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PLoS One. 2015 Jul 15;10(7):e0132551. doi: 10.1371/journal.pone.0132551. eCollection 2015.

Predisposition to Childhood Otitis Media and Genetic Polymorphisms within the Toll-Like Receptor 4 (TLR4) Locus.

Author information

1
Department of Otorhinolaryngology, Helsinki University Central Hospital, Helsinki, Finland.
2
Department of Biosciences and Nutrition, Center for Innovative Medicine, Karolinska Institutet, Huddinge, Sweden.
3
UCL Ear Institute, London, United Kingdom.
4
Department of Otolaryngology, Head & Neck Surgery, Oregon Health & Science University, Portland, Oregon, United States of America.
5
Oregon Clinical and Translational Research Institute and Division of Bioinformatics and Computational Biology, Oregon Health & Science University, Portland, Oregon, United States of America.
6
Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
7
Department of Nursing and Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
8
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
9
Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland.
10
Department of Vaccination and Immune Protection, National Institute for Health and Welfare (THL), Helsinki, Finland.
11
Molecular Neurology Research Program, University of Helsinki and Folkhälsan Institute of Genetics, Helsinki, Finland.
12
Department of Biosciences and Nutrition, Center for Innovative Medicine, Karolinska Institutet, Huddinge, Sweden; Molecular Neurology Research Program, University of Helsinki and Folkhälsan Institute of Genetics, Helsinki, Finland.

Abstract

BACKGROUND:

Predisposition to childhood otitis media (OM) has a strong genetic component, with polymorphisms in innate immunity genes suspected to contribute to risk. Studies on several genes have been conducted, but most associations have failed to replicate in independent cohorts.

METHODS:

We investigated 53 gene polymorphisms in a Finnish cohort of 624 cases and 778 controls. A positive association signal was followed up in a tagging approach and tested in an independent Finnish cohort of 205 cases, in a British cohort of 1269 trios, as well as in two cohorts from the United States (US); one with 403 families and the other with 100 cases and 104 controls.

RESULTS:

In the initial Finnish cohort, the SNP rs5030717 in the TLR4 gene region showed significant association (OR 1.33, P = .003) to OM. Tagging SNP analysis of the gene found rs1329060 (OR 1.33, P = .002) and rs1329057 (OR 1.29, P = .003) also to be associated. In the more severe phenotype the association was stronger. This finding was supported by an independent Finnish case cohort, but the associations failed to replicate in the British and US cohorts. In studies on TLR4 signaling in 20 study subjects, the three-marker risk haplotype correlated with a decreased TNFα secretion in myeloid dendritic cells.

CONCLUSIONS:

The TLR4 gene locus, regulating the innate immune response, influences the genetic predisposition to childhood OM in a subpopulation of patients. Environmental factors likely modulate the genetic components contributing to the risk of OM.

PMID:
26177520
PMCID:
PMC4503307
DOI:
10.1371/journal.pone.0132551
[Indexed for MEDLINE]
Free PMC Article

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