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

退伍军人中终末期骨关节炎(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：(I)退伍军人管理局的医疗费用 每年治疗超过8.8亿美元；(Ii)退伍军人医疗系统中约30%的退伍军人患有骨性关节炎，这是 明显高于普通人群；(3)每年有10,000名退伍军人患有终末期关节炎 接受全髋关节置换术(3500例)或膝关节置换术(6500例)及随后的康复治疗； 接受THA/TKA的退伍军人经历了严重的健康相关生活质量(HRQL)缺陷，严重 日常生活活动(ADL)的功能限制、医疗保健利用率的提高以及更高的发病率 合并症和住院；和(V)中-重度功能障碍的发生率 手术是全髋关节置换术后的30-35%，全膝关节置换术后的46-50%，尽管规定的是康复。骨质疏松症有很强的遗传 遗传力估计为30%的成分。疼痛是最常见的症状，会导致残疾和 HRQL降低。THA/TKA术后活动受限和疼痛的主要表型预测因子为 已确认身份。然而，预测骨性关节炎进展和全髋关节置换术/全膝关节置换术恢复成功的遗传因素如下 但还不清楚。这样的发现将推动精确的康复前和手术后的进展 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有意义的比例的OA患病率，进展到终末期 导致THA/TKA的疾病，以及康复成功。这一假设将通过三个具体目标进行检验。 目的1：鉴定与骨性关节炎相关的遗传变异。我们将在292,516名MVP参与者中进行GWAS 40-80岁--其中90,000人患有骨质疏松症--努力复制已知并识别新的 与骨性关节炎相关的遗传变异和区域。作为二次分析，我们将执行GWAS以确定 3696名患有创伤后关节炎的退伍军人中与骨性关节炎相关的基因变异。我们将尝试 利用英国生物库中392,304人的数据重复重要的发现，其中41,217人患有骨性关节炎。 目的2：确定THA/TKA所示的进展到终末期骨性关节炎的遗传变异的预后。我们 将对90,000名患有OA的MVP参与者进行GWA检查，以确定与达到 结束阶段(即临屋区/将军澳)。在这个诊断为骨性关节炎的队列中，我们将识别出独有的遗传变异 进展到最后阶段的亚群--即7600名MVP参与者，他们经历了THA或 骨关节炎诊断后行全膝关节置换术。作为二次分析，我们将进行GWAS以确定遗传变异 与初次THA/TKA术后5年内的翻修手术相关，提示存在独特的遗传变异 可能会使一些退伍军人对最初的THA/TKA适应能力较差。我们将复制重要的发现 使用英国生物库中13,071个THA和12,794个TKA的数据。探索性目标：识别基因变异 THA/TKA恢复的预后由活动受限(主要结果)、疼痛和HRQL(次要结果)确定 结果)。我们将在过去有THA/TKA的7600名MVP参与者中进行GWA检查，以确定变异 与康复成功或失败有关，如MVP基线和生活方式调查回答所示。AS 在二次分析中，我们将调查康复是否调节了遗传 变异体和THA/TKA恢复。我们将使用两种策略最大限度地提高异构性：(I)通过执行GWAS 在每个主要民族中独立并结合结果使用Meta分析来解释反式 种族混杂；以及(Ii)通过分析整个MVP队列来执行多种族GWA。终极的 目标是确定预测骨性关节炎预后的遗传变异以及不良的骨性关节炎和THA/TKA预后。 有针对性的精确的术前康复和术后康复策略，改善行动能力； 退伍军人的HRQL和医疗保健利用。

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.