Background The Gly-to-Arg substitution at the 16 position (rs1042713) in the β2 -adrenoceptor gene (ADRB2) is associated with enhanced downregulation and uncoupling of β2 -receptors. Objectives We ...sought to undertake a meta-analysis to test the hypothesis that there is an interaction between the A allele of rs1042713 (Arg16 amino acid) and long-acting β-agonist (LABA) exposure for asthma exacerbations in children. Methods Children with diagnosed asthma were recruited in 5 populations (BREATHE, Genes-Environments and Admixture in Latino Americans II, PACMAN, the Paediatric Asthma Gene Environment Study, and the Pharmacogenetics of Adrenal Suppression with Inhaled Steroid Study). A history of recent exacerbation and asthma treatment was determined from questionnaire data. DNA was extracted, and the Gly16Arg genotype was determined. Results Data from 4226 children of white Northern European and Latino origin were analyzed, and the odds ratio for exacerbation increased by 1.52 (95% CI, 1.17-1.99; P = .0021) for each copy of the A allele among the 637 children treated with inhaled corticosteroids (ICSs) plus LABAs but not for treatment with ICSs alone (n = 1758) or ICSs plus leukotriene receptor antagonist (LTRAs; n = 354) or ICSs plus LABAs plus LTRAs (n = 569). Conclusions The use of a LABA but not an LTRA as an “add-on controller” is associated with increased risk of asthma exacerbation in children carrying 1 or 2 A alleles at rs1042713. Prospective genotype-stratified clinical trials are now required to explore the potential role of rs1042713 genotyping for personalized asthma therapy in children.
Background Atopic disease is a major health problem. Mutations in the filaggrin gene (FLG) confer major susceptibility to eczema and related asthma. Objective We sought to determine the natural ...history and burden of atopic disease conferred by the 2 most common FLG mutations in a large, population-based birth cohort study. Methods We analyzed the effect of the most common null alleles (R501X and 2282del4) on several atopic phenotypes in a cohort of approximately 7000 English children born in 1990-1991. Results FLG null alleles associated strongly with eczema; eczema associated with these mutations presents in early life and is more persistent (hazard ratio for eczema resolution for those with FLG mutations to FLG wild type, 0.67; 95% CI, 0.58-0.77; P = 5 × 10−8 ). FLG mutations conferred a population asthma risk of 1.80 (95% CI, 1.34-2.41; P = .00019); asthma risk was especially high in the context of eczema (odds ratio, 3.16; 95% CI, 2.25-4.43; P = 1.4 × 10−11 ). Strong associations were identified with sensitization to grass, house dust mite, and cat dander and sensitization to multiple allergens (odds ratio, 2.12; 95% CI, 1.03-4.37; P = 5.42 × 10−27 ). Conclusion FLG mutations are strong genetic determinants of eczema, early wheeze, asthma in the context of eczema, and atopic sensitization. They confer risk of a particular trajectory for eczema, with increased duration of disease and greater risk of asthma and multiple allergic sensitizations. FLG alleles help define the risk profile of children with eczema and help define the “eczema plus early wheeze” and “eczema plus asthma” phenotypes.
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.
Background On-demand inhaled albuterol is commonly prescribed worldwide. We have shown that the Arg16 allele of the adrenergic β2 -receptor agonist gene (ADRB2) predisposes to exacerbations in young ...asthmatic patients taking regular salmeterol. Objective We have now extended our previous population by 636 patients and explored the role of the Arg16 allele on asthma exacerbations in the context of the use of on-demand albuterol and regular salmeterol. Methods Arg/Gly status at position 16 of ADRB2 was assessed in 1182 young asthmatic patients (age, 3-22 years) from Scotland. Asthma exacerbations, use of β-agonists and other medications over the previous 6 months, and lung function were also studied. Results An increased risk of exacerbations per copy of he Arg16 allele was observed in asthmatic patients, regardless of treatment regimen (odds ratio OR, 1.30; 95% CI, 1.09-1.55; P = .003). This appears to be largely due to exposure to β2 -agonists because the risk of exacerbations observed in patients with the Arg16 allele was only observed in those receiving daily inhaled long- or short-acting β2 -agonist treatment (OR, 1.64; 95% CI, 1.22-2.20; P = .001). In contrast, there was no genotypic risk for exacerbations in patients using inhaled β2 -agonists less than once a day (OR, 1.08; 95% CI, 0.85-1.36; P = .525). The Arg16 genotype–associated risk for exacerbations was significantly different in those exposed to β2 -agonists daily versus those that were not (test for interaction, P = .022). Conclusion The Arg16 genotype of ADRB2 is associated with exacerbations in asthmatic children and young adults exposed daily to β2 -agonists, regardless of whether the exposure is to albuterol or long-acting agonists, such as salmeterol.
