucasian) were genotyped for eight single nucleotide polymorphisms at four loci (CYP2B6, CYP3A4, CYP3A5 and MDR1). Nevirapine plasma concentrations were determined using high‐performance liquid chromatography.

Results

Non‐Caucasian ethnicity [5609 ng/mL (n=27) for non‐Caucasians vs. 3771 ng/mL (n=77) for Caucasians; P<0.0001] and CYP2B6 516G→T [GG, 3574 ng/mL (n=50); GT, 4634 ng/mL (n=50); TT, 8170 ng/mL (n=4); P_{analysis of variance (anova)} =0.001] were significantly associated with a higher nevirapine trough concentration (C_trough). The latter association was maintained with both 200 mg twice daily (bid) and 400 mg once daily (qd) dosing [GG, 3527 ng/mL (n=30); GT, 4525 ng/mL (n=32); TT, 7020 ng/mL (n=2); P_anova =0.05 and GG, 3645 ng/mL (n=20); GT, 4861 ng/mL (n=17); TT, 9508 ng/mL (n=2); P_anova =0.01, respectively]. In a multivariable analysis, CYP2B6 516G→T and non‐Caucasian ethnicity remained significant predictors of nevirapine C_trough but CYP2B6 516G→T homozygosity had the greatest effect (108% higher, 46% higher). No associations were found between nevirapine C_trough and the remaining polymorphisms.

Conclusion

In this population, both non‐Caucasian ethnicity and carriage of the variant allele of CYP2B6 516G→T were significant predictors of nevirapine C_trough. The association between CYP2B6 516G→T and higher plasma nevirapine exposure was maintained at both bid and qd dosing.     

Impact of pharmacokinetics and pharmacogenetics on the efficacy of pranlukast in Japanese asthmatics

Background and objective:   Wide inter-individual variability in therapeutic effects limits the efficacy of leukotriene (LT) receptor antagonists in the treatment of asthma. We have reported that genetic variability in the expression of LTC₄ synthase is associated with responsiveness to pranlukast in Japanese asthmatic patients. However, the effects of pharmacokinetic variability are less well known. This was an analysis of the pharmacokinetics of pranlukast in a population of adult asthmatics, and its effect on clinical responses. Other factors that may be related to the therapeutic effects of pranlukast, including LTC₄ synthase gene polymorphisms, were also investigated.
Methods:   The population pharmacokinetics of pranlukast was analysed in a one-compartment model, using data collected in 50 Japanese adults with moderate to severe asthma, who were treated with pranlukast, 225 mg bd for 4 days. In 32 of these patients, in whom the clinical response to pranlukast (increase in FEV₁ after 4 weeks of treatment) was measured in a previous study, a combined pharmacokinetic and pharmacogenetic analysis was performed.
Results:   Using the population pharmacokinetic model, the estimated the mean oral clearance (CL/F) of pranlukast was 16.4 L/h, and the inter-individual variability was 30.1%. Univariate and multivariate analyses showed that LTC₄ synthase polymorphisms, but not the CL/F of the drug, predicted an improvement in pulmonary function with pranlukast treatment ( P  < 0.05).
Conclusions:   There was marked inter-individual variability in the pharmacokinetics of pranlukast among adult asthmatics, but this had little impact on the clinical effectiveness of the drug.     

氯吡格雷药物基因组学及个体化治疗研究进展与展望

通过与阿司匹林联合应用,氯吡格雷已经成为治疗急性冠脉综合征和预防经皮冠状动脉介入术后支架内血栓形成和再发缺血事件的经典口服抗血小板药物。尽管如此,氯吡格雷抗血小板的反应性和疗效存在显著的个体间差异。近年来的研究证实,除临床环境因素外,遗传变异是导致氯吡格雷抗血小板反应性个体间差异的重要因素之一。多项大规模临床药物基因组学研究发现,参与氯吡格雷代谢的关键酶—CYP2C19功能缺失型等位基因与氯吡格雷治疗期间高血小板反应性及心血管一级缺血终点事件的发生密切相关。另外,与氯吡格雷代谢相关的其他基因变异型也被证实可能与氯吡格雷抗血小板反应性及不良心血管事件相关。在此基础上,利用药物基因组学基因型检测指导氯吡格雷个体化抗血小板治疗,可能部分克服氯吡格雷治疗期间的高血小板反应性,但研究结果之间仍存在争议,尚需深入研究以提供更有力的证据。除此之外,未来有必要进一步深入研究基因型检测联合血小板功能监测共同指导氯吡格雷抗血小板个体化治疗的效果。     

Variants of the ADRB2 Gene in COPD: Systematic Review and Meta-Analyses of Disease Risk and Treatment Response

The β₂-adrenergic receptor (ADRB₂) is an important regulator of airway smooth muscle tone in chronic obstructive pulmonary disease (COPD). Variants that impair ADRB₂ function could increase disease risk or reduce the response to endogenous and inhaled adrenergic agonists in COPD. We performed a systematic review and three meta-analyses to assess whether three functional variants (Thr164Ile, Arg16Gly, and Gln27Glu) in the ADRB₂ gene are associated with elevated risk of disease or reduced therapeutic response to inhaled β₂-agonists in COPD. We searched the medical literature from 1966 to 2017 and found 16 relevant studies comprising 85381 study subjects. The meta-analyses found no significant association between ADRB₂ genotype and COPD risk. The summary odds ratios (ORs) for COPD in Thr164Ile homozygotes and heterozygotes were 2.57 (95% confidence interval (CI): 0.54–12.4) and 1.17 (95% CI: 0.96–1.44), respectively. Corresponding summary ORs for COPD in Arg16Gly homozygotes and heterozygotes were 0.97 (95% CI: 0.76–1.22) and 1.01 (95% CI: 0.81–1.26), while summary ORs for COPD in Gln27Glu homozygotes and heterozygotes were 1.00 (95% CI: 0.80–1.25) and 0.94 (95% CI: 0.69–1.24), respectively. When stratified by ethnicity, the summary ORs for COPD did not differ from 1.0 for any of the ADRB₂ variants among Asian, Caucasian, or African populations. We found no consistent associations between ADRB₂ genotype and treatment response to inhaled β₂-agonists in COPD. This systematic review and meta-analyses found that COPD risk and response to inhaled β₂-agonists were not associated with Thr164Ile, Arg16Gly, and Gln27Glu genotypes. However, identified cases of Thr164Ile were few, and additional studies of rare ADRB₂ genotypes are required.