Shoulder pain accounted for 12.6 million ambulatory physician visits in 2015 in the United States. Rotator cuff tears are one of the leading causes of shoulder pain and disability and accounted for 272,148 surgeries in 2006. The etiology of degenerative atraumatic rotator cuff tears is unknown. Data from familial aggregation studies provide convincing preliminary evidence suggesting genetic predisposition to rotator cuff tears. However, large-scale genome-wide association studies (GWAS) using imaging-verified rotator cuff tear cases and controls are lacking, and the search for causal genetic variants and causal genes remains elusive. The degree of fatty infiltration (FI) of rotator cuff muscles is critical for treatment decision-making since higher grades of FI are associated with worse outcomes. About 40 to 50% of patients with rotator cuff tears develop FI. The genetic etiology behind FI has not yet been assessed, and whether the relationship between obesity and FI is causal remains unclear. Patient-reported outcomes after rehabilitation and surgery for cuff tear are also variable. There is supportive evidence for the role of genetic variants in predicting treatment outcomes, but this has not been well-studied. Our research team is recruiting for a 12-site, NIH- and PCORI-funded, clinical trial of 700 patients randomized to arthroscopic surgery versus physical therapy for atraumatic cuff tears called Arthroscopic Rotator Cuff (ARC). This provides a unique opportunity to leverage our existing infrastructure and recruit 2,500 patients in an imaging-verified, case-control study on the genetics of cuff tears. We have developed standardized approaches to ascertain image-verified cases and controls using electronic health record (EHR) data. By applying these standardized approaches to EHR-linked biorepositories at Vanderbilt (BioVU) and Kaiser Permanente (GERA), each with approximately 100,000 genotyped individuals, and by collaborating with investigators from Utah and Stanford who are leaders in the only two existing GWAS of cuff tear, we have convened the largest consortium (cuffGEN) to study the genetics of rotator cuff disorders. We will perform one-of-a-kind GWAS investigations with well-classified discovery and replication samples of 5,000 imaging- verified rotator cuff tear cases and 5,000 imaging-verified controls. This well-designed study will identify associations between genetic variants and cuff tears, FI, and optimal patient-reported outcomes after surgery or rehabilitative treatments. We will prioritize gene discovery by incorporating gene-expression data from adipose and muscle using reference databases with GWAS results. Through Mendelian randomization, our study will clarify if there is a causal relationship between obesity and FI. The proposed study allows NIH funds to leverage existing infrastructure without which this large genetic study would be difficult. Genetic profiling to assess intervention readiness and rehabilitation progress are NIH priorities which the proposed study will deliver upon. Data on genetic predisposition to cuff tear, FI, and optimal treatment outcomes will help in identifying high-risk individuals and developing optimal interventions based on an individual's genetic profile.
The proposed study will convene cuffGEN, the largest consortium to date, to study the genetics of imaging- confirmed rotator cuff tears and fatty infiltration, which lead to shoulder pain and disability. In addition to identifying high-risk individuals with genetic variants associated with rotator cuff tear and fatty infiltration, the study prioritizes gene discovery by incorporating gene expression information and assesses causality between obesity and fatty infiltration. Data from this study can also help identify individuals for whom treatments are most likely to be successful based on their genetic profile.