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TOLL-like Receptor 10 Genetic Variation Is Associated with Asthma in Two Independent Samples

Channing Laboratory, Division of Pulmonary and Critical Care Medicine, Hematology Division, Brigham and Women's Hospital and Harvard Medical School; Harvard School of Public Health; and Harvard Partners Center for Genetics and Genomics, Boston, Massachusetts; and Arizona Respiratory Center, College of Medicine, University of Arizona, Tucson, Arizona

Correspondence and requests for reprints should be addressed to Scott T. Weiss, M.D., Channing Laboratory, Brigham and Women's Hospital, 181 Longwood Ave., Boston, MA 02115. E-mail: scott.weiss{at}channing.harvard.edu

TOLL-like receptor 10 (TLR10) is the most recently identified human homolog 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 control subjects) of European American subjects nested within the Nurses' Health Study cohort. The association for these same two SNPs (p 0.015) replicated in an independent family based cohort, where a measure of airway hyperresponsiveness (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: asthma • single nucleotide polymorphisms • TOLL-like receptor 10

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