Continuing tissue destruction in osteoarthrosis is maintained by molecular pathways related to an unbalanced chondrocyte metabolism, the loss of reactive oxygen species (ROS) homeostasis, increase catabolism in a degraded matrix and the limited response to growth factors due to cell aging. Rare deleterious gene variants driving relevant molecular pathways may play a key role in the pathogenesis and genetic control of common diseases and may also influence the common gene variants observed in GWAS. We use molecular profiling technologies based on massive sequencing of genes to interrogate clinical samples for a variety of molecules involved in the pathogenesis pathways of OA and also to derive new insights for drug targeting discovery at an early stage of the disease. By whole-exome sequencing performed in OA patients with extreme phenotypes and in non-related individuals without clinical evidence of OA, the most predominant of the rare gene variants found were non-synonymous single-nucleotide variants (SNV) from exonic DNA regions and with missense functional effects predicting a moderate impact on protein function. A total of 629, 577, and 639 gene variants for the TPF, COA, and ANHNF patients, respectively, were found not to be shared with the 20 non-disease-related individuals. After subtraction of the 306 variants shared among the OA patients, we obtained the individual profiles of 323, 271, and 333 gene variants, for the TPF, COA, and ANHNF patients, respectively. After filtering by the bioinformatics, genetic, and biological criteria established to assess the clinical consequences, comparative analysis of trio sequences using integrative genome visualization tool clearly demonstrate the differences between patients. Analysis of the collagen gene variants identified 78, 20, and 43 genetic collagen variants for the three extreme phenotypes. Rare gene variants encoding for proteins that are less abundant in the trabecular bone matrix, together with those responsible for the control and regulation of bone turnover and plasticity of subchondral trabecular bone, play important roles in OA and help to define the clinical phenotype.
Keywords: INDEL mutation; bioinformatics analysis; computational biology; coxarthrosis; femoral neck; fractures; gene variants; genome; osteoarthritis; osteoarthrosis; polymorphism; trabecular bone; whole-Exome sequencing.
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