title: Modifier effect of the Toll-like receptor 4 D299G polymorphism in children with cystic fibrosis.
abstract: BACKGROUND
  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.
  
  
  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 FEV(1)/year (0.9 +/- 2.3 (DD) vs. - 3.9 +/- 2.8 (DG), p = 0.22), %predicted FEV(1) (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.
authors.affiliation: Portex Anaesthesia, Intensive Therapy and Respiratory Medicine Unit, Institute of Child Health, Great Ormond Street Hospital for Children NHS Trust, London, UK. UrquhD@gosh.nhs.uk
authors.forename: Donald S
authors.initials: DS
authors.lastname: Urquhart
authors.forename: Jennifer
authors.initials: J
authors.lastname: Allen
authors.forename: Mohamed
authors.initials: M
authors.lastname: Elrayess
authors.forename: Katy
authors.initials: K
authors.lastname: Fidler
authors.forename: Nigel
authors.initials: N
authors.lastname: Klein
authors.forename: Adam
authors.initials: A
authors.lastname: Jaffé
mesh_terms: D000293:Adolescent; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003550:Cystic Fibrosis / Q000235:genetics* / Q000503:physiopathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D010641:Phenotype; D011110:Polymorphism, Genetic; D012129:Respiratory Function Tests; D051197:Toll-Like Receptor 4 / Q000235:genetics*
chemical_list: C505032:CFTR protein, human; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D019005:Cystic Fibrosis Transmembrane Conductance Regulator