Association of asthma with a functional promoter polymorphism in the IL16 gene.

BACKGROUND: IL-16, a multifunctional cytokine with increased expression in the airways of asthmatic subjects, inhibits allergic airway inflammation in animal models. A T-->C single nucleotide polymorphism (SNP) at the -295 position in the promoter region of the IL16 gene has been described. OBJECTIVE: We sought to examine the functional significance of this promoter SNP and its relationship to asthma. METHODS: We examined the effect of the -295 SNP on promoter activity in cell-line (HBE4-E6/E7) transfection experiments. We investigated the association of the IL16 -295 genotype with asthma among 341 affected sib-pair white families and 184 unrelated nonasthmatic control subjects. We analyzed the association between the IL16 genotype and asthma using family-based association test and case-control analyses. RESULTS: In in vitro transfection experiments the T allele in the -295 position was associated with substantially reduced promoter activity compared with the C allele. In the family study the more common T allele at the -295 position was significantly associated with all asthma phenotypes (P = .002 to P = .015). In the case-control analysis asthmatic subjects were more likely than unrelated nonasthmatic control subjects to have the -295 TT genotype, but this did not reach statistical significance (odds ratio, 1.36; 95% CI, 0.92-2.02). CONCLUSIONS: The T allele at the -295 position in the IL16 promoter region is associated with reduced promoter activity relative to the C allele and with asthma in this white population. Further investigation is needed to delineate the mechanisms underlying these findings and the relationship of the IL16 -295 genotype to asthma in other populations.

Gas cooking and smoking habits and the risk of childhood and adolescent wheeze.

The authors investigated the risk of wheezing illnesses in relation to contemporaneous pollutant exposures (gas cooking, heating, and smoking) in childhood and adolescence in a cohort of 2,289 United Kingdom subjects. Data from two questionnaires assessing wheezing at ages 7-8 and 15-17 years and one questionnaire on current and past pollutant exposures at age 16-18 years were studied (1987-1996). The 1,868 subjects returning all three questionnaires were divided into three groups representing childhood (10.5%), adolescent (10.9%), and persistent (i.e., both; 16.3%) wheezing and compared with 1,165 controls (62.4%) without wheezing. The estimated risks of childhood wheezing were increased by exposure to any gas in childhood (odds ratio (OR) = 1.47, 95% confidence interval (CI): 1.05, 2.04) and exposure to a gas hob in childhood (OR = 1.56, 95% CI: 1.13, 2.16) and were increased further in those persistently exposed. Risk of persistent wheezing in adolescence was paradoxically reduced by exposure to a gas hob (OR = 0.67, 95% CI: 0.50, 0.91), possibly because of selection avoidance. Contemporaneous exposure to combined smoking by both parents was associated with wheezing in all groups (odds ratios ranged from 1.62 (95% CI: 1.06, 2.46) to 1.93 (95% CI: 1.10, 3.38)). Maternal smoking alone was associated with persistent wheezing and with both childhood (OR = 1.90, 95% CI: 1.06, 3.39) and persistent (OR = 2.18, 95% CI: 1.15, 4.14) wheezing if smoking occurred throughout childhood and adolescence. The authors conclude that exposures to gas cooking and smoking in childhood and adolescence increase the overall risk of wheezing.

Small size at birth and greater postnatal weight gain: relationships to diminished infant lung function.

Recent evidence suggests that impaired lung development is linked with diminished lung function and an increased risk of chronic obstructive airway disease in adulthood. To examine environmental influences on early lung development, we measured lung function in 131 normal-term infants aged 5-14 weeks. Adjusting for age at measurement, FEV at 0.4 seconds fell by 4.4% for each standard deviation decrease in birth weight (p = 0.047); when adjusted for FVC, FEV at 0.4 seconds was not related to birth weight but fell by 3.2% per standard deviation increase in infant weight gain (p = 0.001). Age- and sex-adjusted total respiratory system compliance fell by 7.0% per standard deviation decrease in birth weight (p < 0.001) but was not related to infant weight gain. In univariate analyses, age-adjusted forced expiratory flow at functional residual capacity was not related to birth weight, but decreased by 11.0% per standard deviation increase in infant weight gain (p = 0.007). The respiratory rate rose by 5.1% per standard deviation increase in infant weight gain (p = 0.001). Lung function measurements were not related to infant feeding. The observations suggest that lower rates of fetal growth and higher rates of early infancy weight gain are associated with impaired lung development.

Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness.

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.