Filaggrin null mutations are associated with increased asthma severity in children and young adults.

BACKGROUND: Filaggrin is a key protein involved in skin barrier function. Filaggrin (FLG) null mutations are important genetic predisposing factors for atopic disease. OBJECTIVE: To study the role of FLG null alleles in the clinical phenotype in children and young adults with asthma. METHODS: FLG mutations R501X and 2282del4 were assayed in 874 subjects 3 to 22 years old with asthma from Tayside. Lung function and disease severity were also studied. RESULTS: The filaggrin mutations were significantly associated with greater disease severity for asthma. Independent of eczema, mean FEV(1)/forced vital capacity of FLG wild-type individuals differed from those carrying either FLG null allele (0.89 vs 0.86; P = .012). Individuals bearing FLG null alleles were more likely to be prescribed increased medication (chi(2) = 10.3; P = .001), with the homozygote null individuals having an odds ratio of 6.68 (95% CI, 1.7-27.0; P = .008) for being prescribed long-acting beta-agonists in addition to inhaled steroids. FLG null alleles were also associated with increased rescue medication use (P = .004). Individuals with asthma and with FLG null alleles were more likely to have eczema, and individuals with eczema tended to have more severe asthma; however, the association of FLG null alleles with all markers of asthma disease severity was similar in children with and without eczema. CONCLUSION: FLG mutations are associated not only with eczema-associated asthma susceptibility but also with asthma severity independent of eczema status. CLINICAL IMPLICATIONS: FLG status influences controller and reliever medication requirements in children and young adults with asthma.

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.