title: Predisposition to Childhood Otitis Media and Genetic Polymorphisms within the Toll-Like Receptor 4 (TLR4) Locus.
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.
authors.affiliation: Department of Otorhinolaryngology, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Lena
authors.initials: L
authors.lastname: Hafrén
authors.affiliation: Department of Biosciences and Nutrition, Center for Innovative Medicine, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Einarsdottir
authors.affiliation: Department of Otorhinolaryngology, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Erna
authors.initials: E
authors.lastname: Kentala
authors.affiliation: Department of Otorhinolaryngology, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Sari
authors.initials: S
authors.lastname: Hammarén-Malmi
authors.affiliation: UCL Ear Institute, London, United Kingdom.
authors.forename: Mahmood F
authors.initials: MF
authors.lastname: Bhutta
authors.affiliation: Department of Otolaryngology, Head & Neck Surgery, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Carol J
authors.initials: CJ
authors.lastname: MacArthur
authors.affiliation: Oregon Clinical and Translational Research Institute and Division of Bioinformatics and Computational Biology, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Beth
authors.initials: B
authors.lastname: Wilmot
authors.affiliation: Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Margaretha
authors.initials: M
authors.lastname: Casselbrant
authors.affiliation: Department of Nursing and Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Yvette P
authors.initials: YP
authors.lastname: Conley
authors.affiliation: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Weeks
authors.affiliation: Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Mandel
authors.affiliation: Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Outi
authors.initials: O
authors.lastname: Vaarala
authors.affiliation: Department of Vaccination and Immune Protection, National Institute for Health and Welfare (THL), Helsinki, Finland.
authors.forename: Anna
authors.initials: A
authors.lastname: Kallio
authors.affiliation: Department of Vaccination and Immune Protection, National Institute for Health and Welfare (THL), Helsinki, Finland.
authors.forename: Merit
authors.initials: M
authors.lastname: Melin
authors.affiliation: Department of Vaccination and Immune Protection, National Institute for Health and Welfare (THL), Helsinki, Finland.
authors.forename: Janne K
authors.initials: JK
authors.lastname: Nieminen
authors.affiliation: Molecular Neurology Research Program, University of Helsinki and Folkhälsan Institute of Genetics, Helsinki, Finland.
authors.forename: Eira
authors.initials: E
authors.lastname: Leinonen
authors.affiliation: 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.
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
authors.affiliation: Department of Otorhinolaryngology, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Petri S
authors.initials: PS
authors.lastname: Mattila
mesh_terms: D002648:Child; D015331:Cohort Studies; D003713:Dendritic Cells / Q000378:metabolism; D005387:Finland; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D010033:Otitis Media / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D051197:Toll-Like Receptor 4 / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D006113:United Kingdom; D014481:United States
chemical_list: D012333:RNA, Messenger; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha