title: Toll-like receptor 4 polymorphism and severity of atopy in asthmatics.
abstract: Endotoxin exposure may have a protective effect against asthma and atopy. An Asp299Gly polymorphism in the Toll-like receptor 4 (TLR4) gene reduces responsiveness to endotoxin. This study determined the effect of TLR4 polymorphism on the risk and severity of asthma and atopy. In all, 336 UK Caucasian families with > or = 2 affected sibs (physician's diagnosis of asthma and current medication use) and 179 Caucasians without asthma or a family history of asthma were genotyped using ARMS-PCR. No association of the TLR4 polymorphism was found with the risk of developing asthma, either in parent-affected sibling trios, or in case-control analyses (P>0.05). In the first affected asthmatic siblings, the atopy severity score (based on size and number of positive skin-prick tests and specific IgE) was higher in those with the Asp/Gly or Gly/Gly genotypes (mean 1.8, s.d. 1.1, n=39) compared to those with the Asp/Asp genotype (mean 1.2, s.d. 1.0, n=279) (P=0.003, t-test). No associations were found with total IgE, FEV(1) % predicted, slope of FEV(1) response to methacholine or asthma severity score (P>0.05). This study confirms the previously observed lack of association of TLR4 polymorphisms with asthma. In contrast, the findings suggest that genetically determined hyporesponsiveness to endotoxin may increase atopy severity.
authors.affiliation: Asthma Genetics Laboratory, Division of Human Genetics and Infection, University of Southampton, Southampton, UK. I.Yang@soton.ac.uk
authors.forename: I A
authors.initials: IA
authors.lastname: Yang
authors.forename: S J
authors.initials: SJ
authors.lastname: Barton
authors.forename: S
authors.initials: S
authors.lastname: Rorke
authors.forename: J A
authors.initials: JA
authors.lastname: Cakebread
authors.forename: T P
authors.initials: TP
authors.lastname: Keith
authors.forename: J B
authors.initials: JB
authors.lastname: Clough
authors.forename: S T
authors.initials: ST
authors.lastname: Holgate
authors.forename: J W
authors.initials: JW
authors.lastname: Holloway
mesh_terms: D019943:Amino Acid Substitution; D001249:Asthma / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D011110:Polymorphism, Genetic; D011956:Receptors, Cell Surface / Q000235:genetics*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
chemical_list: D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D007073:Immunoglobulin E