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PMID: 18091991 Published · epublish English Journal Article Research Support, N.I.H., Intramural

Full-exon resequencing reveals toll-like receptor variants contribute to human susceptibility to tuberculosis disease.

PloS one ·Vol. 2 ·No. 12 ·2007-12-19 ·Pages e1318

Ma X, Liu Y, Gowen BB, Graviss EA, Clark AG, Musser JM

Abstract

Tuberculosis (TB) is the leading cause of death worldwide due to an infectious agent. Data have accumulated over decades suggesting that variability in human susceptibility to TB disease has a genetic component. Toll-like receptors (TLRs) play a critical role in initiating the innate immune response to many pathogens in mouse models, but little is known about their role in human infections. Human TLRs have been reported to recognize mycobacterial antigens and initiate an immune response. We tested the hypothesis that amino acid-altering polymorphisms in five TLRs were associated with susceptibility to TB disease using a population-based case-control study with 1,312 adult TB patients and controls. Full-coding region sequencing of the five TLR genes in all 1,312 subjects yielded a data set in excess of 16 Mb. Rare nonsynonymous polymorphisms in TLR6-TLR1-TLR10 were significantly overrepresented among African-American TB cases compared with ethnically-matched control subjects. Common nonsynonymous polymorphisms in TLR6-TLR1-TLR10 also were significantly associated with TB disease in certain ethnic groups. Among African Americans, homozygotes for the common-variant haplotype TLR1-248S, TLR1-602I, and TLR6-249S had a significantly increased TB disease risk. A transmission/disequilibrium test on an independent sample found that the TLR1-248S variant was preferentially transmitted to diseased children, thereby confirming disease association. These results are consistent with recent reports implicating TLR1 variants, including TLR1-602, in significantly altered innate immune responses. Also consistent with disease association, rare TLR6 variants were defective in their ability to mediate NF-kappaB signal transduction in transfected human cells. Taken together, the data suggest that variant TLRs contribute to human susceptibility to TB disease. Extensive full-exon resequencing was critical for revealing new information about the role of TLRs in human-pathogen interactions and the genetic basis of innate immune function.

MeSH Terms
Adult Case-Control Studies Exons Female Genetic Predisposition to Disease Genotype Humans Male Middle Aged Molecular Sequence Data Multigene Family Mutagenesis, Site-Directed Mycobacterium tuberculosis/genetics Toll-Like Receptors/genetics Tuberculosis/genetics
Chemicals
Toll-Like Receptors
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Ma Xin
Center for Human Bacterial Pathogenesis, Department of Pathology, Baylor College of Medicine, Houston, Texas, United States of America.
Liu Yuhua
Gowen Brian B
Graviss Edward A
Clark Andrew G
Musser James M
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Article Info
Journal
PloS one
Abbr.
PLoS One
ISSN
1932-6203
DOI
10.1371/journal.pone.0001318
Published
2007-12-19
Epub
2007-00-19
Pages
e1318
Language
English
Region
United States
NLM ID
101285081
PMCID
PMC2117342
Subset
IM
Grants
Intramural NIH HHS · United States
Databases
GENBANK
AB020807
External Links
PubMed source DOI: 10.1371/journal.pone.0001318 PMC Full Text View journal details
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