Abstract
Anterior cruciate ligament (ACL) rupture is a common condition that disproportionately affects young people, 50% of whom will develop knee osteoarthritis (OA) within 10 years of rupture. ACL rupture exhibits both hereditary and environmental risk factors, but the genetic basis of the disease remains unexplained. Spontaneous ACL rupture in the dog has a similar disease presentation and progression, making it a valuable genomic model for ACL rupture. We leveraged the dog model with Bayesian mixture model (BMM) analysis (BayesRC) to identify novel and relevant genetic variants associated with ACL rupture. We performed RNA sequencing of ACL and synovial tissue and assigned single nucleotide polymorphisms (SNPs) within differentially expressed genes to biological prior classes. SNPs with the largest effects were on chromosomes 3, 5, 7, 9, and 24. Selection signature analysis identified several regions under selection in ACL rupture cases compared to controls. These selection signatures overlapped with genome-wide associations with ACL rupture as well as morphological traits. Notable findings include differentially expressed ACSF3 with MC1R (coat color) and an association on chromosome 7 that overlaps the boundaries of SMAD2 (weight and body size). Smaller effect associations were within or near genes associated with regulation of the actin cytoskeleton and the extracellular matrix, including several collagen genes. The results of the current analysis are consistent with previous work published by our laboratory and others, and also highlight new genes in biological pathways that have not previously been associated with ACL rupture. The genetic associations identified in this study mirror those found in human beings, which lays the groundwork for development of disease-modifying therapies for both species.
Highlights
The anterior cruciate ligament (ACL) is a ligament spanning from the lateral femoral condyle to the proximal tibia that provides crucial stability to the knee joint, counteracting anterior translation, hyperextension, and internal rotation of the tibia (Noyes, 2009)
After adjustment for multiple testing and without imposing a threshold for log fold change, we identified 200 genes from ACL tissue and 444 genes from synovium tissue that were significantly differentially expressed between case and control dogs (Supplementary Tables 2, 3)
It is unclear whether ACL rupture-associated synovitis is a cause or effect of ligament rupture, as signs of synovial effusion are often present on radiographs and synovitis can be seen arthroscopically before development of complete ACL rupture and associated joint instability (Muir et al, 2011; Little et al, 2014), and these signs are predictive of future ACL rupture (Chuang et al, 2014)
Summary
The anterior cruciate ligament (ACL) is a ligament spanning from the lateral femoral condyle to the proximal tibia that provides crucial stability to the knee joint, counteracting anterior translation, hyperextension, and internal rotation of the tibia (Noyes, 2009). ACL rupture is most often a midsubstance failure of this ligament (van der List et al, 2017), which occurs for multiple and complex reasons including genetic predisposition (Smith et al, 2012a,b). Standard of care includes physical therapy alone or after surgical reconstruction. Neither treatment prevents the long-term development of posttraumatic osteoarthritis (OA) (Lohmander et al, 2007) and disease-modifying therapies are critically needed. The key to disease-modifying therapy may lie within the underlying genetic predisposition to ACL rupture. Multiple studies have been performed in search of genetic drivers of disease, but discoveries have been limited, mostly due to inadequate sample composition (e.g., male-only samples) and size (John et al, 2016)
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