THE GENETICS OF OSTEOLYSIS AND HETEROTOPIC OSSIFICATION AFTER TOTAL HIP ARTHROPLASTY

Aseptic loosening, the clinical end point of osteolysis, is the most common complication resulting in revision surgery of total hip arthroplasty (THA). It is the result of focal peri-prosthetic inflammatory bone loss at the prosthesis-host interface, and is driven by particulate wear debris generated primarily at the articular bearing surface. There is variation between individuals in their inflammatory response to wear debris suggesting a genetic component. Candidate gene studies have shown that susceptibility to osteolysis associates with polymorphic variation in genes encoding several inflammatory cytokines and bone regulatory molecules. Better understanding of the genetic component is required to address the pathogenesis of aseptic loosening. Advances in high throughput genotyping and mapping of genomic variation has made it possible to examine common genetic variation or quantitative traits as possible risk factors of disease through genome wide association studies (GWAS). This thesis which forms my PhD candidature, describes several studies undertaken to understand the biological processes contributing to osteolysis. We have followed the advances in genotyping and bioinformatics progressing from a candidate gene study to undertaking whole genome analysis. We describe the largest candidate gene study to date looking at tagging SNPs in genes thought to play important roles in bone turnover and inflammatory pathways. We have undertaken the first GWAS for osteolysis susceptibility and time to prosthesis failure following THA in over 3,700 patients. During the recruitment process of the replication cohort from the Norwegian arthroplasty register we have proved the feasibility of using such registries for recruitment to answer research questions and establish linked biobanks for the study of musculoskeletal disease. Heterotopic ossification is also a common complication following THA and similarly its pathogenesis is poorly understood. We also describe a GWAS looking for variants associated with the development of HO and its severity following THA