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

退伍军人终末期骨关节炎（OA）的社会和以患者为中心的影响-包括 很大一部分人患有创伤后关节炎-影响深远：（一）退伍军人事务部的保健费用， 治疗每年超过8.8亿美元;（ii）VA医疗保健系统中约30%的退伍军人患有OA， 一个显着高于一般人群的比率;（iii）每年，10,000退伍军人与终末期关节炎 接受全髋关节（n~3500）或膝关节（n~6500）关节置换术（THA/TKA）和后续康复;（iv） 接受THA/TKA的退伍军人在健康相关生活质量（HRQL）方面存在严重缺陷， 日常生活活动（ADL）功能受限，医疗保健利用增加， 合并症和住院治疗;和（v）术后2-5年中重度功能限制的发生率 尽管进行了规定的康复治疗，但THA后手术率为30-35%，TKA后手术率为46-50%。OA有很强的遗传性 遗传率估计值> 30%。疼痛是最常见的症状，导致残疾， 降低HRQL。THA/TKA术后活动受限和疼痛的主要表型预测因子是 识别。然而，OA进展和THA/TKA成功恢复的遗传预测因子是， 还不知道这一发现将推动在术前和术后精确测量的进展。 退伍军人的康复。我们寻求利用丰富的MVP资源来测试总体 假设遗传变异解释了OA患病率、进展至终末期的有意义的比例 导致THA/TKA的疾病和恢复成功。将以三个具体目标来检验这一假设。 目的1：鉴定与OA相关的遗传变异。我们将在292，516名MVP参与者中执行GWAS 40-80岁-其中90，000人携带OA诊断-努力复制已知并识别新的 与OA相关的遗传变异和区域。作为二次分析，我们将执行GWAS以识别 3,696名创伤后关节炎退伍军人中与OA相关的遗传变异。我们将尝试 使用英国生物库中392，304人的数据复制了重要的发现，其中41，217人患有OA。 目的2：确定THA/TKA所示进展为终末期OA的遗传变异预后。我们 将在90，000名患有OA的MVP参与者中进行GWAS，以识别与达到 终末期（即THA/TKA）。在诊断为OA的这一队列中，我们将鉴定出OA患者特有的遗传变异。 进展至终末期的亚群-即7，600例接受THA或 OA诊断后的TKA。作为二次分析，我们将进行GWAS以识别遗传变异 与初次THA/TKA后5年内的翻修手术相关，这表明独特的遗传变异， 可能使一些退伍军人对初次THA/TKA的适应性较差。我们将复制重要的发现 使用英国生物样本库中13，071例THA和12，794例TKA的数据。探索性目的：识别遗传变异 通过活动受限（主要结局）、疼痛和HRQL（次要结局）定义THA/TKA恢复的预后 成果）。我们将在7，600名既往THA/TKA的MVP参与者中进行GWAS，以识别变体 与MVP基线和生活方式调查答复所示的恢复成功或失败相关。作为 二次分析，我们将调查康复是否介导遗传之间的关系， 变体和THA/TKA恢复。我们将使用两种策略最大限度地提高异质性：（i）通过执行GWAS 在每个主要的种族群体独立，并结合结果，使用荟萃分析占跨- 种族混合;和（ii）通过分析整个MVP队列进行多种族GWAS。最终 目的是确定OA的遗传变异预后以及OA和THA/TKA结局不良， 有针对性的、精确的术前和术后康复策略，改善移动功能， HRQL和退伍军人的医疗保健利用率。

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.