Determining Genetic Variants Associated with Rotator Cuff Tearing, Tear Progression and Tendon Repair Healing

Rotator cuff tearing affects over 17 million U.S. people accounting for over 3.8 million physician visits per year and is the most common shoulder disorder affecting Veteran’s over the age of 40. We have previously shown that an inherited predisposition contributes to the risk of rotator cuff tearing. We have also identified various genetic variants associated with the predisposition to rotator cuff tearing including SNPs in ESRRB, SASH1, SAP30BP, GLCCI1, THSD7A and ZNF804A genes and have confirmed association of variants in TNC variants with rotator cuff tearing. Finally, we have shown that a family history of rotator cuff tearing as well as the same genetic variant of the ESRRB gene associated with rotator cuff tearing are associated with failure of rotator cuff healing after repair. These variants were identified utilizing a genetic database developed using funding from a VA Merit Review Grant as well as large genetic databases including the UK Biobank and the Kaiser Permanente Research Bank [KPRB]. There are multiple limitations of the current genetic variant information with regards to rotator cuff tearing. 1.) There is no information regarding the association of genetic variants and the severity of rotator cuff injury. 2.) There is limited genetic information regarding rotator cuff variants associated with requirement for revision repair. 3.) There is no genetic information regarding progression of rotator cuff tear severity in patients treated nonoperatively. The current proposed study will address all these limitations which is possible using the unique data within the Million Veteran’s Program (MVP) datasets. Non-operative treatment and surgical repair are both reasonable options for the management of rotator cuff tears. Clinical decision making between the two treatment options partly depends on the risk of tear enlargement with non-operative treatment versus failure of healing with surgical repair and being able to effectively identify these tears prior to treatment. Currently no biologic or genetic markers have been identified to be associated with tear progression and only ESRRB and TNC variants have been identified to associate with failure of healing. No genetic variants have been identified to associate with tear severity. Identification of genes or genetic variants predictive of tear severity, tear enlargement as well as failure of surgical repair requiring revision repair would enhance the clinical decision-making process regarding a recommendation of early operative or non-operative treatment. The purpose of this study is to expand the current list of genetic variants associated with rotator cuff tearing, increasing rotator cuff severity, increasing tear severity with non-operative treatment and rotator cuff repair failure requiring revision repair. Patients with rotator cuff tears defined by having had a rotator cuff repair will be identified in the MVP cohort. A GWAS will be performed to identify genetic variants associated with rotator cuff tearing using MVP cases and controls and a regression analysis will be performed to identify demographic and tear anatomic factors from MRIs associated with the identified variants. Patients who have undergone multiple repairs on the same shoulder (revision repair) in the MVP cohort will be identified and candidate gene analysis will be performed to determine variants associated with the requirement for multiple repairs. Finally, all patients with sequential MRIs on the same shoulder without preceding or intervening surgery will be identified in the MVP cohort and evaluated for tear enlargement. Candidate gene analysis will be performed to determine variants associated with tear enlargement. Polygenic risk calculators will be created for both tear progression and requirement for revision repair that will translate the data directly to the clinical care of patients with rotator cuff tears to optimize surgical versus nonsurgical decision making. Project Number: 1I01CX002571-01A1 | Fiscal Year: 2025 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: Robert Tashjian | Institution: VA SALT LAKE CITY HEALTHCARE SYSTEM, SALT LAKE CITY, UT | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 SURG-P (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/10914393