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 FEV1 /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 (χ2 = 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 β-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.
Background Atopic dermatitis (AD) is a major inflammatory condition of the skin caused by inherited skin barrier deficiency, with mutations in the filaggrin gene predisposing to development of AD. ...Support for barrier deficiency initiating AD came from flaky tail mice, which have a frameshift mutation in Flg and also carry an unknown gene, matted , causing a matted hair phenotype. Objective We sought to identify the matted mutant gene in mice and further define whether mutations in the human gene were associated with AD. Methods A mouse genetics approach was used to separate the matted and Flg mutations to produce congenic single-mutant strains for genetic and immunologic analysis. Next-generation sequencing was used to identify the matted gene. Five independently recruited AD case collections were analyzed to define associations between single nucleotide polymorphisms (SNPs) in the human gene and AD. Results The matted phenotype in flaky tail mice is due to a mutation in the Tmem79/Matt gene, with no expression of the encoded protein mattrin in the skin of mutant mice. Matt ft mice spontaneously have dermatitis and atopy caused by a defective skin barrier, with mutant mice having systemic sensitization after cutaneous challenge with house dust mite allergens. Meta-analysis of 4,245 AD cases and 10,558 population-matched control subjects showed that a missense SNP, rs6694514, in the human MATT gene has a small but significant association with AD. Conclusion In mice mutations in Matt cause a defective skin barrier and spontaneous dermatitis and atopy. A common SNP in MATT has an association with AD in human subjects.
The DNA binding property of a Cu(II) complex, viz., Cu(mal)2(picH)2·2H2O, (mal)2 = malonic acid, picH = protonated 2-amino-4-picoline, has been investigated in this study. The binding of this complex ...with plasmid and chromosomal DNA has been characterized by different biophysical techniques. From the absorption and fluorescence spectroscopic studies, it has been observed that the said copper complex binds strongly with pUC19 plasmid and CT DNA with a binding affinity of 2.368 × 103 and 4.0 × 103 M−1, respectively, in 10 mM citrate-phosphate buffer, pH 7.4. Spectrofluorimetric studies reveal that the copper complex exhibits partial DNA intercalation as well as partial DNA minor groove binding properties. Consequently, in agarose gel electrophoresis study, it has been observed that the complex alone induces positive supercoiling in plasmid DNA while in the presence of H2O2 it exhibits nuclease activity. The induction of the breakage in DNA backbone depends upon the relative concentrations of H2O2 and copper complex followed by the time of incubation with DNA. Optical DNA melting study, isothermal titration calorimetry, and absorption spectroscopy have been used to characterize the nuclease activity of this complex in the presence of H2O2. Further, 1H NMR study indicates that Cu(II) in the complex is converted into the Cu(I) state by the reduction of H2O2. Finally, agarose gel electrophoresis study with different radical scavengers concludes that the production of both hydroxyl radicals and reactive oxygen species is responsible for this nuclease activity.
Using cyclodextrin with budesonide enables it to be formulated in a solution for nebulization.
To observe the effects of a Captisol-enabled budesonide solution (CBIS), 60 microg twice daily, ...delivered via a nebulizer (eFlow), compared with a conventional budesonide suspension (Pulmicort Respules), 250 microg twice daily, delivered via another nebulizer (LC Plus), using fraction of exhaled nitric oxide (FE(NO)) and overnight urinary cortisol to creatinine ratio as the primary outcomes for efficacy and systemic bioactivity.
A randomized, open-label, crossover study was conducted in 12 children with mild-to-moderate persistent asthma (aged 5-12 years). Measurements were performed after a 2-week steroid washout at baseline and at the end of each 2-week randomized treatment.
The nebulization time was shorter (95% confidence interval CI, 0.83-5.63 minutes; P = .03) with CBIS (mean, 1.77 minutes) than with Pulmicort Respules (mean, 5.01 minutes). The reduction in FE(NO) with CBIS from pooled baseline was 2.45-fold (95% CI, 1.87-3.21; P < .001); and with Pulmicort Respules, 3.18-fold (95% CI, 2.26-4.47; P < .001). No statistically significant changes from pooled baseline in lung function and overnight urinary cortisol to creatinine ratio were observed with either treatment.
The nebulization time was shorter with CBIS compared with Pulmicort Respules. Both formulations exhibited similar anti-inflammatory activity in terms of reducing FE(NO), with no detectable difference between them when used in a putative microgram nominal dose ratio of 1:4. Neither formulation produced significant adrenal suppression.
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