National Heart, Lung, and Blood Institute's Asthma Clinical Research Network. Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomized, placebo-controled cross-over trial
The issue of whether regular use of an inhaled beta2-adrenergic agonist worsens airflow and clinical outcomes in asthma is controversial. Retrospective studies have suggested that adverse effects occur in patients with a genetic polymorphism that results in homozygosity for arginine (Arg/Arg), rather than glycine (Gly/Gly), at aminoacid residue 16 of the beta2-adrenergic receptor. However, the existence of any genotype-dependent difference has not been tested in a prospective clinical trial.
Patients with mild asthma, not using a controller medication, were enrolled in pairs matched for forced expiratory volume in 1 s (FEV1) according to whether they had the Arg/Arg (n=37; four of 41 matches withdrew before randomisation) or Gly/Gly (n=41) genotype. Regularly scheduled treatment with albuterol or placebo was given in a masked, cross-over design, for 16-week periods. During the study, as-needed albuterol use was discontinued and ipratropium bromide was used as needed. Morning peak expiratory flow rate (PEFR) was the primary outcome variable. The primary comparisons were between treatment period for each genotype; the secondary outcome was a treatment by genotype effect. Analyses were by intention to treat.
During the run-in period, when albuterol use was kept to a minimum, patients with the Arg/Arg genotype had an increase in morning PEFR of 23 L/min (p=0.0162); the change in patients with the Gly/Gly genotype was not significant (2 L/min; p=0.8399). During randomised treatment, patients with the Gly/Gly genotype had an increase in morning PEFR during treatment with regularly scheduled albuterol compared with placebo (14 L/min [95% CI 3 to 25]; p=0.0175). By contrast, patients with the Arg/Arg genotype had lower morning PEFR during treatment with albuterol than during the placebo period, when albuterol use was limited (-10 L/min [-19 to -2]; p=0.0209). The genotype-attributable treatment difference was therefore -24 L/min (-37 to -12; p=0.0003). There were similar genotype-specific effects in FEV1, symptoms, and use of supplementary reliever medication.
Genotype at the 16th aminoacid residue of the beta2-adrenergic receptor affects the long-term response to albuterol use. Bronchodilator treatments avoiding albuterol may be appropriate for patients with the Arg/Arg genotype.
"Studies have reported an association between glioma susceptibility and various inflammatory factors that either modulate the immune response or serve as a surrogate for immune dysfunction (e.g., polymorphisms in immune genes, immunoglobulin E levels (IgE), atopic conditions and use of antihistamine) 22, 23. Interleukin-4 is one of the key players in an immune response and dysregulation in the production of this cytokine and/or its receptor may strongly influence the immune system with subsequent decreased or increased susceptibility to glioma 24. The results from our current study clearly indicate a protective role of SNPs in the IL-4 (rs2070784) and IL-4R (rs1805015) gene against glioma. "
[Show abstract][Hide abstract] ABSTRACT: Glioma is the most common and believed to be one of the most aggressive tumors of the central nervous system (CNS) in humans. Very little information is available on the etiology and pathogenesis of these tumors to date. A significant gap remains in our current understanding of the molecular pathways involved in the genesis, progression and clinical behavior of these tumors. Recently, several single nucleotide polymorphisms (SNPs) have been identified in cytokine gene sequences, particularly within the promoter region of these genes, and have been shown to be associated with the development of different types of brain tumors. The present study investigates the association of C-33T SNP in the interleukin-4 (IL-4) gene with systemic IL-4 level and the S503P SNP in the IL-4R gene with the incidence of glioma.
