title: Genetic association and gene expression profiles of TGFB1 and the contribution of TGFB1 to otosclerosis susceptibility.
abstract: 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.
authors.affiliation: Institute of Life Sciences, Chandrasekharpur, Bhubaneswar, India.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Priyadarshi
authors.forename: Chinmay Sundar
authors.initials: CS
authors.lastname: Ray
authors.forename: Khirod Chandra
authors.initials: KC
authors.lastname: Panda
authors.forename: Ashim
authors.initials: A
authors.lastname: Desai
authors.forename: Soumya Ranjan
authors.initials: SR
authors.lastname: Nayak
authors.forename: Narayan Chandra
authors.initials: NC
authors.lastname: Biswal
authors.forename: Puppala Venkat
authors.initials: PV
authors.lastname: Ramchander
mesh_terms: D016022:Case-Control Studies; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005787:Gene Frequency / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D016017:Odds Ratio; D010040:Otosclerosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1
keywords: GENETIC ASSOCIATION; OTIC CAPSULE; OTOSCLEROSIS; SINGLE-NUCLEOTIDE POLYMORPHISM; SNP; TGFB1