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Published ahead of print on September 25, 2002, doi:10.1164/rccm.200207-634OC

Am. J. Respir. Crit. Care Med., Volume 166, Number 11, December 2002, 1449-1456

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Submitted on July 1, 2002
Accepted on September 23, 2002

Polymorphisms in Toll-like Receptor 4 are not associated with asthma or atopy-related phenotypes

Benjamin A Raby1*, Walter T Klimecki2, Catherine Laprise3, Mathieu Lemire4, Celia Greenwood5, Katherine M Weiland6, Christoph Lange7, Lyle J Palmer6, Ross Lazarus6, Donata Vercelli2, David J Kwiatkowski8, Edwin K Silverman6, Fernando D Martinez2, Thomas J Hudson9, and Scott T Weiss10

1 Medicine, Channing Laboratory, Brigham and Women's Hospital, Boston, MA, USA; Montreal Genome Centre, McGill University Health Centre, Montreal, QC, Canada, 2 Medicine, University of Arizona, Tucson, AZ, USA, 3 Medicine, Community Genomic Medicine Center, University of Montreal, Chicoutimi, QC, Canada; Fundamental Sciences and Human Sciences, University of Québec at Chicoutimi, Chicoutimi, QC, Canada, 4 Montreal Genome Centre, McGill University Health Centre, Montreal, QC, Canada; Research Institute, McGill University Health Centre, Montreal, QC, Canada, 5 Montreal Genome Centre, McGill University Health Centre, Montreal, QC, Canada; Research Institute, McGill University Health Centre, Montreal, QC, Canada; Human Genetics and Medicine, McGill University, Montreal, QC, Canada, 6 Medicine, Channing Laboratory, Brigham and Women's Hospital, Boston, MA, USA, 7 Biostatistics, Harvard School of Public Health, Boston, MA, USA, 8 Hematology Division, Brigham and Women's Hospital, Boston, MA, USA, 9 Montreal Genome Centre, McGill University Health Centre, Montreal, QC, Canada; Human Genetics and Medicine, McGill University, Montreal, QC, Canada, 10 Medicine, Channing Laboratory, Brigham and Women's Hospital, Boston, MA, USA; Harvard Partners Center for Genetics and Genomics, Brigham and Women's Hospital, Boston, MA, USA

* To whom correspondence should be addressed. 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 (TLR4), genetic association




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