Tracking the peer-review process.
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Internet↗
Biomedical subjects
J M Drazen
Publications and source records attributed to J M Drazen.
The Republican and Democratic candidates speak on health care.
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Confidentiality↗
Looking forward to serving you every week.
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Genome, Human↗
A neuronal NO synthase (NOS1) gene polymorphism is associated with asthma.
Recent family-based studies have revealed evidence for linkage of chromosomal region 12q to both asthma and high total serum immunoglobulin E (IgE) levels. Among the candidate genes in this region for asthma is neuronal nitric oxide synthase (NOS1). We sought a genetic association between a polymorphism in the NOS1 gene and the diagnosis of asthma, using a case-control design. Frequencies for allele 17 and 18 of a CA repeat in exon 29 of the NOS1 gene were significantly different between 490 asthmatic and 350 control subjects. Allele 17 was more common in the asthmatics (0.83 vs 0.76, or 1.49 [95% CI 1.17-1.90], P = 0.013) while allele 18 was less common in the asthmatics (0.06 vs 0.12, or 0.49 [95% CI 0.34-0. 69], P = 0.0004). To confirm these results we genotyped an additional 1131 control subjects and found the frequencies of alleles 17 and 18 to be virtually identical to those ascertained in our original control subjects. Total serum IgE was not associated with any allele of the polymorphism. These findings provide support, from case-control association analysis, for NOS1 as a candidate gene for asthma.
Adult↗
5' flanking region polymorphism of the gene encoding leukotriene C4 synthase does not correlate with the aspirin-intolerant asthma phenotype in the United States.
BACKGROUND: Approximately 10% of patients with asthma have a distinct clinical entity in which their symptoms are exacerbated by aspirin and most other nonsteroidal anti-inflammatory agents. These individuals typically have significant basal overproduction of cysteinyl leukotrienes, and within their biosynthetic pathway, the terminal enzyme, leukotriene C(4) synthase (LTC(4)S), is significantly overexpressed. A single nucleotide polymorphism consisting of an adenine (A) to cytosine (C) transversion -444 nucleotides upstream of the ATG translation start site in the LTC(4)S gene has been associated with a relative risk of 3.89 for the aspirin-intolerant phenotype in Polish patients. OBJECTIVE: These studies were undertaken to further investigate the functional effect of this allele in LTC(4)S gene expression and subsequently to determine whether an association between the presence of this polymorphism and aspirin-intolerant asthma existed within patients of the United States. METHODS: Functionality of the C-444 allele was assessed by using promoter-reporter constructs and transient transfection assays in the THP-1 monocytic cell line. Genotyping was performed on 137 unaffected control subjects, 33 patients with aspirin-tolerant asthma, and 61 patients with aspirin-intolerant asthma from the United States. RESULTS: Promoter-reporter constructs containing the C-444 allele revealed no significant upregulatory or downregulatory effects in the transcription of the LTC(4)S gene. The LTC(4)S genotype distribution was consistent with the Hardy-Weinberg equilibrium in patients with aspirin-tolerant asthma and unaffected control subjects but not in patients with aspirin-intolerant asthma; however, the distributions were not significantly different among the phenotype groups. CONCLUSIONS: Our data demonstrate that the C-444 allele in the LTC4S gene is not statistically different among patients with the aspirin-intolerant asthmatic phenotype, patients with the aspirin-tolerant asthmatic phenotype, and unaffected control subjects in the United States. This finding, along with the lack of functionality of this polymorphism, suggest that it is not related to a specific asthma phenotype and may represent a population-stratified polymorphism within patients of eastern European descent.
Alleles↗
Asthma exacerbations during long term beta agonist use: influence of beta(2) adrenoceptor polymorphism.
