Asthma is a common respiratory disorder characterized by recurrent episodes of coughing, wheezing and breathlessness. Although environmental factors such as allergen exposure are risk factors in the development of asthma, both twin and family studies point to a strong genetic component. To date, linkage studies have identified more than a dozen genomic regions linked to asthma. In this study, we performed a genome-wide scan on 460 Caucasian families and identified a locus on chromosome 20p13 that was linked to asthma (log(10) of the likelihood ratio (LOD), 2.94) and bronchial hyperresponsiveness (LOD, 3.93). A survey of 135 polymorphisms in 23 genes identified the ADAM33 gene as being significantly associated with asthma using case-control, transmission disequilibrium and haplotype analyses (P = 0.04 0.000003). ADAM proteins are membrane-anchored metalloproteases with diverse functions, which include the shedding of cell-surface proteins such as cytokines and cytokine receptors. The identification and characterization of ADAM33, a putative asthma susceptibility gene identified by positional cloning in an outbred population, should provide insights into the pathogenesis and natural history of this common disease.

Recent in vitro studies suggest that IgE production in adults is co-ordinately regulated by negative signals from gamma IFN-producing CD4+ T-helper-1 (TH-1) and positive signals from IL-4 producing (TH-2) T-cells. Additionally, seroepidemiological evidence has pinpointed infancy as the period of maximum lifetime risk for T-cell sensitization to ubiquitous environmental antigens. The present study sought to elucidate the relationship between these observations, by examination of CD4+ T-cell function in normal children and those genetically at 'high risk' for atopy, spanning the age range (up to 4 years) in which IgE responses to environmental allergens is typically manifest. Immunocompetent T-cell precursor frequencies (determined by cloning at limiting dilution) were markedly reduced in 'high risk' children relative to normals (0.53 +/- 0.29 vs 0.26 +/- 0.19; P = 0.0025). Consistent with reports from other laboratories employing bulk T-cell culture techniques, the gamma IFN producing capacity of CD4+ T-cell clones from both groups of children were markedly reduced relative to adults, and was lowest in the high risk group (P < 0.02). IL-4 production by CD4+ T-cell clones from the normal children was within the adult range, but again was significantly lower in the high risk group (P < 0.00005). This indicates that initial immune responses to environmental allergens in early childhood occur against a background of maturational 'deficiency' in CD4+ T-cell function, and suggests the possibility that variations in the rate of postnatal maturation of T-cell competence may be a contributing factor in the development of differing patterns of immunological responsiveness to environmental allergens.

Endotoxin exposure may have a protective effect against asthma and atopy. An Asp299Gly polymorphism in the Toll-like receptor 4 (TLR4) gene reduces responsiveness to endotoxin. This study determined the effect of TLR4 polymorphism on the risk and severity of asthma and atopy. In all, 336 UK Caucasian families with Z2 affected sibs (physician's diagnosis of asthma and current medication use) and 179 Caucasians without asthma or a family history of asthma were genotyped using ARMS-PCR. No association of the TLR4 polymorphism was found with the risk of developing asthma, either in parent-affected sibling trios, or in case-control analyses (P40.05). In the first affected asthmatic siblings, the atopy severity score (based on size and number of positive skin-prick tests and specific IgE) was higher in those with the Asp/Gly or Gly/Gly genotypes (mean 1.8, s.d. 1.1, n¼39) compared to those with the Asp/Asp genotype (mean 1.2, s.d. 1.0, n¼279) (P¼0.003, t-test). No associations were found with total IgE, FEV 1 % predicted, slope of FEV 1 response to methacholine or asthma severity score (P40.05). This study confirms the previously observed lack of association of TLR4 polymorphisms with asthma. In contrast, the findings suggest that genetically determined hyporesponsiveness to endotoxin may increase atopy severity.

Our data suggest that polymorphisms in the IL-4 and IL-4Ralpha chain genes might play a role both conferring susceptibility to and modulating severity of atopy and asthma.

