Modifier effect of the Toll-like receptor 4 D299G polymorphism in children with cystic fibrosis
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Introduction: Clinical phenotype varies amongst cystic fibrosis (CF) patients with identical CF transmembrane regulator (CFTR) genotype, suggesting genetic modifiers exist. One potential modifier is the Toll-like receptor 4 (TLR4) gene. TLR4 binds lipopolysaccharide (LPS), a constituent of Pseudomonas aeruginosa (PA), activating innate immunity and promoting inflammation. TLR4 polymorphisms are associated with LPS-hyporesponsiveness and may be protective in CF due to decreased inflammation. Materials and Methods: DNA was extracted from blood of recruited CF subjects, and PCR performed to establish TLR4 D299G genotype. Case-notes were reviewed to obtain clinical data. Subjects possessing the TLR4 299G allele were compared with age, sex, and CFTR genotype-matched wild-type (299DD) subjects and also with all controls. Results: 100 subjects (mean age 8.9 years) were studied, with 11 299DG heterozygotes identified. On case-matched analyses, no statistically significant differences between groups were found for mean?SEM rates of change of %predicted FEV1/year (0.9?2.3 (DD) vs. ?3.9?2.8 (DG), p=0.22), %predicted FEV1 (76?8 vs. 74?11), p=0.91), or z scores for height (?0.47?0.26 vs. ?0.24?0.19, p=0.48) and weight (?0.01?0.22 vs. ?0.29?0.27, p=0.44). Median?SE survival age at first PA isolation was also not significantly different (3.5?2.1 vs. 6.5?2.4 years, p=0.29). No statistically significant differences were noted when 299DG heterozygotes were compared with all controls. Conclusions: Potential reasons for absence of modifier effect include the basolateral location of TLR4 receptors on respiratory epithelium, or because inflammatory response to PA in the CF airway is so overwhelming that even a blunted response (as suggested for the 299G allele) results in increased inflammation and lung damage.
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Donald S. Urquhart, Cystic Fibrosis Research Fellow, Great Ormond Street Hospital for Children NHS Trust, Great Ormond Street, London, WC1N 3JH, UK