BACKGROUND: Polymorphisms of the beta(2) adrenoceptor influence receptor function in vitro and asthma phenotypes in vivo. However, their importance in determining responses to inhaled beta agonist treatment has not been clearly defined. METHODS: In a retrospective analysis of previously published data we have examined relationships between polymorphisms at codons 16 and 27 of the beta(2) adrenoceptor and clinical outcomes in a randomised, placebo controlled, crossover trial of regularly scheduled salbutamol and salmeterol in 115 patients with mild to moderate asthma. Genotyping was obtained for positions 16 and 27 in 108 and 107 patients, respectively. For position 16, 17 patients (16%) were homozygous Arg-Arg, 40 (37%) were heterozygous Arg-Gly, and 51 (47%) were homozygous Gly-Gly. RESULTS: Within the homozygous Arg-16 group major exacerbations were more frequent during salbutamol treatment than with placebo (1.91 (95% CI 1.07 to 3.12) per year versus 0.81 (95% CI 0.28 to 1.66) per year; p = 0.005). No significant treatment related differences occurred for heterozygous Arg-Gly patients (salbutamol 0.11 (95% CI 0.01 to 0.40), placebo 0.54 (95% CI 0.26 to 1.00) exacerbations per year) or homozygous Gly-16 patients (salbutamol 0.38 (95% CI 0.17 to 0.73), placebo 0.30 (95% CI 0.12 to 0.61) exacerbations per year). No adverse changes occurred for any position 16 subgroup with salmeterol. There was no significant relationship between position 27 genotypes and treatment related outcomes. CONCLUSION: Homozygous Arg-16 patients are susceptible to clinically important increases in asthma exacerbations during chronic dosing with the short acting beta(2) agonist salbutamol.
Adolescent↗
Molecular responses of rat tracheal epithelial cells to transmembrane pressure.
Smooth muscle constriction in asthma causes the airway to buckle into a rosette pattern, folding the epithelium into deep crevasses. The epithelial cells in these folds are pushed up against each other and thereby experience compressive stresses. To study the epithelial cell response to compressive stress, we subjected primary cultures of rat tracheal epithelial cells to constant elevated pressures on their apical surface (i.e., a transmembrane pressure) and examined changes in the expression of genes that are important for extracellular matrix production and maintenance of smooth muscle activation. Northern blot analysis of RNA extracted from cells subjected to transmembrane pressure showed induction of early growth response-1 (Egr-1), endothelin-1, and transforming growth factor-beta1 in a pressure-dependent and time-dependent manner. Increases in Egr-1 protein were detected by immunohistochemistry. Our results demonstrate that airway epithelial cells respond rapidly to compressive stresses. Potential transduction mechanisms of transmembrane pressure were also investigated.
Animals↗
Exhaled nitric oxide following repeated spirometry or repeated plethysmography in healthy individuals.
Subjects with asthma have higher concentrations of exhaled nitric oxide (NO) than normal individuals. It has been demonstrated that in asthmatics, repeated FVC maneuvers reduce NO. Although the cause of this phenomenon is not known, it has been hypothesized that deep breaths associated with FVC maneuvers reduce exhaled NO by affecting neural sources of NO, possibly via a mechanism related to the pathobiology of asthma. To establish whether FVC maneuvers influence NO concentrations in normal individuals, we measured exhaled NO at baseline values and after FVC maneuvers performed every 15 min for 1 h in subjects without asthma. To investigate the role of deep breaths in reducing exhaled NO, we compared these results with concentrations of exhaled NO after plethysmography. Repeated FVC maneuvers over 60 min produced a decrease in NO concentrations in mixed expired gas (F(E)NO; 24.6 +/- 5.1% decrease for F(E)NO, p < 0. 01 versus baseline). In contrast to the results after spirometry, repeated specific airway conductance (sGaw) maneuvers do not have a significant effect on F(E)NO (p = 0.16). These results, which demonstrate that in nonasthmatic subjects FVC maneuvers-but not panting maneuvers-produce a fall in NO, suggest that the mechanism responsible for the reduction in exhaled NO after FVC maneuvers is related to volume history of the lung rather than the pathobiology of asthma.
Adult↗
Genetic variations in the 5-lipoxygenase core promoter. Description and functional implications.
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Animals↗
The effect of polymorphisms of the beta(2)-adrenergic receptor on the response to regular use of albuterol in asthma.
