title: Genetic association analysis in a clinically and histologically confirmed otosclerosis population confirms association with the TGFB1 gene but suggests an association of the RELN gene with a clinically indistinguishable otosclerosis-like phenotype.
abstract: OBJECTIVE
  Otosclerosis is a frequent cause of hearing impairment characterized by abnormal resorption and deposition of bone in the human otic capsule. It is a disease of complex etiopathogenesis that is caused by both environmental and genetic factors. The goal of this study is to replicate association for genes that were previously reported to be associated with otosclerosis. However, in this study, patients were used in which the presence of otosclerotic foci was confirmed by histologic investigation, in contrast to previous studies, that did not use histologic confirmation.
  
  
  METHODS
  Case-control association study using 153 cases and 300 controls. Thirteen single nucleotide polymorphisms (SNPs) in 6 genes (COL1A1, TGFB1, BMP2, BMP4, AGT, and RELN) were genotyped.
  
  
  RESULTS
  An association between TGFB1 (rs1800472) and otosclerosis was detected, confirming several previous reports. It is surprising that no association was found between RELN and otosclerosis because the current analysis had very reasonable power and the RELN association has been published before in different articles using several independent populations.
  
  
  CONCLUSIONS
  Our findings strengthen the association of TGFB1 (rs1800472) with otosclerosis. The fact that other genes did not replicate could be due to different reasons like lack of power (BMP2 and BMP4) and possible false-positive initial association (COL1A1 and AGT). A plausible explanation for the lack of association for RELN is that RELN could be associated with a specific otosclerosis-like phenotype that is different from the histologically confirmed phenotype of the patients in this study, and that is clinically not distinguishable.
authors.affiliation: *University of Antwerp, Department of Medical Genetics, Antwerp, Belgium; †Bajcsy-Zsilinszky Hospital, ENT Department, Budapest; and ‡University of Debrecen, Medical and Health Science Center, Department of Otolaryngology and Head and Neck Surgery, Debrecen, Hungary.
authors.forename: Manou
authors.initials: M
authors.lastname: Sommen
authors.forename: Guy
authors.initials: G
authors.lastname: Van Camp
authors.forename: Balázs
authors.initials: B
authors.lastname: Liktor
authors.forename: Péter
authors.initials: P
authors.lastname: Csomor
authors.forename: Erik
authors.initials: E
authors.lastname: Fransen
authors.forename: István
authors.initials: I
authors.lastname: Sziklai
authors.forename: Isabelle
authors.initials: I
authors.lastname: Schrauwen
authors.forename: Tamás
authors.initials: T
authors.lastname: Karosi
mesh_terms: D000328:Adult; D000808:Angiotensinogen / Q000235:genetics; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics; D016022:Case-Control Studies; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D024042:Collagen Type I / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010040:Otosclerosis / Q000235:genetics* / Q000473:pathology*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000235:genetics*; D053773:Transforming Growth Factor beta1 / Q000235:genetics*; D055815:Young Adult
chemical_list: C534931:AGT protein, human; C525718:BMP2 protein, human; C525809:BMP4 protein, human; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D015816:Cell Adhesion Molecules, Neuronal; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D000808:Angiotensinogen; C000717127:RELN protein, human; D012697:Serine Endopeptidases