The Genetic Epidemiology of Rotator Cuff Tears: The cuffGEN Study

项目总结 2015年，在美国，肩痛占了1260万次门诊医生的就诊次数。肩袖 撕裂是导致肩痛和残疾的主要原因之一，2006年共有272,148例手术。 退行性非创伤性肩袖撕裂的病因尚不清楚。来自家庭聚集研究的数据 提供令人信服的初步证据，表明肩袖撕裂的遗传易感性。然而， 使用经成像验证的肩袖撕裂病例和 缺乏控制，对因果遗传变异和因果基因的搜索仍然难以捉摸。 肩袖肌肉的脂肪渗透程度(FI)是治疗决策的关键，因为 FI的等级与更差的结果相关。约40%至50%的肩袖撕裂患者发生 菲尔。FI背后的遗传病因还没有得到评估，以及肥胖和 FI的因果关系尚不清楚。患者报告的袖口撕裂康复和手术后的结果也是 变量。有证据支持基因变异在预测治疗结果中的作用，但这一点 还没有得到很好的研究。 我们的研究团队正在招募一项由美国国立卫生研究院和PCORI资助的12个地点的临床试验，随机选择700名患者进行试验 关节镜手术与物理疗法治疗无创性袖带撕裂称为关节镜肩袖 (弧形)。这提供了一个独特的机会来利用我们现有的基础设施，并在 一项经影像验证的袖口撕裂遗传学病例对照研究。我们已经制定了标准化的 使用电子健康记录(EHR)数据确定影像核实病例和对照的方法。通过 将这些标准化方法应用于Vanderbilt(BioVU)和Kaiser的EHR链接生物仓库 Permanente(GERA)，每个有大约100,000个基因分型的个人，并通过与 来自犹他州和斯坦福大学的调查人员是仅存的两起袖口撕裂事件的领头羊，我们有 召集了最大的联合会(CuffGEN)来研究肩袖疾病的遗传学。我们将表演 独一无二的GWAS研究，具有分类良好的发现和5,000个成像-复制样本- 经验证的肩袖撕裂病例和5000例经成像验证的对照。这项精心设计的研究将确定 基因变异与袖口撕裂、FI和手术后患者报告的最佳结果之间的关系 或者康复治疗。我们将优先考虑基因发现，将来自 脂肪和肌肉，使用参考数据库和GWAS结果。通过孟德尔随机化，我们的 研究将澄清肥胖和FI之间是否存在因果关系。这项拟议的研究允许NIH提供资金 利用现有的基础设施，如果没有这些基础设施，这项大规模的基因研究将是困难的。 评估干预准备情况和康复进展的遗传图谱是NIH的优先事项 拟议的研究将产生效果。关于袖口撕裂、FI和最佳治疗的遗传易感性的数据 结果将有助于识别高危个人并根据 个人的基因特征。

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 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.