The coding polymorphism T263I in TGF-beta1 is associated with otosclerosis in two independent populations.

Fulltext:
36578.pdf
Embargo:
until further notice
Size:
210.7Kb
Format:
PDF
Description:
publisher's version
Publication year
2007Source
Human Molecular Genetics, 16, 17, (2007), pp. 2021-2030ISSN
Publication type
Article / Letter to editor

Display more detailsDisplay less details
Organization
Spectroscopy of Solids and Interfaces
Otorhinolaryngology
Journal title
Human Molecular Genetics
Volume
vol. 16
Issue
iss. 17
Page start
p. 2021
Page end
p. 2030
Subject
DCN 1: Perception and Action; DCN 2: Functional Neurogenomics; Spectroscopy of Solids and Interfaces; UMCN 3.3: Neurosensory disorders; UMCN 5.1: Genetic defects of metabolism; UMCN 5.1: Genetic defects of metabolismAbstract
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.
This item appears in the following Collection(s)
- Academic publications [205104]
- Electronic publications [103316]
- Faculty of Medical Sciences [81055]
- Faculty of Science [32347]
Upload full text
Use your RU credentials (u/z-number and password) to log in with SURFconext to upload a file for processing by the repository team.