Single-nucleotide polymorphisms in the COL1A1 regulatory regions are associated with otosclerosis

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 alpha 1(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.