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Toll-like receptor 4 polymorphism and severity of atopy in asthmatics

Genes & Immunity volume 5, pages 41–45 (2004)Cite this article

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 ≥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, FEV1 % predicted, slope of FEV1 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.

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Acknowledgements

We thank the patients and families who participated in this study. The collection of families was funded by Genome Therapeutics Corporation and Schering-Plough. IAY was supported by an Allen+Hanburys/Thoracic Society of Australia and New Zealand Respiratory Research Fellowship. JWH was supported by a Medical Research Council (MRC) Research Training Fellowship.

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Authors and Affiliations

  1. Divisions of Human Genetics & Infection, Asthma Genetics Laboratory, Inflammation and Repair, University of Southampton, Southampton, UK

    I A Yang, S J Barton, S Rorke, J A Cakebread, J B Clough, S T Holgate & J W Holloway

  2. Genome Therapeutics Corporation, Waltham, MA, USA

    T P Keith

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  1. I A Yang
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  2. S J Barton
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  3. S Rorke
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  4. J A Cakebread
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  6. J B Clough
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  7. S T Holgate
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Correspondence to I A Yang.

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Contributions of authors

ST Holgate, JB Clough and TP Keith designed the original study in which the subjects were recruited. JW Holloway and IA Yang initiated this study of the TLR4 polymorphism. IA Yang and JA Cakebread performed the genotyping. SJ Barton and S Rorke undertook the statistical analysis. IA Yang and JW Holloway drafted the report. All authors approved the final version of this report.

Contributions of the funding support

Genome Therapeutics Corporation and Schering-Plough were responsible for the design of the original study and data collection. The funding bodies had no role in the genotyping, data analysis or writing of the report.

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Yang, I., Barton, S., Rorke, S. et al. Toll-like receptor 4 polymorphism and severity of atopy in asthmatics. Genes Immun 5, 41–45 (2004). https://doi.org/10.1038/sj.gene.6364037

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