Human Molecular Genetics Advance Access originally published online on June 22, 2007
Human Molecular Genetics 2007 16(17):2021-2030; doi:10.1093/hmg/ddm150
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The coding polymorphism T263I in TGF-ß1 is associated with otosclerosis in two independent populations
1 Department of Medical Genetics, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk (Antwerp), Belgium, 2 Molecular Otolaryngology Research Laboratories, Department of Otolaryngology, University of Iowa, 200 Hawkins Drive, Iowa City IA 52242, USA, 3 Laboratoire de Genetique Moleculaire et chromosomique CHU, IURC Montpellier, 641 avenue du Doyen Gaston Giraud, 34093 Montpellier Cedex 5, France, 4 Department of Otorhinolaryngology, University Medical Centre St Radboud, Philips van Leydenlaan 15, 6500 HB Nijmegen, The Netherlands, 5 Department of Otorhinolaryngology, University Hospital of Ghent, De Pintelaan 185, 9000 Ghent, Belgium, 6 Department of ORL, University Hospital of Antwerp, Wilrijkstraat 10, 2650 Edegem, Belgium, 7 Jean Causse Ear Clinic, Traverse de Béziers, 34440 Colombiers, France and 8 University Department of Otolaryngology, St-Augustinus Hospital Antwerp, Oosterveldlaan 24, 2610 Antwerp, Belgium
* To whom correspondence should be addressed. Tel: +32 38202491; Fax: +32 38202566; Email: guy.vancamp{at}ua.ac.be
Received May 8, 2007; Accepted June 8, 2007
Otosclerosis is a progressive hearing loss characterized by an abnormal bone homeostasis of the otic capsule that leads to stapes fixation. Although its etiology remains unknown, otosclerosis can be considered a complex disease. Transforming growth factor-beta 1 (TGF-ß1) was chosen for a case–control association study, because of several non-genetic indications of involvement in otosclerosis. Single nucleotide polymorphism (SNP) analysis in a large Belgian–Dutch sample set gave significant results (P = 0.0044) for an amino acid changing SNP, T263I. Analysis of an independent French population replicated this association with SNP T263I (P = 0.00019). The results remained significant after multiple testing correction in both populations. Haplotype analysis and the results of an independent effect test using the weighted haplotype (WHAP) computer program in both populations were both compatible with SNP T263I being the only causal variant. The variant I263 is under-represented in otosclerosis patients and hence protective against the disease. Combining the data of both case–control groups for SNP T263I with a Mantel–Haenszel estimate of common odds ratios gave a very significant result (P = 9.2 x 10–6). Functional analysis of SNP T263I with a luciferase reporter assay showed that the protective variant I263 of TGF-ß1 is more active than the WT variant T263 (P = 1.6 x 10–6). On the basis of very low P-values, replication in an independent population and a functional effect of the protective variant, we conclude that TGF-ß1 influences the susceptibility for otosclerosis, and that the I263 variant is protective against the disease.
Present address: European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, 69117 Heidelberg, Germany.
Present address: Stem Cell Institute Leuven (SCIL), Catholic University Leuven, Herestraat 49, 3000 Leuven, Belgium.