Genetic Epidemiology of Rotator Cuff Tears: The cuffGEN Study

NCT ID: NCT04831164

Last Updated: 2026-02-10

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Total Enrollment

3500 participants

Study Classification

OBSERVATIONAL

Study Start Date

2021-03-04

Study Completion Date

2031-12-31

Brief Summary

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Rotator cuff tear is one of the most common reasons to seek musculoskeletal care, and cuff repair is one of the fastest growing ambulatory surgery procedures. However, the etiology of cuff tears, reasons for variability treatment success, and causes of FI are poorly understood. A large-scale genome-wide association studies (GWAS) using imaging-verified rotator cuff tear cases and controls can address limitations in rigor of prior research and assess the genetic basis of FI and functional outcomes of cuff tear treatments.

Primary Objective: To conduct a case-control GWAS of imaging-verified symptomatic rotator cuff tear in approximately 3000-6000 individuals and replicate findings in an independent set of 3000-6000 or more imaging-verified individuals to identify common variants in several genetic loci that increase risk for rotator cuff tears.

Hypothesis: Common variants in several genetic loci increase risk for rotator cuff tears.

Secondary Objectives:

1. To perform an imputed transcriptome-wide association study (TWAS) to identify and prioritize gene targets associated with rotator cuff tear by integrating GWAS summary statistics and gene-expression weights from muscle and adipose tissue available in the GTEx project.

Hypothesis: Genetically predicted gene expression of multiple genes in muscle and adipose tissue are associated with rotator cuff tear.
2. To identify if single nucleotide polymorphisms (SNPs) associated with rotator cuff tear and their genetic risk score (GRS) predict improved pain and function as measured by American Shoulder and Elbow Surgeons Standardized Form (ASES) and other outcome measures.

Hypothesis: Select SNPs and GRS predict ASES outcome.
3. To identify genetic variants associated with Fatty Infiltration (FI) in patients with cuff tears in a two stage GWAS of imaged rotator cuffs and to prioritize gene targets through an imputed-TWAS in muscle and adipose tissue.

Hypothesis: Multiple genetic variants are associated with FI and some exert their influence by altering gene expression in the muscle and adipose tissue.

Detailed Description

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Participants will complete a structured questionnaire (Appendix B) that includes medical and musculoskeletal comorbidities, Mental Health Inventory-5148, Fear Avoidance Beliefs Questionnaire (FABQ)149, and expectations of improvement from treatment. The primary patient-reported outcome (Aim 2) of our study is American Shoulder and Elbow Surgeons Standardized Form (ASES), which is a composite pain and function measure. ASES was chosen because it is widely used; is shoulder-specific and takes 2 minutes to complete; has an established minimally clinically important difference (MCID) of \>9 points151; and has good psychometric properties152-155. We will use the Shoulder Pain and Disability Index (SPADI)as a secondary outcome. SPADI has good psychometric properties and an established MCID of \>10 points.

We will perform a genome-wide association meta-analysis (GWAMA) in approximately 10,000 imaging-verified rotator cuff tear cases and imaging-verified controls. Discovery meta-analysis will consist of samples from cuffGEN cohort with MRI imaging (N=1,250 cases and 1,250 controls) and samples from BioVU based on MRI report-confirmed cases and controls (N \~ 2400 with equal cases and controls). Targeted variants showing some evidence of association (P \< 5 x 10-6) will be replicated in an independent cohort of imaging confirmed cuff tear cases (N \> 2,500) and controls (N \> 2,500) from the GERA study. In addition to providing careful selection of cases via imaging confirmation, equal attention to the confirmation of lack of tears via imaging greatly reduces misclassification of cases and controls and allows for detection of effect estimates that are likely larger (away from the null). Adhering to the same stringent criteria for discovery and replication greatly improves our ability over previous studies to identify variants associated with cuff tears.

Conditions

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Rotator Cuff Tears

Study Design

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Observational Model Type

CASE_CONTROL

Study Time Perspective

OTHER

Study Groups

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Case

Patients with MRI confirmed rotator cuff tears

NA (not an interventional study)

Intervention Type OTHER

(not an interventional study)

Control

Patients without rotator cuff tears

NA (not an interventional study)

Intervention Type OTHER

(not an interventional study)

Interventions

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NA (not an interventional study)

(not an interventional study)

Intervention Type OTHER

Eligibility Criteria

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Inclusion Criteria

* Aged ≥40 years to \< 85 years
* Confirmed diagnosis of partial or full-thickness cuff tear on MRI (Cases) OR absence of rotator cuff tear on shoulder MRI (Controls)
* Ability and willingness to provide informed consent
* Ability to complete questionnaires in English (to maintain scientific integrity since standardized questionnaires are extensively validated in English)

Exclusion Criteria

* Acute rotator cuff tear caused by a severe trauma
Minimum Eligible Age

40 Years

Maximum Eligible Age

85 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

NIH

Sponsor Role collaborator

University of Michigan

OTHER

Sponsor Role lead

Responsible Party

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Nitin Jain

Professor of Physical Medicine & Rehabilitation, and Orthopaedics

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Nitin Jain, MD

Role: PRINCIPAL_INVESTIGATOR

University of Michigan

Locations

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University of Iowa

Iowa City, Iowa, United States

Site Status RECRUITING

Brigham and Women's Hospital

Boston, Massachusetts, United States

Site Status COMPLETED

Boston Medical Center

Boston, Massachusetts, United States

Site Status COMPLETED

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States

Site Status COMPLETED

University of Michigan

Ann Arbor, Michigan, United States

Site Status RECRUITING

Ohio State University

Columbus, Ohio, United States

Site Status NOT_YET_RECRUITING

Orthopedic Institute

Sioux Falls, South Dakota, United States

Site Status COMPLETED

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Site Status COMPLETED

Parkland Health and Hospital System

Dallas, Texas, United States

Site Status COMPLETED

University of Texas Southwestern Medical Center

Dallas, Texas, United States

Site Status RECRUITING

Countries

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United States

Central Contacts

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Nitin Jain, MD

Role: CONTACT

734-936-8178

Sravanthi Kaza, MS

Role: CONTACT

814-323-4754

Facility Contacts

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Brian R Wolf, MD

Role: primary

Nitin Jain, MD

Role: primary

734-936-8178

Gregory Cvetanovich, MD

Role: primary

Michael Khazzam, MD

Role: primary

214-645-8917

Other Identifiers

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1R01AR074989-01A1

Identifier Type: NIH

Identifier Source: secondary_id

View Link

STU-2020-0689

Identifier Type: -

Identifier Source: org_study_id

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