Abstract
Abstract Co-segragating missense mutations of Asp299Gly and Thr399Ile in TLR4 are found in 10% of general population. Heterozygousity of these mutations is implicated with hyporesponsiveness to a TLR4 agonist (LPS). This study addressed the association between heterozygousity of these TLR4 alleles and NFA with or without recurrent OM/CRS. The study included 203 children: inflammatory bowel disease (IBD; N=11 median 14.5 y), OM/CRS/no NFA (N=21, median 7.3 y), NFA alone (N=64, median 3.8 y), OM/CRS+NFA (N=30, median 5.5 y) and controls (N=78, median 6.9 y). Production of proinflammatory cytokines (TNF-α, IL-1ß, IL-6, and IL-12) by peripheral blood mononuclear cells and TLR2 Arg753Gln allele were also assessed. In this study, 20/203 (9.85%) and 7/203 (3.4%) subjects were heterozygous for TLR4 Asp299Gly/Thr399Ile and TLR2 Arg753Gln alleles, respectively. Heterozygousity of these TLR4 alleles were associated with OM/CRS+NFA (57.1% vs 9.7%, p<0.00001), IgE mediated FA (p<0.001), and atopy (p<0.02) but not with OM/CRS/no NFA or IBD. Such an association was not found in TLR2 Arg753Gln allele. LPS responses did not differ irrespective with these TLR2/4 mutated alleles. Among 21 children with OM/CRS/no NFA, 16 revealed other immunodeficiencies. Thus individuals heterozygous for TLR4 Asp299Gly/Thr399Ile alleles may be predisposed to OM/CRS/NFA and possibly IgE mediated FA. Funded by Jonty Foundation.
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