Inhaled beta-adrenergic agonists are the most commonly used medications for the treatment of asthma although there is evidence that regular use may produce adverse effects in some patients. Polymorphisms of the beta(2)-adrenergic receptor (beta(2)-AR) can affect regulation of the receptor. Smaller studies examining the effects of such polymorphisms on the response to beta-agonist therapy have produced inconsistent results. We examined whether polymorphisms at codon 16 (beta(2)-AR-16) and codon 27 (beta(2)-AR-27) of the beta(2)-AR might affect the response to regular versus as-needed use of albuterol by genotyping the 190 asthmatics who had participated in a trial examining the effects of regular versus as needed albuterol use. During the 16-wk treatment period there was a small decline in morning peak expiratory flow in patients homozygous for arginine at B(2)-AR-16 (Arg/Arg) who used albuterol regularly. This effect was magnified during a 4-wk run out period, during which all patients returned to using as-needed albuterol, so that by the end of the study Arg Arg patients who had regularly used albuterol had a morning peak expiratory flow 30. 5 +/- 12.1 L/min lower (p = 0.012) than Arg/Arg patients who had used albuterol on an as needed basis. There was no decline in peak flow with regular use of albuterol in patients who were homozygous for glycine at beta(2)-AR-16. Evening peak expiratory flow also declined in the Arg/Arg patients who used albuterol regularly but not in those who used albuterol on an as-needed basis. No significant differences in outcomes between regular and as-needed treatment were associated with polymorphisms at position 27 of the beta(2)-AR. No other differences in asthma outcomes that we investigated occurred in relation to these beta(2)-AR polymorphisms. Polymorphisms of the beta(2)-AR may influence airway responses to regular inhaled beta-agonist treatment.
Adolescent↗
Exhaled nitric oxide in patients with asthma: association with NOS1 genotype.
An increased concentration of nitric oxide (NO) in exhaled air (FENO) is now recognized as a critical component of the asthmatic phenotype. When we identified patients with asthma on the basis of a standard case definition alone, we found that they were remarkably heterogeneous with respect to their FENO. However, when we included genotype at a prominent asthma candidate gene (i.e., NOS1) in the case definition, and determined the number of AAT repeats in intron 20, we identified a remarkably homogeneous cohort of patients with respect to FENO. Both mean FENO (p = 0.00008) and variability around the mean (p = 0.000002) were significantly lower in asthmatic individuals with a high number (> or = 12) of AAT repeats at this locus than in those with fewer repeats. These data provide a biologically tenable link between genotype at a candidate gene in a region of linkage, NOS1, and an important component of the asthmatic phenotype, FENO. We show that addition of NOS1 genotype to the case definition of asthma allows the identification of a uniform cohort of patients, with respect to FENO, that would have been indistinguishable by other physiologic criteria. Our isolation of this homogeneous cohort of patients ties together the well-established associations among asthma, increased concentrations of NO in the exhaled air of asthmatic individuals, and variations of trinucleotide repeat sequences as identified in several neurologic conditions.
Adult↗
Airway nitric oxide levels in cystic fibrosis patients are related to a polymorphism in the neuronal nitric oxide synthase gene.
Patients with cystic fibrosis (CF) have decreased concentrations of expired nitric oxide (FENO) as compared with healthy individuals. A number of factors, including viscous mucus as a diffusion barrier for airway NO, consumption of NO by bacterial enzymes, and decreased NO production have been hypothesized to account for these low levels of FENO. We examined the relationship between the size of an AAT repeat polymorphism in intron 20 of the NOS1 gene and FENO in 75 patients with CF. Mean FENO was significantly (p = 0.027) lower in CF patients who harbored two alleles with a high number of repeats (>/= 12) than in those who harbored alleles with fewer repeats at this locus (4.0 +/- 0.8 [mean +/- SEM] ppb versus 6.4 +/- 0.9 ppb). Colonization of the airways with Pseudomonas aeruginosa was significantly (p = 0.0358) more common in CF patients with high numbers of AAT repeats in the NOS1 gene. Significant differences between NOS1 genotypes were also observed among patients homozygous for the cystic fibrosis transmembrane regulator delta F508 mutation for FENO (2.3 +/- 0.4 ppb versus 5.3 +/- 0.7 ppb, p = 0.0006), and this was also true for colonization of the airways with P. aeruginosa (p = 0.0147) and Aspergillus fumigatus (p = 0.0221). These data provide evidence that the NOS1 gene is not only associated with the variability of FENO, but also with P. aeruginosa colonization of airways in CF patients.
