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.
Arthritis (i.e. osteoarthritis or OA) of the hip or knee is a major public health problem among our nation?s Veterans, and it often progresses to joint replacement surgery. VA healthcare costs for OA treatment exceed $880 million annually. About 10,000 Veterans undergo hip or knee replacement each year, and many experience deficits in health-related quality of life, severe functional limitations, increased healthcare utilization, and higher incidence of other diseases and hospitalization. OA has a strong genetic component; however, genetic predictors of disease progression and success of joint replacement recovery are not yet known. We seek to leverage the Million Veterans Program to test the hypothesis that genetic variants explain a meaningful proportion of OA prevalence, progression to joint replacement, and recovery success. Such discovery would fuel progress toward precision pre-habilitation and post-surgical rehabilitation among Veterans.