Blood samples were collected from 100 histologically confirmed adult patients with glioma, and 30 apparently healthy individuals from the same area. DNA was extracted from each blood sample, and the IL-4 and IL-4R genes were amplified using polymerase chain reaction (PCR) with gene-specific primers. Systemic IL-4 concentration was assessed in serum samples from each participant by enzyme-linked immunosorbent assay (ELISA). We observed a negative association between the homozygous genotype (CC) of the SNP C-33T of the IL-4 gene with the incidence of glioma (OR=0.19, 95% CI=0.035-1.02), while the T allele of the SNP demonstrated a significant protective association against glioma. Similarly, the heterozygous (CT) and homozygous mutant (CC) of the SNP S503P of the IL-4R gene demonstrated a significant association with glioma development (OR=0.405, 95% CI=0.17-0.969 and OR=0.147, 95% CI=0.036-0.6 respectively), while the C allele exhibited a highly significant association with protection from glioma formation.
These findings suggest that the T allele of the SNP C-33T in the IL-4 gene and the C allele of the SNP S503P in IL-4R may have a protective role against glioma development.
International journal of medical sciences 08/2014; 11(11):1147-1153. DOI:10.7150/ijms.9412 · 2.00 Impact Factor
"These results supported an ADRB2 genotype effect on responses to LABA therapy. Furthermore, two retrospective studies showed an ADRB2 genotype effect on response to therapy with the β2-agonists [15,16]. In addition, our results were different from a Korean study which suggested that the ADRB2 genotype may dictate choice of treatment strategy [17,18]. "
[Show abstract][Hide abstract] ABSTRACT: To evaluate the effect of variation of the Arg16Gly polymorphism of the beta2-adrenergic receptor gene on clinical response to salmeterol administered with fluticasone propionate in Chinese Han asthmatic patients.
Moderate persistent asthmatic patients (n = 62) currently receiving short-acting beta2-agonists were administered twice-daily therapy with salmeterol/fluticasone propionate 50/250 mug in a single inhaler for 12 weeks, followed by a 2-to-4-day run-out period. Using direct DNA sequencing, five single nucleotide polymorphisms (SNPs) in the promoter and coding block regions of beta2-adrenergic receptor gene were determined in 62 subjects and haplotypes were combined.
There was sustained and significant improvement (p < 0.001) over baseline in all measures of asthma control in subjects receiving salmeterol and fluticasone, regardless of Arg16Gly genotype. However, there was no significant difference in the improvement among three genotypes (p > 0.05). Responses to salmeterol did not appear to be modified by haplotype pairs (p > 0.05). During the run-out period, all subjects had similar decreases in measures of asthma control, with no differences between genotypes (p > 0.05).
Response to salmeterol does not vary with Arg16Gly polymorphism after chronic dosing with inhaled corticosteroids in Chinese Han asthmatic patients.
Multidisciplinary respiratory medicine 04/2014; 9(1):22. DOI:10.1186/2049-6958-9-22 · 0.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Glycine allele at codon 16 has previously been associated with the increase in asthma severity, bronchial hyperresponsiveness and also the increase in inhaled corticosteroid dependence. This study was designed to evaluate the genetic alleles in mild asthma.
Thirty-four patients with diagnosis of mild asthma (FEV1 ≥ 80%, positive methacholine test) and body mass index (BMI ≤ 30 Kg/m2) were included in the study. They could only use short acting beta-2 agonists for asthma control. Smoking, infection, occupational sensitizers’ exposure, gastroesophageal reflux, diabetes mellitus and heart failure were also considered as exclusion criteria. All patients were genotyped at 16th and 27th codons.
Among all, 20 (58.8%) Arg/Gly, 14 (41.2%) Arg/Arg and no Gly/Gly genotype were detected at codon 16. Genotyping at codon 27 revealed 2 (5.9%) Glu/Glu, 13 (38.2%) Glu/Gln and 18 Gln/Gln (52.9%).
Based on the obtained results, Arg/Gly mutation had a higher rate among the studied subjects compared to Arg/Arg polymorphism. This is a pilot study which shows a probable usefulness of genotyping for predicting of asthma severity.
Iranian journal of pharmaceutical research (IJPR) 03/2013; 12(1):199-204. · 1.07 Impact Factor
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