Published ahead of print on June 16, 2004, doi:10.1164/rccm.200404-491OC
Am. J. Respir. Crit. Care Med., Volume 170, Number 6, September 2004, 594-600
A more recent version of this article appeared on September 15, 2004
Submitted on April 12, 2004
Accepted on June 12, 2004
Toll-like Receptor 10 (TLR10) Genetic Variation is Associated with Asthma in Two Independent Samples
Ross Lazarus1, Benjamin A Raby2, Christoph Lange3, Edwin K Silverman2, David J Kwiatkowski4, Donata Vercelli5, Walt J Klimecki5, Fernando D Martinez5, and Scott T Weiss6*
1 Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA,
2 Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA,
3 Harvard School of Public Health, Boston, MA, USA,
4 Hematology Division, Brigham and Women's Hospital, Boston, MA, USA; Harvard Partners Center for Genetics and Genomics, Boston, MA, USA,
5 Arizona Respiratory Center, College of Medicine, University of Arizona, Tucson, AZ, USA,
6 Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA; Harvard Partners Center for Genetics and Genomics, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: scott.weiss{at}channing.harvard.edu.
Toll-like receptor 10 (TLR10) is the most recently identified human homologue of the Drosophila TOLL protein. In humans, the Toll-like receptors recognize pathogen-associated molecular patterns (PAMPs) as part of innate immune host defenses. Localized to chromosome 4p14, the specific ligands and functions of TLR10 are currently unknown although it is expressed in lung and in B-lymphocytes. TLR10 is a potential asthma candidate gene because early life innate immune responses to ubiquitous inhaled allergens and PAMPs may influence asthma susceptibility. Resequencing in 47 subjects revealed a total of 78 single nucleotide polymorphisms (SNPS) (1 SNP per 106 bp) of which only 11 had been previously published.
A significant association (p <= 0.02) between two SNPs (c.+1031G>A, c.+2322A>G) and physician diagnosed asthma was observed in a case control study (517 cases, 519 controls) of European American subjects nested within the Nurses Health Study cohort. The association for these same 2 SNPs (p <= 0.015) replicated in an independent family based cohort, where a measure of airways hyper-responsiveness (PC20) was also associated (p = 0.026 for c.+1031G>A). Consistent association in two independent samples and association with an intermediate phenotype provides strong support for TLR10 genetic variation contributing to asthma risk.
Key words: toll like receptor 10, single nucleotide polymorphisms, asthma
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