John Tsanakas

A coding polymorphism in the CYSLT2 receptor with reduced affinity to LTD4 is associated with asthma

BACKGROUND Cysteinyl leukotrienes (CYSLTR) are potent biological mediators in the pathophysiology of asthma for which two receptors have been characterized, CYSLTR1 and CYSLTR2. The leukotriene modifying agents currently used to control bronchoconstriction and inflammation in asthmatic patients are CYSLTR1-specific leukotriene receptor antagonists. In this report, we investigated a possible role for therapeutic modulation of CYSLTR2 in asthma by investigating genetic association with asthma and further characterization of the pharmacology of a coding polymorphism. METHODS The association of CYSLTR2 polymorphisms with asthma was assessed by transmission disequilibrium test in two family-based collections (359 families from Denmark and Minnesota, USA and 384 families from the Genetics of Asthma International Network). RESULTS A significant association of the coding polymorphism, 601A>G, with asthma was observed (P = 0.003). We replicated these findings in a collection of 384 families from the Genetics of Asthma International Network (P = 0.04). The G allele is significantly under-transmitted to asthmatics, indicating a possible role for this receptor in resistance to asthma. The potency of cysteinyl leukotrienes at the wild-type CYSLTR2 and the coding polymorphism 601A>G were assessed using a calcium mobilization assay. The potency of LTC4 and LTE4 was similar for both forms of the receptor and LTB4 was inactive, however, LTD4 was approximately five-fold less potent on 601A>G compared to wild-type CYSLTR2. CONCLUSIONS Since 601A>G alters the potency of LTD4 and this variant allele may be associated with resistance to asthma, it is possible that modulation of the CYSLTR2 may be useful in asthma pharmacotherapy.

A genome-wide search for linkage to asthma phenotypes in the genetics of asthma international network families: evidence for a major susceptibility locus on chromosome 2p

Asthma is a complex disease and the intricate interplay between genetic and environmental factors underlies the overall phenotype of the disease. Families with at least two siblings with asthma were collected from Europe, Australia and the US. A genome scan using a set of 364 families with a panel of 396 microsatellite markers was conducted. Nonparametric linkage analyses were conducted for asthma and three asthma-related phenotypes: bronchial hyper-reactivity (BHR), strict definition of asthma and atopic asthma. Nine chromosomal regions with LOD scores greater than 1.5 were identified (chromosomes 1q, 2p, 3q, 4p, 4q, 6q, 12q, 20p and 21). Linkage refinement analysis was performed for three BHR loci by genotyping single nucleotide polymorphisms at an average marker density of 1 cM. The LOD scores increased to 3.07 at chromosome 4p and 4.58 at chromosome 2p, while the chromosome 6p locus did not refine. The LOD score at the chromosome 2p locus is highly significant on a genome-wide basis. The refined locus covers a region with a physical size of 12.2 Mb. Taken together, these results provide evidence for a major asthma susceptibility locus on chromosome 2p.

Loss of FEV1 in cystic fibrosis: correlation with HRCT features

Abstract. The purpose of this study was to determine which high-resolution computed tomography (HRCT) features in patients with cystic fibrosis are most strongly associated with functional impairment as expressed by forced expiratory volume in one second (FEV1). Forty-seven patients with cystic fibrosis underwent chest HRCT and had pulmonary function tests. The HRCT examinations were evaluated for 11 features scored using a modification of Bhalla system and FEV1 was recorded as percentage of the predicted value. Univariate and multivariate correlations between HRCT scores and FEV1 were performed. The most common HRCT feature was bronchiectasis (98%) followed by atelectasis–consolidation (81%), bronchial wall thickening (77%), tree-in-bud sign (74%), mucous plugging (72%) and mosaic perfusion pattern (47%). On univariate analysis the following features correlated strongly with FEV1: bronchial wall thickening (p<0.0000001), tree-in-bud sign (p<0.0000001), mucous plugging (p<0.0000001), atelectasis–consolidation (p<0.0000001), thickening of interlobular septa (p<0.0002), severity (p<0.0002) and extent of bronchiectasis (p<0.0002). On multivariate analysis bronchial wall thickening and atelectasis–consolidation were the strongest independent determinants of the FEV1. We found a regression equation between FEV1 and the two HRCT features: FEV1=constant variable+a multiplied by bronchial wall thickening+b multiplied by atelectasis–consolidation (a and b=regression coefficients, R2=0.48). The major morphological determinants of functional abnormality in cystic fibrosis, as expressed by the loss of FEV1, are bronchial wall thickening and atelectasis–consolidation.

International variations in associations of allergic markers and diseases in children: ISAAC Phase Two.

To cite this article: Weinmayr G, Genuneit J, Nagel G, Björkstén B, van Hage M, Priftanji A, Cooper P, Rijkjärv M‐A, von Mutius E, Tsanakas J, Forastiere F, Doekes G, Garrido JB, Suarez‐Varela MM, Bråbäck L, Strachan DP, the ISAAC Phase Two Study Group. International variations in associations of allergic markers and diseases in children: ISAAC Phase Two. Allergy 2010; 65: 766–775.

