PROJECT SUMMARY/ABSTRACT: Degenerative rotator cuff tear (DCT) is among the most common causes of shoulder pain, yet little is known about the genetic and physical risk factors for these tears. Contrary to prior belief that DCTs were fully attributable to repetitive microtrauma, new evidence has emerged on intrinsic tendinous abnormalities that could predispose DCT risk. Obesity and diabetes are common health conditions associated with intrinsic tendinous changes (such as tendon fat and aberrant microstructural fiber composition, as well as increased tendon cell death and abnormal nutrient vessel anatomy) and may contribute to predisposing conditions that promote rotator cuff injury. Several epidemiologic studies link obesity and diabetes with cuff disease. However, most are limited in their scope to establish causal links in part due to inconsistent definitions of cuff disease, lack of temporality between exposure and outcome, and biases inherent to these studies. The objective of the proposed work is to leverage several large international DNA and patient health databases, as well as an ongoing prospective cohort, to evaluate causal roles of diabetes and obesity on DTCs, by incorporating methods rooted in instrumental variable analysis (Mendelian Randomization [MR]) which can overcome traditional challenges faced by previous studies. For my first aim, I will build, validate and compare two algorithms to classify cases and non-cases of DCT. These algorithms will be appropriately matched and applied to a variety of international biorepositories with genetic data that linked to electronic health records (EHR). Using genome-wide association study (GWAS) data for DCT generated from these sources, and GWAS data on obesity and diabetes traits from published studies, I will evaluate evidence for causal relationships between diabetes and DCT (Aim 2), and obesity and DCT (Aim 3) using MR techniques. Additionally, I will determine the potential mediating role of diabetes on the association between obesity and rotator cuff tear using two-step MR methods. DCT is a debilitating condition with great long-term morbidity. With the ever-increasing rates of diabetes and obesity in our population, conclusions drawn from this work (null or otherwise) will be timely and impactful. Together, this work taps into unknown and understudied musculoskeletal consequences of diabetes and obesity, and will inform approaches to mitigating risk of injury, opening the door for future studies on treatment and prevention of DCT in these populations.

NARRATIVE Degenerative rotator cuff injury is one of the leading causes of decreased functional capability of the upper body and increasing evidence suggests that intrinsic tendinous changes, such as those consistent with diabetes and obesity, promote development of degenerative tears. Although diabetes and obesity are among the most common, and rapidly increasing, chronic conditions, their impact on musculoskeletal health is largely understudied. This work directly contributes to understanding whether observed links between diabetes, obesity and degenerative tears of the cuff are merely associational, or causal; and such knowledge can guide strategies in prevention and management of this debilitating condition.