Three Sibling Genes Involved in Genetic Risk for Lateral Epicondylopathy

Abstract Objectives To screen the entire genome for genes associated with risk for lateral epicondylopathy and improve understanding of underlying biological mechanisms and inform future research aimed at risk stratification and personalized prevention and treatment strategies. Methods A genome-wide association study was conducted using UK Biobank data. Lateral epicondylopathy cases were identified based on electronic health records from individuals of European ancestry. Logistic regression tested associations between single-nucleotide polymorphisms and disease status, adjusting for sex, age, height, weight and ancestry principal components. Previously-identified candidate genes from the literature were also tested for association with lateral epicondylopathy. Results Among 20,390 cases of lateral epicondylopathy, two loci reached genome-wide significance: one comprising 144 linked SNPs and one single SNP. The first locus, led by rs13127477 (p=7.7×10 −12 ; OR 0.93, 95% CI 0.91 to 0.95), is located near three SIBLING genes (IBSP, MEPE and SPP1) involved in extracellular matrix remodelling at fibrocartilaginous entheses. The risk allele was associated with increased SIBLING gene expression, suggesting that excessive entheseal matrix remodelling contributes to disease susceptibility. The second locus was defined by rs138254824 (p=3.69×10 −8 ; OR 3.42, 95% CI 2.23 to 5.25) near NEDD9 and TMEM170B. Previously reported collagen gene associations were not replicated. Conclusion In the first genome-wide screen for lateral epicondylopathy, two loci were identified. These loci provide insight regarding the pathophysiology of lateral epicondylopathy and a roadmap for preventing and treating this injury with personalized medicine. Summary Box What is already known on this topic Lateral epicondylopathy is a common and disabling overuse tendon condition, yet its genetic basis has remained poorly characterised, with prior studies limited to small candidate gene analyses. What this study adds This study provides the first genome-wide association analysis of lateral epicondylopathy, identifying two risk loci on chromosomes 4 and 6 and implicating SIBLING genes (IBSP, MEPE, and SPP1) involved in entheseal extracellular matrix remodelling. How this study might affect research, practice or policy These findings offer new biological insight into disease susceptibility and challenge previously reported collagen gene associations.