Published online October 1, 2007
PEDIATRICS Vol. 120 No. 4 October 2007, pp. 814-823 (doi:10.1542/peds.2007-0524)
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ARTICLE

Genetic Polymorphisms in Immunoresponse Genes TNFA, IL6, IL10, and TLR4 Are Associated With Recurrent Acute Otitis Media

Marieke Emonts, MDa, Reinier H. Veenhoven, MD, PhDb, Selma P. Wiertsema, PhDc, Jeanine J. Houwing-Duistermaat, PhDd, Vanessa Walraven, Bscc, Ronald de Groot, MD, PhDe, Peter W.M. Hermans, PhDe and Elisabeth A.M. Sanders, MD, PhDc

a Department of Pediatrics, Erasmus MC-Sophia Children's Hospital, University Medical Center, Rotterdam, Netherlands
b Department of Pediatrics, Spaarne Hospital Hoofddorp, Hoofddorp, Netherlands
c Department of Pediatric Immunology, University Medical Center Utrecht, Utrecht, Netherlands
d Department of Medical Statistics, Leiden University Medical Center, Leiden, Netherlands
e Department of Pediatrics, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands

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.

PATIENTS AND METHODS. DNA samples from 348 children with ≥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.

Key Words: genotype-phenotype correlation • human • cytokines • inflammation • otitis media

Abbreviations: AOM—acute otitis media • TNFA—tumor necrosis factor A • IL—interleukin • NOS2A—inducible nitric oxide synthase • C1INH—complement component inhibitor-1 • PARP—poly(ADP-ribose) polymerase • TLR—Toll-like receptor • SNP—single-nucleotide polymorphism • OR—odds ratio • rs—reference SNP • IgG—immunoglobulin G

Accepted Apr 26, 2007.


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