Lysyl oxidase polymorphisms and susceptibility to osteosarcoma

Despite the knowledge of many genetic alterations present in osteosarcoma, the complexity of this disease precludes placing its biology into a simple conceptual framework. Lysyl oxidase (LOX) catalyzes the cross-linking of elastin and collagen, which is essential for the structural integrity and function of bone tissue. In the current study, we performed genomic sequencing on all seven exons -including the intron-exon splice sites, and the putative promoter region of LOX gene - followed by luciferase reporter assay to analyze the function of newly identified polymorphisms. Associations between LOX polymorphisms and osteosarcoma were then evaluated. Our sequencing data revealed three polymorphisms (?22G/C, 225C/G, and 473G/A) in the exons and promoter region of LOX. The ?22G/C polymorphism lies in the downstream core promoter element (DPE) region and caused a decrease in promoter activity of LOX. The prevalence of the ?22C allele and 473A allele were significantly increased in osteosarcoma patients compared to controls (odds ratio OR]?=?3.88, 95% confidence interval CI] ?=?1.94?7.78, p?=?4.18×10^?5, and OR?=?1.38, 95%CI?=?1.07?1.78, p?=?0.013; p 0.0167 was considered significant after Bonferroni correction). Analyzing haplotype showed that the frequency of CCG haplotype (?22, 225, 473) was significantly higher in osteosarcoma cases than in healthy controls after Bonferroni correction (p?=?4.46×10^?4). These results indicate that the ?22G/C polymorphism may affect the expression of LOX, and that ?22G/C and 473G/A polymorphisms may be new risk factors for osteosarcoma. These findings reveal a potential new pathway by which genetic polymorphisms may affect human diseases.