Tailored second-line therapy in asthmatic children with the Arg(16) genotype.

The Arg(16) ß(2) receptor genotype confers increased susceptibility to exacerbations in asthmatic children taking regular LABA (long-acting ß(2) agonists). We therefore evaluated using montelukast as an alternative to salmeterol as tailored second-line asthma controller therapy in children expressing this susceptible genotype. A total of 62 persistent asthmatic children with the homozygous Arg16 genotype were randomized to receive salmeterol (50 µg, b.i.d.) or montelukast (5 or 10 mg, once daily) as an add-on to inhaled fluticasone for 1 year. School absences (the primary outcome) were reduced with montelukast compared with salmeterol {difference in score=-0.40 [95% CI (confidence interval), -0.22 to -0.58]; P=0.005}. Salbutamol use was also reduced with montelukast compared with salmeterol [difference in score=-0.47 (95% CI, -0.16 to -0.79); P<0.0001]. Greater improvements occurred in both symptom and quality of life scores with montelukast against salmeterol, whereas there was no difference in FEV(1) (forced expiratory volume in 1 s). In conclusion, montelukast may be suitable as tailored second-line controller therapy instead of salmeterol in asthmatic children expressing the susceptible Arg(16) genotype, a move towards a personalized medicine approach to management.

Matrix metalloproteinase-12 is a therapeutic target for asthma in children and young adults.

BACKGROUND: Matrix metalloproteinase (MMP)-12-mediated pathologic degradation of the extracellular matrix and the subsequent repair cycles influence the airway changes in patients with asthma and chronic obstructive pulmonary disease (COPD). The common serine variant at codon 357 of the MMP12 gene (rs652438) is associated with clinical manifestations consistent with more aggressive matrix degradation in other tissues. OBJECTIVE: We sought to explore the hypothesis that MMP12 represents a novel therapeutic target in asthma. METHODS: The role of the rs652438 variant on clinical phenotype was explored in young asthmatic patients and patients with COPD. Candidate MMP-12 inhibitors were identified on the basis of potency and selectivity against a panel of other MMPs. The role of MMP-12-specific inhibition was tested in vitro, as well as in animal models of allergic airway inflammation. RESULTS: The odds ratio for having greater asthma severity was 2.00 (95% CI, 1.24-3.24; P = .004) when comparing asthmatic patients with at least 1 copy of the serine variant with those with none. The carrier frequency for the variant increased in line with asthma treatment step (P = .000). The presence of the variant nearly doubled the odds in favor of asthmatic exacerbations (odds ratio, 1.90; 95% CI, 1.19-3.04; P = .008) over the previous 6 months. The serine variant was also associated with increased disease severity in patients with COPD (P = .016). Prior administration of an MMP-12-specific inhibitor attenuated the early airway response and completely blocked the late airway response with subsequent Ascaris suum challenge in sheep. CONCLUSION: Studies on human participants with asthma and COPD show that the risk MMP12 gene variant is associated with disease severity. In allergen-sensitized sheep pharmacologic inhibition of MMP12 downregulates both early and late airway responses in response to allergic stimuli.

A polymorphism controlling ORMDL3 expression is associated with asthma that is poorly controlled by current medications.

BACKGROUND: The specific genetic contributions to childhood asthma have been difficult to elucidate. A recent whole-genome association study suggested that single nucleotide polymorphisms at loci controlling the expression of the ORMDL3 gene and others in the neighborhood of the NRG1 and ERO1LB genes might be important. OBJECTIVE: We sought to replicate the associations of these genetic markers with asthma in a large population of asthmatic patients from Scotland and to assess the effect of these variants on asthma outcomes. METHODS: Using mouthwash-derived DNA and clinical interviews and measurements, we investigated the association of 3 single nucleotide polymorphisms in the candidate genes with susceptibility to asthma in a case-control study and also exacerbations in a group of 1054 patients aged 3 to 22 years. RESULTS: A common C/T polymorphism at a locus controlling ORMDL3 gene expression (rs7216389) was significantly associated with the risk of childhood asthma (P = 1.73 x 10(-12)), with a single copy of the T allele conferring an odds ratio of 1.50 (95% CI, 1.24-1.81) and 2 copies of the T allele conferring an odds ratio of 2.11 (95% CI, 1.71-2.61), respectively. In asthmatic patients the T allele was associated with exacerbations of the condition (P = .008). Polymorphisms at the loci of nearby genes for NRG1 (rs4512342) and ERO1LB (rs10924993) were associated with neither the occurrence of nor exacerbations of asthma. CONCLUSION: A common genetic variation at a locus controlling the expression of the ORMDL3 locus increases the susceptibility to asthma and is associated with poor control of the condition in children and young adults.

Glutathione S-transferase M1 and P1 genotype, passive smoking, and peak expiratory flow in asthma.

OBJECTIVES: Our purpose with this work was to assess the contribution of glutathione S-transferase gene variants to asthma susceptibility and pulmonary function in relation to tobacco smoke exposure in the home. METHODS: Young individuals with asthma (age: 3-21 years; n = 504) were recruited through primary and secondary care throughout Tayside, Scotland (BREATHE Study). Spirometry was obtained on 407 individuals. Binary logistic regression and general linear modeling were used to explore phenotypic characteristics by genotype and tobacco smoke exposure status in younger children (3-12 years; n = 384) and teenagers and young adults (13-21 years; n = 120). RESULTS: Three- to 12-year-olds with asthma, null for the GSTM1 gene or homozygous for the GSTP1Val105 allele, were overrepresented in the group exposed to environmental tobacco smoke. No differences in lung function values could be detected in this group. In contrast, 13- to 21-year-olds with the GSTM1-null genotype or homozygous for the GSTP1Val105 allele from smoking households were more likely to have a substantially lower percentage of predicted peak expiratory flow rates than those from nonsmoking households (83% vs 98%). CONCLUSIONS: Three- to 12-year-olds who are null for GSTM1 or homozygous for the GSTP1Val105 allele are more susceptible to asthma associated with environmental tobacco smoke exposure than those with more intact glutathione S-transferase status. In the 13- to 21-year-olds, GSTM1-null status interacts with environmental tobacco smoke exposure to substantially reduce peak expiratory flow rate. The environmental tobacco smoke effect in GSTM1-null children with asthma could be cumulative over time, resulting in detrimental effects on peak expiratory flow rate in 13- to 21-year-olds with asthma.