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

Melissa Thys; Isabelle Schrauwen; Kathleen Vanderstraeten; Katrien Janssens; Nele Dieltjens; Kris Van Den Bogaert; Erik Fransen; Wenjie Chen; Megan Ealy; Mireille Claustres; Cor R W J Cremers; Ingeborg Dhooge; Frank Declau; Jos Claes; Paul Van de Heyning; Robert Vincent; Thomas Somers; Erwin Offeciers; Richard J H Smith; Guy Van Camp

doi:10.1093/hmg/ddm150

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

Journal article

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

Melissa Thys, Isabelle Schrauwen, Kathleen Vanderstraeten, Katrien Janssens, Nele Dieltjens, Kris Van Den Bogaert, Erik Fransen, Wenjie Chen, Megan Ealy, Mireille Claustres, …

Human molecular genetics, Vol.16(17), pp.2021-2030

09/01/2007

DOI: 10.1093/hmg/ddm150

PMID: 17588962

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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.

Phenotype

Haplotypes

Genetics, Population

Disease Susceptibility

Humans

Otosclerosis - etiology

European Continental Ancestry Group

Genotype

Transforming Growth Factor beta1 - genetics

Sequence Analysis, DNA

Case-Control Studies

Genetic Variation

Models, Biological

Otosclerosis - ethnology

Otosclerosis - genetics

Polymorphism, Single Nucleotide

Amino Acid Substitution

Details

Title: Subtitle: The coding polymorphism T263I in TGF-beta1 is associated with otosclerosis in two independent populations
Creators: Melissa Thys - Department of Medical Genetics, University of Antwerp, Antwerp, Belgium
Isabelle Schrauwen
Kathleen Vanderstraeten
Katrien Janssens
Nele Dieltjens
Kris Van Den Bogaert
Erik Fransen
Wenjie Chen
Megan Ealy
Mireille Claustres
Cor R W J Cremers
Ingeborg Dhooge
Frank Declau
Jos Claes
Paul Van de Heyning
Robert Vincent
Thomas Somers
Erwin Offeciers
Richard J H Smith
Guy Van Camp
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.16(17), pp.2021-2030
DOI: 10.1093/hmg/ddm150
PMID: 17588962
NLM abbreviation: Hum Mol Genet
ISSN: 0964-6906
eISSN: 1460-2083
Publisher: England
Grant note: R01 DC05218 / NIDCD NIH HHS
Language: English
Date published: 09/01/2007
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
Record Identifier: 9984007172802771

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