Genetic association and gene expression profiles of TGFB1 and the contribution of TGFB1 to otosclerosis susceptibility.

Otosclerosis (OTSC) is a common form of acquired hearing loss resulting from disturbed bone remodeling in the otic capsule of the middle ear. Transforming growth factor-beta1 (TGFB1) produced by osteoblasts is the most abundant growth factor in human bone. Previous studies have shown the contribution of single-nucleotide polymorphisms (SNPs) in TGFB1 toward the risk of developing OTSC in some ethnic populations. The present study was aimed at investigating the genetic association and expression profiles of TGFB1 in OTSC patients. Two SNPs (c.-800G > A and c.-509C > T) in the promoter region and three SNPs (c.29T > C, c.74G > C, and c.788C > T) in the coding region were genotyped in 170 cases and 170 controls. The genetic association analysis revealed the significant association between c.-509C > T (p = 0.0067; odds ratio [OR] = 1.562; 95% confidence interval [CI], 1.140-2.139) and OTSC. The increased minor allele "T" frequency in cases (0.42) compared to controls (0.31) indicates its possible role in the etiology of the disease. The minor allele frequencies for the SNPs c.-800G > A, c.29T > C, and c.74G >C were similar among the cases (0.04, 0.47, and 0.08, respectively) and controls (0.05, 0.42, 0.07, respectively). We found that c.788C > T was monomorphic in this population. Interestingly, a four-locus haplotype (G-T-T-G) from these SNPs was found to be significantly associated with OTSC (p = 0.0077). We identified a de novo heterozygous mutation c.-832G > A in the promoter region of TGFB1 in 1 patient. In a secondary analysis, we investigated the possibility of abnormal TGFB1 expression and irregular bone growth in OTSC by expression analysis of TGFB1 mRNA in disease tissue compared to control. We found relatively increased expression of TGFB1 mRNA in the stapes tissues of cases compared to controls (p = 0.0057). In conclusion, this study identified a risk variant c.-509C > T and a risk haplotype G-T-T-G in the TGFB1 gene that contribute toward the susceptibility to OTSC.