Evidence of distinct RELN and TGFB1 genetic associations in familial and non-familial otosclerosis in a British population

• Published in: Human genetics 2018-05, Vol.137 (5), p.357-363
• Main Authors: Mowat, Andrew J., Crompton, Michael, Ziff, Joanna L., Aldren, Christopher P., Lavy, Jeremy A., Saeed, Shakeel R., Dawson, Sally J.
• Format: Article
• Language: English
• Subjects: Biomedical and Life Sciences; Biomedicine; Bone Morphogenetic Protein 2 - genetics; Bone morphogenetic proteins; Cell Adhesion Molecules, Neuronal - genetics; Chromosomes; Collagen (type I); Collagen Type I - genetics; Collagen Type I, alpha 1 Chain; Extracellular Matrix Proteins - genetics; Female; Fibroblast growth factor 2; Fibroblast Growth Factor 2 - genetics; Fibroblast growth factors; Gene Expression Regulation; Gene Function; Genetic Association Studies; Genetic Predisposition to Disease; Genetic research; Genome-wide association studies; Genomes; Genomics; Genotype; Hearing loss; Human Genetics; Humans; Male; Membrane Proteins - genetics; Metabolic Diseases; Molecular Medicine; Nerve Tissue Proteins - genetics; Original Investigation; Otosclerosis; Otosclerosis - genetics; Otosclerosis - physiopathology; Polymorphism, Single Nucleotide - genetics; Protein Phosphatase 2 - genetics; Reelin Protein; Serine Endopeptidases - genetics; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Transcription; Transforming Growth Factor beta1 - genetics; Transforming growth factor-b1; United Kingdom
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-018-1889-9

Otosclerosis is a common form of hearing loss which typically presents in young adults. The disease has a familial, monogenic form and a non-familial form with a more complex aetiology. A previous genome wide association study identified evidence that variants within RELN are associated with the condition. Other genes in which an association has been reported include BMP2, COL1A1, FGF2, PPP2R5B and TGFB1 . However, follow up studies have often failed to replicate initial positive results. The aim of this study was to establish if an association exists between eight single nucleotide polymorphisms (SNPs) in these six previously implicated genes and otosclerosis in a British case–control cohort ( n  = 748). Evidence of an association between rs1800472 in TGFB1 and otosclerosis was found ( p  = 0.034), this association was strongest amongst non-familial cases ( p  = 0.011). No evidence of an association was detected with variants in COL1A1, FGF2, BMP2 , and PPP2R5B . No association between variation in RELN and otosclerosis was observed in the whole cohort. However, a significant association ( p  = 0.0057) was detected between one RELN SNP (rs39399) and otosclerosis in familial patients. Additionally, we identify expression of one RELN transcript in 51 of 81 human stapes tested, clarifying previous conflicting data as to whether RELN is expressed in the affected tissue. Our findings strengthen the association of TGFB1 (rs1800472) with otosclerosis and support a relationship between RELN and familial otosclerosis only, which may explain previous variable replications.