Adolescent↗
Gender-related differences in severe, early-onset chronic obstructive pulmonary disease.
Men have higher prevalence rates of chronic obstructive pulmonary disease (COPD) than women, which has been attributed to the historically higher rates of cigarette smoking in males. However, the increased rates of cigarette smoking in females within the last several decades have been associated with steadily increasing rates of COPD in women. As part of a study of the genetics of severe, early-onset COPD, we assembled a group of 84 probands with severe, early-onset COPD (without severe alpha(1)-antitrypsin deficiency) and 348 of their first-degree relatives. We found a markedly elevated prevalence (71.4%) of females among the early-onset COPD probands. Among the entire group of first-degree relatives of early-onset COPD probands, univariate analysis demonstrated similar spirometric values and bronchodilator responsiveness in males and females; however, among current or ex-smokers, female first-degree relatives had significantly lower FEV(1)/ FVC (81.4 +/- 17.2% in females versus 87.0 +/- 12.9% in males, p = 0.009) and significantly greater bronchodilator responsiveness (expressed as percentage of baseline FEV(1)) (7.7 +/- 9.4% pred in females versus 4.1 +/- 6.4% pred in males, p = 0.002). Female smoking first-degree relatives were significantly more likely to demonstrate profound reductions in FEV(1) (< 40% pred) than male smoking first-degree relatives (p = 0. 03). Multivariate analysis, performed with generalized estimating equations, demonstrated that current or ex-smoking female first-degree relatives had significantly greater risk of FEV(1) < 80% pred (OR 1.91, 95% CI 1.03- 3.54), FEV(1) < 40% pred (OR 3.56, 95% CI 1.08-11.71), and bronchodilator response greater than 10% of baseline FEV(1) (OR 4.74, 95% CI 1.91-11.75). These results suggest that women may be more susceptible to the development of severe COPD.
Adult↗
Polymorphism of the beta(2)-adrenergic receptor gene and desensitization in human airway smooth muscle.
We examined the influence of two common polymorphic forms of the beta(2)-adrenergic receptor (beta(2)AR): the Gly16 and Glu27 alleles, on acute and long-term beta(2)AR desensitization in human airway smooth muscle (HASM) cells. In cells from 15 individuals, considered without respect to genotype, pretreatment with Isoproterenol (ISO) at 10(-7) M for 1 h or 24 h caused approximately 25% and 64% decreases in the ability of subsequent ISO (10(-6) M) stimulation to reduce HASM cell stiffness as measured by magnetic twisting cytometry. Similar results were obtained with ISO-induced cyclic adenosine monophosphate (cAMP) as the outcome indicator. Data were then stratified post hoc by genotype. Cells containing at least one Glu27 allele (equivalent to presence of the Gly16Glu27 haplotype) showed significantly greater acute desensitization than did cells with no Glu27 allele, whether ISO-induced cell stiffness (34% versus 19%, p < 0.03) or cAMP formation (58% versus 11%, p < 0.02) was measured. Likewise, cells with any Glu27 allele showed greater long-term desensitization of cell stiffness and cAMP formation responses than did cells without the Glu27 allele. The distribution of genotypes limited direct conclusions about the influence of the Gly16 allele. However, presence of the Gly16Gln27 haplotype was associated with less acute and long-term desensitization of ISO-induced cAMP formation than was seen in cells without the Gly16Gln27 haplotype (14% versus 47%, p < 0.09 for short-term desensitization; 32% versus 84%, p < 0.01 for long-term desensitization), suggesting that the influence of Glu27 is not through its association with Gly16. The Glu27 allele was in strong linkage disequilibrium with the Arg19 allele, a polymorphic form of the beta(2)AR upstream peptide of the 5'-leader cistron of the beta(2)AR, and this polymorphism in the beta(2)AR 5'-flanking region may explain the effects of the Glu27 allele. Cells with any Arg19 allele showed significantly greater acute and long-term desensitization of ISO-induced cAMP formation than did cells without the Arg19 allele (54% versus 2%, p < 0.01 for short-term desensitization; 73% versus 35%, p < 0.05 for long-term desensitization). Similar results were obtained for ISO-induced changes in cell stiffness. Thus, the presence of the Glu27 allele is associated with increased acute and long-term desensitization in HASM.
