title: Single-nucleotide polymorphisms in the COL1A1 regulatory regions are associated with otosclerosis.
abstract: Otosclerosis (MIM 166800) has a prevalence of 0.2-1% among white adults, making it the single most common cause of hearing impairment in this ethnic group. Although measles virus, hormones, human leukocyte antigen alleles and genetic factors have been implicated in the development of otosclerosis, its etiology remains unknown. In a focused effort to identify genetic factors in otosclerosis, we have mapped four disease loci (MIM 166800/605727/608244/608787); however, cloning the disease-causing genes in these intervals has not been successful. Here, we used a case-control study design to investigate the association between collagen type I genes and otosclerosis. We identified susceptibility and protective haplotypes in COL1A1 that are significantly associated with otosclerosis in the Caucasian population. These haplotypes alter reporter gene activity in an osteoblast cell line by affecting binding of transcription factors to cis-acting elements. Our data suggest that increased amounts of collagen alpha1(I) homotrimers are causally related to the development of otosclerosis. Consistent with this hypothesis, mouse mutants homozygous for a Col1a2 frameshift mutation on a C57BL/6J background that deposit only homotrimeric type I collagen have hearing loss.
authors.affiliation: Molecular Otolaryngology Research Laboratories, Department of Otolaryngology, The University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: W
authors.initials: W
authors.lastname: Chen
authors.forename: N C
authors.initials: NC
authors.lastname: Meyer
authors.forename: M J
authors.initials: MJ
authors.lastname: McKenna
authors.forename: M
authors.initials: M
authors.lastname: Pfister
authors.forename: D J
authors.initials: DJ
authors.lastname: McBride
authors.forename: K
authors.initials: K
authors.lastname: Fukushima
authors.forename: M
authors.initials: M
authors.lastname: Thys
authors.forename: G V
authors.initials: GV
authors.lastname: Camp
authors.forename: R J H
authors.initials: RJ
authors.lastname: Smith
mesh_terms: D000818:Animals; D001665:Binding Sites; D016022:Case-Control Studies; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics*; D000090602:Collagen Type I, alpha 1 Chain; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D034381:Hearing Loss; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010040:Otosclerosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D050436:Regulatory Elements, Transcriptional; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D014157:Transcription Factors