# The Genetic Epidemiology of Rotator Cuff Tears:  The cuffGEN Study

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $621,532

## Abstract

PROJECT SUMMARY
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 reh...

## Key facts

- **NIH application ID:** 10267669
- **Project number:** 5R01AR074989-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Nitin B Jain
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $621,532
- **Award type:** 5
- **Project period:** 2020-09-22 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10267669

## Citation

> US National Institutes of Health, RePORTER application 10267669, The Genetic Epidemiology of Rotator Cuff Tears:  The cuffGEN Study (5R01AR074989-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10267669. Licensed CC0.

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