Adrenergic beta-Agonists↗
Heterogeneity of therapeutic responses in asthma.
Asthma is a complex clinical syndrome with multiple genetic and environmental factors contributing to its phenotypic expression. This aetiological heterogeneity adds to the complexity when addressing variation in the response to anti-asthma treatment. Currently, there are three main lines of treatment available: (i) inhaled glucocorticoids which have multiple mechanisms of action; (ii) beta 2-agonists which are very effective bronchodilators and act predominantly on airway smooth muscle; and (iii) cysteinyl-leukotriene inhibitors. Analysis of the repeatability (r) of the treatment response, defined as the fraction of the total population variance which results from among-individual differences, shows values of r between 60-80% indicating that a substantial fraction of the variance of the treatment response could be genetic in nature. Among the sources of variability that could contribute to the observed heterogeneity in the response to treatment are the degree of underlying inflammation, such as in glucocorticoid resistance, and polymorphisms in the genes encoding the drug target, such as beta 2-adrenoceptor and 5-lipoxygenase.
Adaptor Protein Complex alpha Subunits↗
Churg-Strauss syndrome in patients receiving montelukast as treatment for asthma.
STUDY OBJECTIVES: We previously reported eight patients who developed Churg-Strauss syndrome in association with zafirlukast treatment for asthma and postulated that the syndrome resulted from unmasking of a previously existing condition due to corticosteroid withdrawal and not from a direct drug effect. The availability of montelukast, a new leukotriene receptor antagonist with a different molecular structure, permitted us to test this hypothesis. Our goals were to ascertain whether the Churg-Strauss syndrome developed in patients taking montelukast and other novel asthma medications, and to describe potential mechanisms for the syndrome. DESIGN: Case series. SETTING: Outpatient and hospital practices of pulmonologists in the United States and Belgium. PATIENTS: Four adults (one man, three women) who received montelukast as treatment for asthma; two women who received salmeterol/fluticasone therapy, but not montelukast. RESULTS: Churg-Strauss syndrome developed in the four asthmatic patients who received montelukast. In each case, there was a long history of difficult-to-control asthma characterized by multiple exacerbations that had required frequent courses of oral systemic corticosteroids or high doses of inhaled corticosteroids for control. Two other asthmatics who received fluticasone and salmeterol but not montelukast therapy developed the same syndrome with tapering doses of oral or high doses of inhaled corticosteroids. CONCLUSIONS: The occurrence of Churg-Strauss syndrome in asthmatic patients receiving leukotriene modifiers appears to be related to unmasking of an underlying vasculitic syndrome that is initially clinically recognized as moderate to severe asthma and treated with corticosteroids. Montelukast does not appear to directly cause the syndrome in these patients.
Acetates↗
Radiation hybrid and cytogenetic mapping of SOCS1 and SOCS2 to chromosomes 16p13 and 12q, respectively.
Suppressor of cytokine signaling (SOCS) proteins are involved in the negative regulation of cytokine-induced STAT (signal transducers and activators of transcription) factor signaling. We cloned genomic regions of SOCS1 and SOCS2 genes and mapped these genes to chromosome 16p12-p13.1 and chromosome 12q21.3-q23 regions, respectively, by cytogenetic and radiation hybrid mapping. In addition, we mapped SOCS2 by yeast artificial chromosome (YAC) pool screening to YAC contig WC 12.5 on chromosome 12 with an unambiguous hit to CHLC.ATA19H12 and WI-5940, which is 461.5 cR from the top of the map.
Carrier Proteins↗
Churg-Strauss syndrome.
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Anti-Asthmatic Agents↗