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

Background Tumour necrosis factor alpha (TNF alpha) is a potent modulator of immune and inflammatory responses, and has been implicated in a variety of autoimmune diseases, including asthma. Increased levels of TNF alpha have been detected in both sputa and bronchoalveolar lavage fluid of asthmatic subjects during acute attacks. Interindividual variation in TNF alpha levels may be genetically determined and polymorphisms within the TNF genes and nearby HLA Class II region have been associated with differences in TNF alpha 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 TNF alpha gene promoter (TNF1 and TNF2 alleles) and an NcoI polymorphism in the first intron of the lymphotoxin alpha gene (LT-alpha*1 and LT-alpha*2 alleles). Methods The regions of interest were amplified from genomic DNA using specific primers and PCR. Dot blot analysis was used for genotyping individuals for the TNF alpha - 308 polymorphism, while restriction enzyme digestion was used for genotyping individuals for the LT-alpha gene NcoI polymorphism. A case-control analysis was then performed on 74 asthmatic and 50 non-asthmatic unrelated children for each polymorphism. Results The TNF alpha - 308 TNF1 allele was present at a significantly higher frequency in cases than controls (OR=2.4, P=0.003), and homozygosity for the TNF1 allele was associated with a fivefold increased risk of physician diagnosed asthma relative to the other genotypes (OR = 5.23, P = 0.004). The LT-alpha*2 allele showed similar associations, including an approximately fivefold higher risk of physician diagnosed asthma for LT-alpha*2 homozygotes (OR = 4.89, P = 0.019). Evidence of a significant linear trend in asthma risk across the three genotypes was found for both polymorphisms, Conclusion These results suggest an important role for the TNF alpha gene or a linked locus in an inherited asthma diathesis.