Association of bone morphogenetic proteins with otosclerosis.

UNLABELLED: We studied the role of polymorphisms in 13 candidate genes on the risk of otosclerosis in two large independent case-control sets. We found significant association in both populations with BMP2 and BMP4, implicating these two genes in the pathogenesis of this disease. INTRODUCTION: Otosclerosis is a progressive disorder of the human temporal bone that leads to conductive hearing loss and in some cases sensorineural or mixed hearing loss. In a few families, it segregates as a monogenic disease with reduced penetrance, but in most patients, otosclerosis is more appropriately considered a complex disorder influenced by genetic and environmental factors. MATERIALS AND METHODS: To identify major genetic factors in otosclerosis, we used a candidate gene approach to study two large independent case-control sets of Belgian-Dutch and French origin. Tag single nucleotide polymorphisms (SNPs) in 13 candidate susceptibility genes were studied in a stepwise strategy. RESULTS: Two SNPs were identified that showed the same significant effect in both populations. The first SNP, rs3178250, is located in the 3' untranslated region of BMP2. Individuals homozygote for the C allele are protected against otosclerosis (combined populations: p = 2.2 x 10(-4); OR = 2.027; 95% CI = 1.380-2.979). The second SNP, rs17563, is an amino acid changing (p.Ala152Val) SNP located in BMP4. The G allele, coding for the amino acid alanine, confers susceptibility in both populations (combined populations: p = 0.002; OR = 1.209; 95% CI: 1.070-1.370). CONCLUSIONS: These results indicate that polymorphisms in the BMP2 and BMP4 genes, both members of the TGF-beta superfamily, contribute to the susceptibility to otosclerosis and further strengthen the results from the recently reported association of TGFB1 with this disease.

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

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.

A seventh locus for otosclerosis, OTSC7, maps to chromosome 6q13-16.1.

Otosclerosis is a common form of hearing impairment among white adults with a prevalence of 0.3-0.4%. It is caused by abnormal bone homeostasis of the otic capsule that compromises free motion of the stapes in the oval window. Otosclerosis is in most patients a multifactorial disease, caused by both genetic and environmental factors. In some cases, the disease is inherited as a monogenic autosomal dominant trait, sometimes with reduced penetrance. However, families large enough for genetic linkage studies are extremely rare. To date, five loci (OTSC1-5) have been reported, but none of the responsible genes have been cloned yet. An additional locus, OTSC6, has been reported to the HUGO nomenclature committee but the relevant linkage study has not been published. In this study, a genome-wide linkage study was performed in a large Greek pedigree segregating autosomal dominant otosclerosis. A seventh locus, OTSC7, was localized on chromosome 6q13-16.1 with a multipoint LOD score of 7.5 in the 13.47 cM region defined by markers D6S1036 (centromeric) and D6S300 (telomeric). Linkage analysis of this new locus in 13 smaller Belgian and Dutch families has identified one family from The Netherlands in which allele segregation suggests linkage to this region. The overlap between the critical regions of these two families is a 1.06 Mb interval between the genetic markers D6S1036 (centromeric) and D6S406 (telomeric) on chromosome 6q13.