Predisposition to childhood otitis media and genetic polymorphisms within the toll-like receptor 4 (TLR4) Locus

Lena Hafren, Elisabet Einarsdottir, Erna Kentala, Sari Hammaren-Malmi, Mahmood F. Bhutta, Carol Macarthur, Beth Wilmot, Margaretha Casselbrant, Yvette P. Conley, Daniel E. Weeks, Ellen M. Mandel, Outi Vaarala, Anna Kallio, Merit Melin, Janne K. Nieminen, Eira Leinonen, Juha Kere, Petri S. Mattila

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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 TNFá 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.

Original languageEnglish (US)
Article numbere0132551
JournalPLoS One
Volume10
Issue number7
DOIs
StatePublished - Jul 15 2015

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otitis media
Toll-Like Receptor 4
Otitis Media
Genetic Polymorphisms
Polymorphism
childhood
Genes
genetic polymorphism
loci
genes
Innate Immunity
Single Nucleotide Polymorphism
Myeloid Cells
dendritic cells
Genetic Predisposition to Disease
Dendritic Cells
Haplotypes
Toll-like receptor 4
haplotypes
risk factors

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Hafren, L., Einarsdottir, E., Kentala, E., Hammaren-Malmi, S., Bhutta, M. F., Macarthur, C., ... Mattila, P. S. (2015). Predisposition to childhood otitis media and genetic polymorphisms within the toll-like receptor 4 (TLR4) Locus. PLoS One, 10(7), [e0132551]. https://doi.org/10.1371/journal.pone.0132551

Predisposition to childhood otitis media and genetic polymorphisms within the toll-like receptor 4 (TLR4) Locus. / Hafren, Lena; Einarsdottir, Elisabet; Kentala, Erna; Hammaren-Malmi, Sari; Bhutta, Mahmood F.; Macarthur, Carol; Wilmot, Beth; Casselbrant, Margaretha; Conley, Yvette P.; Weeks, Daniel E.; Mandel, Ellen M.; Vaarala, Outi; Kallio, Anna; Melin, Merit; Nieminen, Janne K.; Leinonen, Eira; Kere, Juha; Mattila, Petri S.

In: PLoS One, Vol. 10, No. 7, e0132551, 15.07.2015.

Research output: Contribution to journalArticle

Hafren, L, Einarsdottir, E, Kentala, E, Hammaren-Malmi, S, Bhutta, MF, Macarthur, C, Wilmot, B, Casselbrant, M, Conley, YP, Weeks, DE, Mandel, EM, Vaarala, O, Kallio, A, Melin, M, Nieminen, JK, Leinonen, E, Kere, J & Mattila, PS 2015, 'Predisposition to childhood otitis media and genetic polymorphisms within the toll-like receptor 4 (TLR4) Locus', PLoS One, vol. 10, no. 7, e0132551. https://doi.org/10.1371/journal.pone.0132551
Hafren, Lena ; Einarsdottir, Elisabet ; Kentala, Erna ; Hammaren-Malmi, Sari ; Bhutta, Mahmood F. ; Macarthur, Carol ; Wilmot, Beth ; Casselbrant, Margaretha ; Conley, Yvette P. ; Weeks, Daniel E. ; Mandel, Ellen M. ; Vaarala, Outi ; Kallio, Anna ; Melin, Merit ; Nieminen, Janne K. ; Leinonen, Eira ; Kere, Juha ; Mattila, Petri S. / Predisposition to childhood otitis media and genetic polymorphisms within the toll-like receptor 4 (TLR4) Locus. In: PLoS One. 2015 ; Vol. 10, No. 7.
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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 TNF{\'a} 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.",
author = "Lena Hafren and Elisabet Einarsdottir and Erna Kentala and Sari Hammaren-Malmi and Bhutta, {Mahmood F.} and Carol Macarthur and Beth Wilmot and Margaretha Casselbrant and Conley, {Yvette P.} and Weeks, {Daniel E.} and Mandel, {Ellen M.} and Outi Vaarala and Anna Kallio and Merit Melin and Nieminen, {Janne K.} and Eira Leinonen and Juha Kere and Mattila, {Petri S.}",
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T1 - Predisposition to childhood otitis media and genetic polymorphisms within the toll-like receptor 4 (TLR4) Locus

AU - Hafren, Lena

AU - Einarsdottir, Elisabet

AU - Kentala, Erna

AU - Hammaren-Malmi, Sari

AU - Bhutta, Mahmood F.

AU - Macarthur, Carol

AU - Wilmot, Beth

AU - Casselbrant, Margaretha

AU - Conley, Yvette P.

AU - Weeks, Daniel E.

AU - Mandel, Ellen M.

AU - Vaarala, Outi

AU - Kallio, Anna

AU - Melin, Merit

AU - Nieminen, Janne K.

AU - Leinonen, Eira

AU - Kere, Juha

AU - Mattila, Petri S.

PY - 2015/7/15

Y1 - 2015/7/15

N2 - 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 TNFá 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.

AB - 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 TNFá 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.

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