Evaluation of the Genetic Association and mRNA Expression of the , , and Genes in the Development of Otosclerosis.

Otosclerosis (OTSC) is a genetically heterogeneous disorder, characterized by abnormal bone growth in the middle ear, affecting the stapes bone. Previous studies have shown that single nucleotide polymorphisms (SNPs) of the and genes are linked to susceptibility of OTSC, musculoskeletal degenerative diseases, and bone remodeling. : To evaluate the genetic association and expression levels of , , and genes with OTSC in the Indian population. : A total of 320 otosclerotic and 320 control samples were screened for four SNPs (rs1107946, rs11327935, rs2269336, and rs1800012) of the gene; rs3178250 of the gene; and rs17563 of the gene using single-strand conformation polymorphism analysis, and restriction fragment length polymorphism analyses. Genotypic, haplotypic, and linkage disequilibrium analyses were performed to assess the potential associations of these SNPs with OTSC. , , and mRNA expression levels were analyzed by semiquantitative RT-PCR and real-time PCR. : Genotypes of two SNPs, rs1800012 and rs17563, were found to be associated with OTSC (the rs1800012 GT genotype,  = 0.0022, OR = 0.481; and the rs17563 TC genotype,  = 0.0225, OR = 1.471). Haplotypic analyses revealed that the haplotype G-T-C-T ( = 0.021) was significantly increased among controls. Functional studies revealed an unexpected decrease in mRNA expression of but an increased expression of the and genes in otosclerotic stapes tissues. : Our findings suggest that OTSC is a heterogeneous disorder, but that the GT genotype of the rs1800012 locus is protective and that the TC genotype at the rs17563 locus is a risk factor. In addition, our studies indicate that changes in the expression of the , , and genes may contribute to the genetic susceptibility of OTSC by regulating their mRNA levels.