Kennedy Trust Prize Studentships
Investigating the genetic risk of post-traumatic osteoarthritis
Osteoarthritis (OA) is the commonest form of arthritis, affecting 9 million people in the UK, and is by the far the main indication for total joint replacement. However, we still have much to understand about its initiation. OA is associated with cartilage loss and other changes in many joint tissues, and often occurs later in life. However, a subgroup of OA (~12%) is so-called ‘post-traumatic’ OA and follows a significant joint injury. This OA subtype affects younger patients (with onset in their 20s to 40s), can lead to lifelong symptoms and often impacts (and ends of the careers of) professional athletes. Around 50% of those who suffer substantial acute knee injuries, such as anterior cruciate ligament (ACL) tears, will develop this post-traumatic OA phenotype within 5-10 years. It is unknown what causes some of these patients to make a full recovery from these injuries, while others go on to develop progressive symptomatic OA, though certain biomarkers may partially predict successful healing (see further reading below). One hypothesis is that this disease is the result of genotype-environment interaction, with disease onset requiring both an environmental trigger (the injury) and a degree of genetic susceptibility.
The genetics of later-onset OA have already been well studied (see further reading below), but the genetics of post-traumatic OA remains un-investigated to date. During this project, you will investigate the role of genetics in this disease (focusing primarily on knee injury), in order to establish:
- Is there a genetic basis for risk of post-traumatic OA?
- Is genetic risk to post-traumatic OA the same, or different to other OA?
- How does genetic risk for post-traumatic OA manifest in patients? (e.g. through inflammatory or repair signalling molecules, or through changes in underlying bone or cartilage structure)
To achieve this aim, you will use two important (and very different) types of dataset. The first is prospective cohorts of patients (mainly professional or semi-professional athletes) who have suffered acute knee joint injury. These include established, local cohorts: the Knee Injury Cohort at the Kennedy (KICK) study (led by Fiona Watt), OxKIC (the Oxford Knee Injury Cohort) and MenTOR (Meniscal Tear and Osteoarthritis Risk), with a potential for international collaborations via a new Consortium in addition. You will correlate the genotypes of these patients with their disease outcomes, as well as to biomarkers in blood and synovial fluid and joint imaging data (X-ray, MRI). The second dataset consists of extremely large population BioBanks, such as the 500,000 individuals in the UK BioBank. You will develop novel techniques for identifying post-traumatic OA in these cohorts, by using routine clinical Electronic Patient Records (including hospital and primary care data) and self-reported phenotypes. The aim will be to identify large numbers of individuals (>2000) with post-traumatic OA, such as those who have undergone ACL reconstruction, and compare the genetics of these individuals to both healthy people and those with other (non-traumatic) OA.
Once you have identified candidate genetic risk variants for post-traumatic OA, you will use a variety of datasets to investigate the functional impact of these variants on gene expression (i.e. expression Quantitative Trait Loci, or eQTLs, some from cohort whole blood RNA data), protein levels (pQTLs, both in blood and in the synovial fluid of the joint) and on other whole-body phenotypes (such as height, weight, bone density and joint structure). The ultimate aim of this research will be to use genetics to understand the biology of joint injury and repair, and to discover biomarkers that will allow us to identify risk at an early stage and develop new treatments for this common disease.
Translational Medicine; Tissue Remodelling and Regeneration.
- Lohmander LS, Englund PM, Dahl LL, Roos EM. The long-term consequence of anterior cruciate ligament and meniscus injuries: osteoarthritis. The American journal of sports medicine. 2007;35(10):1756-69.
- Watt FE, Paterson E, Freidin A, Kenny M, Judge A, Saklatvala J, Williams A, Vincent TL. Acute molecular changes in synovial fluid following human knee injury are associated with early clinical outcomes. Arthritis Rheumatol.2016; 68: 2129-2140.
- arcOGEN Consortium
- UK BioBank