Genetics of Osteoarthritis and Joint Replacement Recovery: Key to Precision Rehabilitation

点击翻译按钮获取中文摘要

The societal and patient-centered impacts of end-stage osteoarthritis (OA) among Veterans – including a significant proportion suffering from post-traumatic arthritis – are profound: (i) VA healthcare costs for treatment exceed $880 million annually; (ii) ~30% of Veterans in the VA healthcare system have OA, which is a significantly higher rate than the general population; (iii) each year, 10,000 Veterans with end-stage arthritis undergo total hip (n~3500) or knee (n~6500) arthroplasty (THA/TKA) and subsequent rehabilitation; (iv) Veterans who undergo THA/TKA experience profound deficits in health-related quality of life (HRQL), severe functional limitations in activities of daily living (ADL), increased healthcare utilization, and higher incidence of comorbidities and hospitalization; and (v) incidence of moderate-severe functional limitations 2-5 years post- surgery is 30-35% post-THA and 46-50% post-TKA despite prescribed rehabilitation. OA has a strong genetic component with heritability estimates >30%. Pain is the most common symptom, contributing to disability and decreased HRQL. Major phenotypic predictors of post-THA/TKA mobility limitation and pain have been identifed. However, genetic predictors of both the progression of OA and success of THA/TKA recovery are as yet unknown. Such discovery would fuel progress toward precision pre-habilitation and post-surgical rehabilitation among Veterans. We seek to leverage the rich MVP resource to test the overarching hypothesis that genetic variants explain a meaningful proportion of OA prevalence, progression to end-stage disease leading to THA/TKA, and recovery success. This hypothesis will be tested with three specific aims. Aim 1: To identify genetic variants associated with OA. We will perform GWAS in 292,516 MVP participants 40-80 years of age – of which 90,000 carry an OA diagnosis – in an effort to replicate known and identify new genetic variants and regions associated with OA. As a secondary analysis, we will perform GWAS to identify genetic variants associated with OA among 3,696 Veterans with post-traumatic arthritis. We will attempt to replicate significant findings using data on 392,304 individuals in the UK Biobank, of which 41,217 have OA. Aim 2: To identify genetic variants prognostic of progression to end-stage OA, as indicated by THA/TKA. We will perform GWAS in the 90,000 MVP participants with OA to identify variants associated with reaching the end-stage (i.e. THA/TKA). Within this cohort with diagnosed OA, we will identify genetic variants unique to the subpopulation that progressed to end-stage – i.e. the 7,600 MVP participants who have undergone THA or TKA subsequent to OA diagnosis. As a secondary analysis, we will perform GWAS to identify genetic variants associated with revision surgery within 5 years of the initial THA/TKA, suggesting unique genetic variants that may predispose some Veterans to poor adaptations to the initial THA/TKA. We will replicate significant findings using data from 13,071 THA and 12,794 TKA in the UK Biobank. Exploratory Aim: To identify genetic variants prognostic of THA/TKA recovery defined by mobility limitation (primary outcome), pain, and HRQL (secondary outcomes). We will perform GWAS among the 7,600 MVP participants with past THA/TKA to identify variants associated with recovery success or failure, as indicated by MVP Baseline and Lifestyle survey responses. As a secondary analysis, we will investigate whether rehabilitation mediates the relationship between genetic variants and THA/TKA recovery. We will maximize heterogeneity using two strategies: (i) By performing GWAS in each major ethnic group independently and combining results using meta-analysis accounting for trans- ethnic admixture; and (ii) By analyzing the entire MVP cohort to perform a multi-ethnic GWAS. The ultimate goal is to identify genetic variants prognostic of OA as well as poor OA and THA/TKA outcomes to develop targeted, precision pre-habilitation and post-surgical rehabilitation strategies improving mobility function, HRQL, and healthcare utilization among Veterans.