title: The coding polymorphism T263I in TGF-beta1 is associated with otosclerosis in two independent populations.
abstract: 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-beta1) 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-beta1 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-beta1 influences the susceptibility for otosclerosis, and that the I263 variant is protective against the disease.
authors.affiliation: Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
authors.forename: Melissa
authors.initials: M
authors.lastname: Thys
authors.forename: Isabelle
authors.initials: I
authors.lastname: Schrauwen
authors.forename: Kathleen
authors.initials: K
authors.lastname: Vanderstraeten
authors.forename: Katrien
authors.initials: K
authors.lastname: Janssens
authors.forename: Nele
authors.initials: N
authors.lastname: Dieltjens
authors.forename: Kris
authors.initials: K
authors.lastname: Van Den Bogaert
authors.forename: Erik
authors.initials: E
authors.lastname: Fransen
authors.forename: Wenjie
authors.initials: W
authors.lastname: Chen
authors.forename: Megan
authors.initials: M
authors.lastname: Ealy
authors.forename: Mireille
authors.initials: M
authors.lastname: Claustres
authors.forename: Cor R W J
authors.initials: CR
authors.lastname: Cremers
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Dhooge
authors.forename: Frank
authors.initials: F
authors.lastname: Declau
authors.forename: Jos
authors.initials: J
authors.lastname: Claes
authors.forename: Paul
authors.initials: P
authors.lastname: Van de Heyning
authors.forename: Robert
authors.initials: R
authors.lastname: Vincent
authors.forename: Thomas
authors.initials: T
authors.lastname: Somers
authors.forename: Erwin
authors.initials: E
authors.lastname: Offeciers
authors.forename: Richard J H
authors.initials: RJ
authors.lastname: Smith
authors.forename: Guy
authors.initials: G
authors.lastname: Van Camp
mesh_terms: D019943:Amino Acid Substitution; D016022:Case-Control Studies; D004198:Disease Susceptibility; D014644:Genetic Variation; D005828:Genetics, Population; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008954:Models, Biological; D010040:Otosclerosis / Q000208:ethnology / Q000209:etiology / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D053773:Transforming Growth Factor beta1 / Q000235:genetics*; D044465:White People
chemical_list: C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1