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Background: Inhaled glucocorticosteroids reduce airway inflammation in asthma patients, thereby improving lung function and reducing airway hyperresponsiveness and symptoms. The response to glucocorticosteroids can be measured with the glucocorticosteroid skin-blanching test. We investigated if asthmatics have a lower skin-blanching response to glucocorticosteroids than non-asthmatic subjects and if asthmatics with airway obstruction have lower skin-blanching response than those without obstruction. Finally, we assessed which clinical and inflammatory parameters influence the variability in skin-blanching response.Methods: We evaluated the skin-blanching response to topical budesonide in a large group of 315 well-characterized asthmatics and their relatives (asthma n = 114, healthy n = 140, other = 61)Results: The skin-blanching scores of the asthma probands and their healthy spouses were not significantly different. The skin-blanching score of patients with FEV1 Conclusions: Asthmatics do not have lower skin-blanching response to glucocorticosteroids than healthy subjects. Furthermore, lower skin-blanching response to glucocorticosteroids is associated with lower FEV1, female gender, higher age and the absence of allergy. Crown Copyright (C) 2012 Published by Elsevier Ltd. All rights reserved.

Inhaled corticosteroids (ICS) provide short term benefits in asthma but the long term effects are still unknown.281 patients diagnosed with moderate to severe asthma in 1963-75 were re-examined in 1991-9. Information was collected on forced expiratory volume in 1 second (FEV(1)), bronchial hyperresponsiveness, atopy, smoking, use and dosage of oral and ICS. Patients were included in the analyses if they had at least three FEV(1) measurements during two consecutive years after the age of 30 and used ICS during follow up.Analyses were performed on 122 patients. During a median follow up period of 23 years, 71 men and 51 women had on average 37 and 40 individual FEV(1) measurements, respectively. Linear mixed effect models showed that men had a mean annual decline in FEV(1) of 20.6 ml/year less after ICS initiation than before (p = 0.011), and in women the decline in FEV(1) was 3.2 ml/year less (p = 0.73). In individuals with5 pack years of smoking the decline in FEV(1) was 36.8 ml/year less after ICS institution in men (p = 0.0097) and 0.8 ml/year less in women (p = 0.94), the difference between the sexes being significant (p = 0.045). These effects were not observed in those withor =5 pack years smoking. A higher daily dose of ICS was associated with a smaller decline in FEV(1) in men (p = 0.006), an effect not observed in women.Treatment with ICS in adult patients with moderate to severe asthma was associated with a reduction in the decline in FEV(1) over a 23 year follow up period in men who had smoked5 pack years. This effect was dose dependent and was not present in women or in men withor =5 pack years of smoking at follow up. The lack of effect of ICS on the decline in FEV(1) in women needs further study.

Single-nucleotide polymorphisms of the beta(2)-adrenergic receptor gene and its 5 ' promoter have been associated with differences in receptor function and desensitization. Linkage disequilibrium may account for inconsistencies in reported effects of isolated polymorphisms. Therefore, we have investigated the three most common homozygous haplotypes of the beta(2)-adrenergic receptor (position 19 [Cys/Arg] of the 5 ' leader cistron and positions 16 [Arg/Gly] and 27 [Gln/Glu] of the receptor) for putative differences in agonist-induced desensitization. Lymphocytes of well defined nonasthmatic, nonallergic subjects homozygous for the haplotype CysGlyGln, ArgGlyGlu, or CysArgGln were isolated. Desensitization of (-)-isoproterenol-induced cyclic adenosine monophosphate (CAMP) accumulation and beta(2)-adrenergic receptor sequestration and downregulation were measured in relation to beta(2)-adrenergic receptor-mediated inhibition of IFN-gamma and interleukin-5 production. We observed that lymphocytes of individuals bearing the CysGlyGln haplotype were more susceptible to desensitization of the P-agonist-induced cAMP response than those of individuals with the ArgGlyGlu or CysArgGln haplotype. The haplotype-dependent desensitization of R-agonist induced CAMP response was not associated with haplotype-dependent beta 2-adrenergic receptor sequestration or downregulation. In addition, our data suggest reduced inhibition, in lymphocytes of subjects with the CysGlyGln haplotype, of interleukin-5 production induced by treatment with antibodies to the T-cell receptor-CD3 complex and to costimulatory molecule CD28 (alpha CD3/alpha CD28). This is the first study demonstrating haplotype-related differences in agonist-induced beta(2)-adrenergic receptor desensitization in primary human cells. This haplotype-related desensitization of the beta(2)-adrenergic receptor in lymphocytes might have consequences regarding the regulation of helper T-cell type 2 inflammatory responses.

Changes in pulmonary function are important in determining asthma outcome. Genetic factors may influence airway obstruction in asthma. We performed a genomewide screen in 200 families of probands objectively diagnosed with asthma in the 1960s to identify chromosomal regions related to changes in pre- and postbronchodilator lung function (FEV1, VC, and FEV1%VC) and assess influences of early-life smoke exposure. Smoking (pack-years), age, sex, and height were covariates in variance component analyses. Significant evidence for linkage of pre- and postbronchodilator FEV1%VC was obtained for chromosome 2q32 (LOD, 4.9, increasing to 6.03 with additional fine-mapping markers, and 3.2, respectively). Linkage existed for chromosome 5q for pre- and postbronchodilator VC (likelihood of disease [LOD], 1.8 and 2.6, respectively). Results for pre- and postbronchodilator FEV1 were less significant (LOD, 1.5 and 1.6, chromosomes 11 p and 10q, respectively). Results were not affected by passive smoke exposure. There is significant evidence for linkage of FEV1%VC to chromosome 2q32 in families of probands with asthma, 35 cM proximal from linkage previously observed in families of probands with early-onset chronic obstructive pulmonary disease. Thus, there may be multiple genes on chromosome 2q that are important in determining presence and degree of airflow limitation in families ascertained for obstructive airway disease.

Background: Childhood asthma is generally believed to be a disorder with a good prognosis. However, some asthmatics develop irreversible airway obstruction, probably as a result of airway remodelling. Methods: After 21–33 years, 228 adults (aged 13–44 years at baseline) with a history of asthma were re-examined to assess risk factors for the development of irreversible airway obstruction (IAO, forced expiratory volume in 1 second (FEV1)

Segregation and linkage analyses were performed for adult height in a population of 200 Dutch families, each of which was ascertained through a proband with asthma. The best-fit model from the segregation analysis was a major recessive gene with a significant residual polygenic background. Models without a polygenic component were rejected. A genomewide scan was performed, and it confirmed previous linkage results for chromosomes 6q25 (LOD = 3.06, D6S2436), 9p1 (LOD = 2.09, D9S301), and 12q1 (LOD = 1.86, D12S375). Our results provide evidence that a combination of segregation and linkage approaches is valuable in understanding genetic determination of common complex traits.