Investigating Causal Relationships of Diabetes and Obesity on Degenerative Rotator Cuff Tear

研究糖尿病和肥胖与退行性肩袖撕裂的因果关系

• 批准号: 10676555
• 负责人: Simone Herzberg
• 金额: $ 3.28万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676555
• 关键词: Academic Medical Centers; Address; Affect; Aging; Algorithms; Anatomy; Belief; Body mass index; Cell Death; Chronic; Classification; Code; Complement; Cross-Sectional Studies; DNA; Data; Databases; Development; Diabetes Mellitus; Diagnostic; Disease; Electronic Health Record; Epidemiologic Methods; Epidemiologist; Etiology; Fatty acid glycerol esters; Fiber; Foundations; Future; Genetic; Genetic Predisposition to Disease; Genetic Variation; Health; Heterogeneity; High Prevalence; Individual; Infiltration; Injury; Institution; Insulin; International; Knowledge; Link; Literature; Measures; Mediating; Mediation; Mendelian randomization; Meta-Analysis; Methods; Modeling; Morbidity - disease rate; Muscular Atrophy; Musculoskeletal; Musculoskeletal Diseases; National Institute of Arthritis, and Musculoskeletal, and Skin Diseases; Natural Language Processing; Nervous System Trauma; Nutrient; Obesity; Observational Study; Outcome; Pain; Participant; Patients; Persons; Phenotype; Physicians; Population; Population Control; Prevalence; Prevention; Prospective cohort; Publishing; Research; Research Design; Risk; Risk Factors; Role; Rotator Cuff; Sampling; Scientist; Shoulder Pain; Source; Structure; Techniques; Tendinopathy; Tendon structure; Testing; Training; Trauma; Waist-Hip Ratio; Work; algorithm development; biobank; career; case control; chronic pain; clinical investigation; design; disease phenotype; epidemiology study; fasting glucose; flexibility; genetic association; genetic variant; genome wide association study; improved; instrument; musculoskeletal injury; novel; precision medicine; repository; risk mitigation; rotator cuff injury; rotator cuff tear; skills; systematic review; theories; trait; vascular injury

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.

项目摘要/摘要： 退化性肩袖撕裂（DCT）是肩痛最常见的原因之一，但鲜为人知 关于这些眼泪的遗传和物理危险因素。与先前的信念相反，DCT完全 归因于重复的微谱系，已经出现了固有的肌腱异常的新证据 可能会倾向于DCT风险。肥胖和糖尿病是与内在有关的常见健康状况 肌腱变化（例如肌腱脂肪和异常微结构纤维组成，并增加 肌腱细胞死亡和养分异常的血管解剖结构），可能有助于诱发的条件 促进肩袖损伤。一些流行病学研究将肥胖和糖尿病与袖口疾病联系起来。然而， 大多数人的范围有限，以建立因果关系，部分原因是袖口疾病的定义不一致， 暴露和结果之间缺乏时间性，以及这些研究固有的偏见。目的 拟议的工作是利用几个大型国际DNA和患者健康数据库，以及 持续的前瞻性队列，通过合并来评估糖尿病和肥胖的因果关系 植根于仪器变量分析（Mendelian随机化[MR]）的方法，该方法可以克服 先前研究面临的传统挑战。为了我的第一个目标，我将建立，验证和比较两个 对DCT的病例和非案例进行分类的算法。这些算法将适当匹配，并且 应用于各种具有与电子健康记录有关的遗传数据的国际生物库 （EHR）。使用全基因组关联研究（GWAS）数据来从这些来源生成的DCT，以及 GWAS关于已发表研究的肥胖和糖尿病特征的数据，我将评估因果的证据 糖尿病与DCT（AIM 2）以及肥胖和DCT（AIM 3）之间的关系使用MR技术。 此外，我将确定糖尿病在肥胖与肥胖和 肩袖撕裂使用两步MR方法。 DCT是一种具有巨大长期发病率的令人衰弱的状况。 随着我们人群中糖尿病和肥胖的不断增长，这项工作得出的结论（无效） 或否则）将是及时和有影响力的。这项工作一起挖掘成未知和研究 糖尿病和肥胖的肌肉骨骼后果，并将告知减轻伤害风险的方法 为这些人群中的DCT治疗和预防DCT的未来研究打开大门。