Extended tumour necrosis factor/HLA-DR haplotypes and asthma in an Australian population sample

Background-Tumour necrosis factor (TNF) is a potent pro-inflammatory cytoki ne which is prominent in asthmatic airways. TNF shows genetic variations in secretion which are linked to polymorphisms in the TNF gene complex and th e surrounding major histocompatibility (MHC) locus. These polymorphisms do not seem to be themselves functionally important. In these circumstances,th e identification of disease associated haplotypes (combination of alleles o n individual chromosomes) may narrow the search for polymorphisms which alt er gene function. Methods-TNF-308, LT alpha NcoI, and HLA-DRB1 polymorphisms were investigate d for association with asthma, bronchial responsiveness, and medication use in 1004 subjects in 230 families from a general population sample. Results-The common LTa NcoI*1/TNF-308*2/HLA-DRB1*03 haplotype, which was pr esent in 11% of unrelated individuals, was weakly associated with asthma (O R = 1.38, p = 0.016, corrected for familial correlation). The rarer LTa Nco I*1/ TNF-308*2/HLA-DRB1*02 haplotype, which was found in 0.6% of unrelated subjects, was more strongly associated with asthma (OR = 6.68, p = 0.002). This haplotype also showed association with bronchial hyperresponsiveness ( OR = 21.9, p = 0.0000) and the use of inhaled or oral steroids (OR 8.0, p = 0.04). Conclusions-The results of this study show only two extended TNF/HLA-DR hap lotypes to be associated with asthma. The search for functional alleles res ponsible for an increased risk of asthma should concentrate on the LTa NcoI *1/TNF-308*2/HLA-DRB1*02 haplotype.