Neil A. Gibson

Association of polymorphisms within the tumour necrosis factor (TNF) genes and childhood asthma

Tumour necrosis factor alpha (TNFα) is a potent modulator of immune and inflammatory responses, and has been implicated in a variety of autoimmune diseases, including asthma. Increased levels of TNFα have been detected in both sputa and bronchoalveolar lavage fluid of asthmatic subjects during acute attacks. Interindividual variation in TNFα levels may be genetically determined and polymorphisms within the TNF genes and nearby HLA Class II region have been associated with differences in TNFα production. Objective To investigate the association of differences in asthma‐related phenotypes with two biallelic polymorphisms: a G to A substitution at position −308 of the TNFα gene promoter (TNF1 and TNF2 alleles) and an NcoI polymorphism in the first intron of the lymphotoxin alpha gene (LT‐α*1 and LT‐α*2 alleles).

A POLYMORPHISM OF THE CC16 GENE IS ASSOCIATED WITH AN INCREASED RISK OF ASTHMA

Several quantitative traits associated with the asthma phenotype have been linked to markers on chromosome 11q13, although the gene responsible has yet to be well established. The gene for Clara cell secretory protein (CC16) is an ideal candidate for involvement in an inherited predisposition to asthma because of its chromosomal location, the role of the CC16 protein in controlling airway inflammation, and differences in levels of the protein between asthmatics and healthy controls. All three CC16 exons were screened in an unselected population of 266 subjects from 76 families and a cohort of 52 severely asthmatic children. A combination of single strand conformational polymorphism (SSCP) analysis, heteroduplex analysis, DNA sequencing, and restriction digestion was used. Mutation detection methods identified an adenine to guanine substitution in the CC16 gene at position 38 (A38G) downstream from the transcription initiation site within the non-coding region of exon 1. In the unselected population, 43.6% were homozygous for the polymorphic sequence (38GG) and 46.2% were heterozygous (38AG). All the asthmatic and unaffected children from both populations were selected for an unmatched case control analysis consisting of 67 asthmatic and 46 unaffected subjects. Those homozygous for the published sequence (38AA) had a 6.9-fold increased risk of developing asthma (p=0.049) and heterozygotes (38AG) a 4.2-fold increased risk (p=0.028). Modelling of genotype as a continuous covariate indicated evidence of a significant linear trend across the three genotypes (odds ratio=2.84 per unit increase in genotype code, p=0.018). These associations were independent of age, gender, and tobacco smoke exposure. These data and the known anti-inflammatory role of CC16 in the respiratory tract suggest that alteration to the gene at position 38 may contribute to asthma.

β2 adrenoceptor Arg16Gly polymorphism, airway responsiveness, lung function and asthma in infants and children

Background We have previously reported a relationship between increased airway responsiveness (AR) in infancy and reduced childhood lung function.

Mutation screening of interferon‐gamma (IFNγ) as a candidate gene for asthma

Background Reduced levels of interferon gamma (IFNγ) mRNA and protein have been detected in the bronchoalveolar lavage fluid of atopic asthmatics. IFNγ is secreted by TH1 cells while IL‐4 and IL‐5 are secreted by TH2 cells and an imbalance in the TH1/TH2 response may be responsible for atopic asthma. The gene for IFN4gM is located on chromosome 12; a region of the genome which has been shown in linkage studies to be associated with asthma.

Association of FcepsilonR1-beta polymorphisms with asthma and associated traits in Australian asthmatic families.

Asthma is a genetically complex disease, and is characterized by elevated serum immunoglobulin E (IgE) levels, elevated blood eosinophil counts and increased airway responsiveness. Polymorphisms in the β subunit of the high affinity receptor for IgE (FcεR1‐β) have been previously associated with these phenotypes and with an increased risk of asthma.

Determinants of airway responsiveness to histamine in children.

Increased airway responsiveness (AR) is associated with asthma, but not all individuals with increased AR have asthma. The aim of this study was to identify factors, other than physician-diagnosed asthma (PDA), which are associated with increased AR. In a longitudinal study, data were collected on atopy and lower respiratory tract illness (LRTI) in infancy, and AR (expressed as dose–response slope (DRS)), atopy, tobacco-smoke exposure and PDA in childhood. At age 6 yrs, DRS was assessed in 102 children, of whom 22 (22%) had PDA; the corresponding figures at 11 yrs of age were 176 and 29 (15%). At age 6 yrs, DRS was significantly associated with PDA, current atopy and parental smoking (n = 83). At age 11 yrs, DRS was significantly associated with PDA, current atopy and LRTI in the first six months (n = 75). There was a significant positive interaction between atopy at age 12 months and PDA age 11 yrs. In conclusion, these data suggest that factors other than asthma or atopy may determine the level of airway responsiveness in children. In children with asthma, airway responsiveness may be influenced by the early onset of atopy. The current findings may explain the inconsistent relationship between airway responsiveness and asthma.

The effect of age on the relationship between birth order and immunoglobulin E sensitization

Background An association between birth order and IgE sensitization or allergic diseases has been reported in many studies.