Recurrent lower respiratory tract symptoms are common and disabling in childhood, but little is known of their natural history and relationship to asthma. We report a 12-month longitudinal study designed to determine the influence of atopy on respiratory symptoms and bronchial responsiveness in 7- and 8-yr-old children. A postal questionnaire inquiring into the presence of respiratory symptoms was sent to 3,698 children aged 7 and 8 yr. Those reporting either current wheeze (14.8%) or current cough in the absence of wheeze (12.8%) were randomized, and a sample was invited to attend for skin testing. The following groups of symptomatic children entered the longitudinal study: 48 atopic children with cough, 48 atopic children with wheeze, 48 nonatopic children with cough, and 48 nonatopic children with wheeze. All children recorded twice daily the best of three peak expiratory flow (PEF) measurements and completed a 10-point symptom score card, each day for 1 yr. They also recorded all treatment taken and made a note of relevant life events. Each child was seen monthly for general assessment and for measurement of methacholine bronchial responsiveness. Despite the arduous nature of the study 183 of the 192 children (95.3%) successfully completed the 12 months of observation. Symptom groups were compared with regard to FEV1, bronchial responsiveness, symptom chronicity and severity, and diurnal and day-to-day variation in PEF. Atopy was associated with a lower FEV1, increased prevalence of bronchial hyperresponsiveness, greater within-day and between-day variation in PEF, and greater severity of respiratory symptoms compared with the absence of atopy. Wheeze was associated with lower FEV1, increased prevalence of bronchial hyperresponsiveness, greater within-day and between-day variation in PEF1 and greater severity of respiratory symptoms compared with cough [corrected].

Early intervention strategies in infant wheezing will be dependent on the ability to predict persistence of disease. We undertook a prospective longitudinal study to determine which factors might be predictive for the persistence of wheeze. We examined a group of 107 children 3 to 36 mo of age with at least one atopic parent. Children were recruited within 12 wk of first wheeze. Factors assessed included: personal atopy (IgE > 1 SD above age-related normal and/or eczema and/or positive skin tests); parental atopy; number of siblings; age at first wheeze; sex; serum-soluble IL-2R; proliferation of peripheral blood mononuclear cells (PBMC) to beta-lactoglobulin and to D. pteronyssinus; production of IFN-gamma on stimulation of PBMC with beta-lactoglobulin and with D. pteronyssinus. A positive clinical outcome (child requiring prophylactic antiasthma treatment after 1 yr) was observed in 53 (49.5%) children. Predictor variables were assessed by univariate and multivariate logistic regression. Wheeze was more likely to be persistent in older, atopic children with biparental atopy. The model offering best prediction of persistent wheeze with least risk of including asymptomatic subjects was age at presentation + sIL-2R. Trials of early intervention strategies using a logistic regression equation based on this model for patient recruitment can now be designed.

A cohort of 2,289 children, previously studied at the age of 6-8 yr, were followed up by means of a postal questionnaire when aged 14 -16 yr to examine the association between potential risk factors and the natural history of respiratory symptoms. Children with current symptoms, persistent symptoms, and late-onset symptoms were identified and multivariate analyses were performed to determine the independent association between risk factors and these various symptom-based subgroups. Personal and family history of atopy was significantly associated with all symptom groups and with the presence of doctor-diagnosed asthma. Smoking, either active or passive, was shown to be significantly associated with current, persistent, and late-onset symptoms. Other factors shown to be significantly associated with certain symptom groups were gender (late-onset wheeze), single-parent households (current cough, persistent cough), social class (late-onset wheeze), number of children in the household (persistent wheeze, late-onset cough), number of furry pets in the household (current wheeze), birth weight (late-onset wheeze), and gas cookers (current wheeze, persistent wheeze). In a subgroup of children studied in more detail in 1987, bronchial hyperresponsiveness in 1987 was positively associated with persistent wheeze in 1995, whereas positive skin-prick testing in 1987 was not.

Taken together, these data do not support a significant role for these polymorphisms in genetic susceptibility to asthma in the Caucasian population.