Factor analysis in the Genetics of Asthma International Network family study identifies five major quantitative asthma phenotypes

Background Asthma is a clinically heterogeneous disease caused by a complex interaction between genetic susceptibility and diverse environmental factors. In common with other complex diseases the lack of a standardized scheme to evaluate the phenotypic variability poses challenges in identifying the contribution of genes and environments to disease expression.

Determinants of Quality of Life in Children With Asthma

HRQoL in children with asthma depends on multiple factors, among which asthma severity and level of control are believed to play a vital role. The determinants of the connection between asthma severity and asthma control with quality of life remain unclear.

Aspergillus and the paediatric lung

Aspergillus spp produce a wide range of saprophytic and invasive syndromes in the lungs, including allergic bronchopulmonary aspergillosis (ABPA), aspergilloma and invasive pulmonary aspergillosis (IPA). ABPA results from hypersensitivity to the fungus, and mainly affects patients with asthma or cystic fibrosis (CF). The treatment of choice consists of systemic corticosteroids and itraconazole. Aspergilloma is managed by observation or surgery. IPA is predominantly seen in patients with haematological malignancies, chronic granulomatous disease or immunosuppressive treatment. With the use of aggressive therapies for end-stage CF, such as heart-lung transplantation, the potential for a patient to convert from colonization or ABPA to IPA has increased. Suggestive clinical and radiological findings, supplemented with mycological data using serology and molecular biology, have enhanced the capacity to diagnose IPA in paediatric patients. While voriconazole is considered the first-line therapy in IPA, several other antifungal agents may be appropriate alternatives.

A Bayesian Approach to Copy-Number-Polymorphism Analysis in Nuclear Pedigrees

Segmental copy-number polymorphisms (CNPs) represent a significant component of human genetic variation and are likely to contribute to disease susceptibility. These potentially multiallelic and highly polymorphic systems present new challenges to family-based genetic-analysis tools that commonly assume codominant markers and allow for no genotyping error. The copy-number quantitation (CNP phenotype) represents the total number of segmental copies present in an individual and provides a means to infer, rather than to observe, the underlying allele segregation. We present an integrated approach to meet these challenges, in the form of a graphical model in which we infer the underlying CNP phenotype from the (single or replicate) quantitative measure within the analysis while assuming an allele-based system segregating through the pedigree. This approach can be readily applied to the study of any form of genetic measure, and the construction permits extension to a wide variety of hypothesis tests. We have implemented the basic model for use with nuclear families, and we illustrate its application through an analysis of the CNP located in gene CCL3L1 in 201 families with asthma.

Cough affects Quality of Life in asthmatic children aged 8-14 more than other asthma symptoms

BACKGROUND Asthma may influence childrens health-related quality of life (QoL) differently by various symptoms, at different severity. The primary aim of this study was to evaluate the QoL in children with asthma and describe the impact of each asthma symptom on the childs well-being at different severity levels. MATERIAL AND METHODS Two hundred randomly selected children and one of their parents who consulted an outpatient asthma clinic, participated in the study. Qol was assessed with DISABKIDS-Smiley measure for children aged 4-7 years and with DISABKIDS DCGM-37 and Asthma Module for children 8-14 year old. RESULTS Most of the children suffered from mild or moderate persistent asthma. Children with uncontrolled asthma stated lower QoL compared to partly controlled or controlled in both age groups (p < 0.05 in all domains). Cough appeared to affect QoL of 8-14 year olds more than other symptoms, especially in girls. In younger children, sex (boys, p = 0.039), age (p = 0.045), proxy sex (father, p = 0.048), frequency of doctor visits (4-6 months, p = 0.001), use of beta-2 agonists (p = 0.007) and fathers smoking habits (p = 0.015) were associated with the QoL of coughing children but no correlation between cough and QoL was detected. In the 8-14 year age group coughers reported lower QoL compared to their counterparts; moreover, cough was found to affect QoL more than other symptoms (p < 0.05 in all domains). CONCLUSIONS Cough has a direct effect on asthmatic childrens QoL but there is still an obvious need for research to reveal all the determinats of this effect.

Pediatric inflammatory myofibroblastic tumor of the trachea: A case report and review of the literature

Inflammatory myofibroblastic tumors (IMTs) are relatively rare entities of a distinct histologic appearance and benign clinical course. Although these lesions have been described in virtually every anatomic location, there are few documented reports with tracheal localization. We add to the short list of pediatric IMTs of the trachea, a 13‐year‐old boy that was referred to our pediatric respiratory unit for evaluation of his respiratory distress. In particular, we describe the clinical and pathologic features of this patient and present a review of all reported lesions in the available literature. Pediatr Pulmonol. 2008; 43:831–835.