Association of proinflammatory cytokine gene polymorphisms with susceptibility to otitis media

OBJECTIVE: Susceptibility to otitis media results from complex interactions among genetic factors of the host, exposure to pathogens, and environmental influences. The objective of this study was to study the role of single-nucleotide polymorphisms of regulatory elements of proinflammatory cytokine genes tumor necrosis factor-alpha(-308), interleukin-1 beta(+3953), and interleukin-6(-174), in susceptibility to recurrent otitis media in childhood. METHODS: A total of 505 children (296 otitis media susceptible, 209 nonsusceptible as control) were enrolled at 2 sites (Texas and Kentucky). DNA of the children was studied for specific single-nucleotide polymorphisms by restriction fragment length polymorphism assay and confirmed by gene sequencing. RESULTS: In the overall study group, tumor necrosis factor-alpha(-308) and interleukin-6(-174) heterozygous or homozygous polymorphisms (high cytokine-producing genotypes) were significantly associated with otitis media susceptibility. The same association was found in a match-paired subgroup of 384 subjects. In the overall study group, there was a significant step-wise increase in otitis media susceptibility with increasing number of concomitant polymorphic genotypes. Simultaneous combination of tumor necrosis factor-alpha(-308) and interleukin-6(-174) polymorphisms further increased the risk for otitis media susceptibility. These 2 polymorphic genotypes also were associated with the increased risk for tympanostomy tube placement. Children who had tumor necrosis factor-alpha(-308) polymorphism and were breastfed for < 1 month or exposed to cigarette smoke were more likely to be otitis media susceptible. CONCLUSIONS: Our data suggest that tumor necrosis factor-alpha(-308) and interleukin-6(-174) polymorphisms are associated with increased risk for otitis media susceptibility and placement of tympanostomy tubes. Environmental factors such as breastfeeding may modify the risk for otitis media susceptibility in polymorphic individuals.