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

美国终末期骨关节炎（OA）的社会和患者中心影响 退伍军人是深刻的。VA医疗保健系统中超过30%的退伍军人患有OA， 高于一般人群。OA的VA治疗费用很高，每年超过8.8亿美元。不过， 除了疼痛和症状管理以及终末期手术干预外， 治疗OA。尽管术后进行了规定的康复治疗， (THA)或全膝关节置换术（TKA）在健康相关生活质量（HRQL）方面存在严重缺陷， 日常生活活动严重受限，医疗保健利用增加， 合并症。OA具有很强的遗传成分，遗传率估计> 30%。我们的研究在百万 退伍军人计划（MVP）队列导致在关键领域的发现。第一，我们的祖先是特定的和多祖先的 对超过477，000名MVP和英国生物银行（UKB）参与者的分析确定了新的遗传区域 与OA有关。第二，MVP中的OA频率高于我们的复制队列（UKB）， 使用相同的电子健康记录诊断代码，这可能妨碍了复制工作。第三、 我们对MVP队列的研究表明，非洲裔美国人和西班牙裔退伍军人的OA遗传率较高 比欧洲白色血统的要多。我们的总体目标是确定康复前后的生物标志物 以增强医生预测患有OA和/或PTOA的退伍军人的患者预后的直觉。 为了实现这一目标，并填补有关遗传因素与OA相关的重要知识空白， 在目标1中，a）我们将确认与OA患病率和进展相关的遗传变异， 阶段OA以及B）开发和评估多基因风险评分（PRS）的性能，以识别退伍军人 有进展为全髋/膝关节置换术的风险;在目标2中，我们将确定预测 THA/TKA恢复;在目标3中，我们将确定是否存在与THA/TKA恢复相关的遗传变异。 创伤后OA（PTOA）的遗传决定因素与特发性OA的已知遗传决定因素不同。我们将确定 生物标志物，以实现有针对性的，精确的术前和术后康复策略， 活动功能、HRQL和医疗保健利用率。

The societal and patient-centered impacts of end-stage osteoarthritis (OA) among United States Veterans are profound. More than 30% of Veterans in the VA healthcare system have OA which is significantly higher than in the general population. VA treatment costs for OA are high, exceeding $880 million annually. Still, apart from pain and symptom management and end stage surgical intervention, there are no effective therapeutic treatments for OA. Despite prescribed rehabilitation post-surgery, Veterans who undergo total hip arthroplasty (THA) or total knee arthroplasty (TKA) experience profound deficits in health-related quality of life (HRQL), severe limitations in activities of daily living, increased healthcare utilization, and higher incidence of comorbidities. OA has a strong genetic component with heritability estimates >30%. Our research in the Million Veteran Program (MVP) cohort led to discoveries in key areas. First, our ancestry specific and multi-ancestry analyses in over 477,000 MVP and the UK Biobank (UKB) participants identified of novel genetic regions associated with OA. Second, OA frequency was higher in the MVP than in our replication cohort (UKB) despite using identical electronic health record diagnosis codes which may have hampered replication efforts. Third, our research in the MVP cohort demonstrated a higher OA heritability in African American and Hispanic Veterans than those of European White descent. Our overall goal is to identify pre- and post-rehabilitative biomarkers to enhance physicians’ intuition for predicting patient prognosis for Veterans with OA and/or PTOA. Toward this goal and to fill important knowledge gaps regarding the association of genetic factors with OA and outcomes, in Aim 1, a) we will confirm genetic variants associated with OA prevalence and progression to end- stage OA as well as b) develop and evaluate the performance of a polygenic risk score (PRS) to identify Veterans at risk of progression to total hip/knee joint arthroplasty; in Aim 2, we will identify genetic variants prognostic of THA/TKA recovery; and in Aim 3, we will determine whether genetic variants associated with the development of post-traumatic OA (PTOA) are distinct from known genetic determinants of idiopathic OA. We will identify biomarkers to enable targeted, precision pre-habilitation and post-surgical rehabilitation strategies improving mobility function, HRQL, and healthcare utilization among Veterans with OA.