title: Genetic polymorphisms in immunoresponse genes TNFA, IL6, IL10, and TLR4 are associated with recurrent acute otitis media.
abstract: OBJECTIVE
  Cytokines and other inflammatory mediators are involved in the pathogenesis of otitis media. We hypothesized that polymorphisms in inflammatory response genes contribute to the increased susceptibility to acute otitis media in otitis-prone children.
  
  
  METHODS
  DNA samples from 348 children with > or = 2 acute otitis media episodes, who were participating in a randomized, controlled vaccination trial, and 463 healthy adult controls were included. Polymorphisms in TNFA, IL1B, IL4, IL6, IL10, IL8, NOS2A, C1INH, PARP, TLR2, and TLR4 were genotyped. Genotype distributions in children with recurrent acute otitis media were compared with those in controls. Within the patient group, the number of acute otitis media episodes before vaccination and the clinical and immunologic response to pneumococcal conjugate vaccinations were analyzed.
  
  
  RESULTS
  The IL6-174 G/G genotype was overrepresented in children with acute otitis media when compared with controls. In the patient group, TNFA promoter genotypes -238 G/G and -376 G/G and the TLR4 299 A/A genotype were associated with an otitis-prone condition. Furthermore, lower specific anticapsular antibody production after complete vaccination was observed in patients with the TNFA-238 G/G genotype or TNFA-863 A allele carriage. Finally, the IL10-1082 A/A genotype contributed to protection from the recurrence of acute otitis media after pneumococcal vaccination.
  
  
  CONCLUSIONS
  Variation in innate immunoresponse genes such as TNFA-863A, TNFA-376G, TNFA-238G, IL10-1082 A, and IL6-174G alleles in the promoter sequences may result in altered cytokine production that leads to altered inflammatory responses and, hence, contributes to an otitis-prone condition.
authors.affiliation: Department of Pediatrics, Erasmus MC-Sophia Children's Hospital, University Medical Center, Dr Molewaterplein 50, Room Ee15-02, 3015 GE, Rotterdam, The Netherlands. m.emonts@erasmusmc.nl
authors.forename: Marieke
authors.initials: M
authors.lastname: Emonts
authors.forename: Reinier H
authors.initials: RH
authors.lastname: Veenhoven
authors.forename: Selma P
authors.initials: SP
authors.lastname: Wiertsema
authors.forename: Jeanine J
authors.initials: JJ
authors.lastname: Houwing-Duistermaat
authors.forename: Vanessa
authors.initials: V
authors.lastname: Walraven
authors.forename: Ronald
authors.initials: R
authors.lastname: de Groot
authors.forename: Peter W M
authors.initials: PW
authors.lastname: Hermans
authors.forename: Elisabeth A M
authors.initials: EA
authors.lastname: Sanders
mesh_terms: D000208:Acute Disease; D000907:Antibodies, Bacterial / Q000032:analysis; D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007223:Infant; D016753:Interleukin-10 / Q000235:genetics*; D015850:Interleukin-6 / Q000235:genetics*; D008297:Male; D009426:Netherlands; D010033:Otitis Media / Q000235:genetics* / Q000628:therapy; D022242:Pneumococcal Vaccines; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D055502:Secondary Prevention; D013296:Streptococcus pneumoniae / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D000907:Antibodies, Bacterial; D007074:Immunoglobulin G; D015850:Interleukin-6; D022242:Pneumococcal Vaccines; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10