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.

Background/hypothesis: 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.

Conclusion: 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.