Caracterización genética del fenotipo de progresión rápida en la patología artrósica

Abstract

This thesis project tries to identify genetic variants capable of altering the risk of developing the rapidly progressive phenotype in knee osteoarthritis. To achieve this, sequencing techniques have been used to search for polymorphisms present in nuclear and mitochondrial DNA that may favor the development of the phenotype of interest. A mitochondrial variant, present at m.16519C, was detected and was significantly associated with rapid progression. After carrying out a small functional study, higher levels of interleukin 6 and cyclooxygenase 2 were detected in cybrids carrying this variant, and the increased inflammatory response could be a triggering mechanism for rapid progression. On the other hand, an interaction between nuclear and mitochondrial DNA has been detected for the first time in the field of osteoarthritis. The presence of the mitochondrial haplogroup UK and the rs12107036 nuclear polymorphism also increases the risk of rapid progression in knee osteoarthritis. Finally, a predictive model of great clinical and pharmacological relevance was generated, based on genetic and clinical variables, which is capable of predicting the risk of developing the rapidly progressive phenotype of knee osteoarthritis.