The coding polymorphism T263I in TGF-β1 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-β1) 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 × 10^-6). Functional analysis of SNP T263I with a luciferase reporter assay showed that the protective variant I263 of TGF-β1 is more active than the WT variant T263 (P = 1.6 × 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-β1 influences the susceptibility for otosclerosis, and that the I263 variant is protective against the disease.