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

骨关节炎的遗传学和关节置换恢复：精准康复的关键

• 批准号: 10839541
• 负责人: Jasvinder A Singh
• 金额: --
• 依托单位: BIRMINGHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10839541
• 关键词: Accounting; Activities of Daily Living; Admixture; Age Years; Arthritis; Data; Degenerative polyarthritis; Diagnosis; Disease; Disease Progression; Ethnic Origin; Ethnic Population; Failure; General Population; Genetic; Goals; Habilitation; Health Care Costs; Healthcare Systems; Heritability; Heterogeneity; Hip region structure; Hospitalization; Incidence; Individual; Knee; Life Style; Mediating; Meta-Analysis; Operative Surgical Procedures; Outcome; Pain; Participant; Phenotype; Prevalence; Public Health; Recording of previous events; Recovery; Rehabilitation therapy; Replacement Arthroplasty; Resources; Second Look Surgery; Surveys; Testing; Traumatic Arthropathy; Treatment Cost; Variant; Veterans; biobank; cohort; common symptom; comorbidity; disability; end stage disease; experience; genetic information; genetic predictors; genetic variant; genome wide association study; genomic locus; health care service utilization; health related quality of life; hip replacement arthroplasty; improved mobility; knee replacement arthroplasty; multi-ethnic; patient oriented; primary outcome; prognostic; programs; recruit; rehabilitation strategy; response; secondary analysis; secondary outcome; success; targeted treatment

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.

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：(i) VA 的医疗费用 每年的治疗费用超过 8.8 亿美元；(ii) 退伍军人管理局医疗系统中约有 30% 的退伍军人患有 OA，即 (iii) 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 (n~3500) 或膝关节置换术 (n~6500) 以及随后的康复治疗 (iv) 接受 THA/TKA 的退伍军人在健康相关的生活质量 (HRQL) 方面存在严重缺陷，严重程度 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 合并症和住院治疗；以及 (v) 术后 2-5 年中度至重度功能限制的发生率 尽管规定的康复治疗具有很强的遗传性，但 THA 后的手术率为 30-35%，TKA 后的手术率为 46-50%。 遗传率估计>30% 的成分疼痛是最常见的症状，导致残疾和残疾。 HRQL。THA/TKA 后活动受限和疼痛的主要表型预测因子已降低。 然而，OA 进展和 THA/TKA 恢复成功的遗传预测因素如下： 但尚不清楚，这样的发现将推动精确术前康复和术后康复的进展。 我们寻求利用丰富的 MVP 资源来测试总体情况。 假设遗传变异解释了 OA 患病率、进展至终末期的有意义比例 该假设将通过三个具体目标进行检验。 目标 1：识别与 OA 相关的基因，我们将对 292,516 名 MVP 变异参与者进行 GWAS。 40-80 岁——其中 90,000 人患有 OA 诊断——努力复制已知的并识别新的 作为二次分析，我们将进行 GWAS 来识别与 OA 相关的遗传变异和区域。 我们将尝试对 3,696 名患有创伤后关节炎的退伍军人进行与 OA 相关的遗传变异。 使用英国生物银行 392,304 人的数据复制了重要发现，其中 41,217 人患有 OA。 目标 2：确定 THA/TKA 变异所指示的进展为终末期 OA 的遗传预后。 将对 90,000 名患有 OA 的 MVP 参与者进行 GWAS，以识别与达到目标相关的变异 在诊断为 OA 的这一队列中，我们将识别出终末期（即 THA/TKA）所特有的遗传变异。 进展到末期的亚人群 – 即 7,600 名接受过 THA 或 OA 诊断后的 TKA 作为二次分析，我们将进行 GWAS 来识别遗传变异。 与初次 THA/TKA 后 5 年内的修复手术相关，表明独特的遗传变异 可能会使一些退伍军人对最初的 THA/TKA 适应不良。我们将重复重要的发现。 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：识别遗传变异。 THA/TKA 恢复的预后由活动受限（主要结果）、疼痛和 HRQL（次要结果）定义 我们将对过去进行过 THA/TKA 的 7,600 名 MVP 参与者进行 GWAS，以识别变异。 与恢复成功或失败相关，如 MVP 基线和生活方式调查响应所示。 二次分析，我们将调查康复是否介导遗传之间的关系 我们将使用两种策略最大化异质性：(i) 通过执行 GWAS。 独立地在每个主要种族群体中进行研究，并使用荟萃分析将结果结合起来 种族混合；以及 (ii) 通过分析整个 MVP 队列来执行多种族 GWAS。 目标是确定 OA 预后的遗传变异以及不良 OA 和 THA/TKA 结局以制定 有针对性、精确的术前康复和术后康复策略可改善行动功能， HRQL 和退伍军人的医疗保健利用率。