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Polymorphisms in Toll-Like Receptor 4 Are Not Associated with Asthma or Atopy-related Phenotypes

Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School; Department of Biostatistics, Harvard School of Public Health; Hematology Division, Brigham and Women's Hospital; Harvard Partners Center for Genetics and Genomics, Boston, Massachusetts; Arizona Respiratory Center, University of Arizona, Tucson, Arizona; Community Genomic Medicine Center, University of Montreal, Chicoutimi Hospital; University of Quebec at Chicoutimi, Departments of Fundamental Sciences and Human Sciences, Chicoutimi; Research Institute of the McGill University Health Centre; and Departments of Human Genetics and Medicine, McGill University, Montreal Genome Centre, McGill University Health Centre, Montreal, Quebec, Canada

Correspondence and requests for reprints should be addressed to Benjamin A. Raby, M.D., Channing Laboratory, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA 02115. E-mail: benjamin.raby{at}channing.harvard.edu

Toll-like receptor 4 (TLR4) is the principal receptor for bacterial endotoxin recognition, and functional variants in the gene confer endotoxin-hyporesponsiveness in humans. Furthermore, there is evidence that endotoxin exposure during early life is protective against the development of atopy and asthma, although this relationship remains poorly understood. It is therefore possible that genetic variation in the TLR4 locus contributes to asthma susceptibility. In this study we characterize the genetic diversity in the TLR4 locus and test for association between the common genetic variants and asthma-related phenotypes. In a cohort of 90 ethnically diverse subjects, we resequenced the TLR4 locus and identified a total of 29 single nucleotide polymorphisms. We assessed five common polymorphisms for evidence of association with asthma in two large family-based cohorts: a heterogeneous North American cohort (589 families), and a more homogenous population from northeastern Quebec, Canada (167 families). Using the transmission-disequilibrium test, we found no evidence of association for any of the polymorphisms tested, including two functional variants. Furthermore, we found no evidence for association between the TLR4 variants and four quantitative intermediate asthma- and atopy-related phenotypes. Based on these results, we found no evidence that genetic variation in TLR4 contributes to asthma susceptibility.

Key Words: asthma • genetics • polymorphism • toll-like receptor 4 • genetic association

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