Genetic Determinants of Outcomes in Diverticular Disease

项目总结/摘要 遗传数据有可能改善常见结直肠疾病患者的护理 憩室炎在美国，每年有超过20万人因憩室炎住院。攻击 憩室炎的特征是腹痛、发烧、发冷和胃肠道不适。对于大多数 患者，发作是轻微的和自限性的，但10-35%继续遭受严重的疾病：多次住院， 结肠穿孔和腹腔败血症每年有成千上万的病人接受大手术， 预防严重疾病。然而，目前，外科医生没有能力预测哪些患者会有严重的 疾病有一个未满足的临床需要，以提高对疾病的理解和风险分层。 历史上，憩室炎被认为是一种与饮食有关的环境疾病，但数据显示， 遗传性的证据;憩室炎的个体风险的40-53%是由于遗传。我的前期工作 描述了憩室炎的基因组结构，并确定了42个与该疾病相关的基因位点。 这项建议建立在初步工作的基础上，进一步研究憩室的遗传贡献。 疾病我的中心假设是，遗传风险因素可以预测憩室炎的严重程度， 可改变的风险因素-如内脏肥胖，并可能表现为憩室炎或其他 临床相关的结缔组织特征，包括疝、脱垂和动脉瘤。 此应用程序的总体目标是支持我作为独立调查员的培训和发展， 基因流行病学职业发展计划包括完成硕士学位， 生物信息学，结构化的导师，并通过研究的性能增强技能。我的主要 研究目标是确定患者的遗传背景如何影响疾病的发展和过程。 憩室病该项目的主要主题体现在具体目标中：1）生成和验证 使用四个大型生物库的严重憩室炎的多基因风险评分，2）纳入多基因和 通过评估内脏肥胖的相互作用改善憩室炎危险分层的形态测量学数据 和遗传风险，3）调查憩室病的常见遗传因果关系，作为一个复合连接 组织变性性状，检查临床上与憩室炎相关的表型的潜在遗传基础。 这些研究的成功完成将提高我们对遗传学在憩室炎中的作用的理解， 导致进一步的大规模前瞻性研究，并转化为有意义的基因组工具， 憩室炎

PROJECT SUMMARY/ABSTRACT Genetic data have the potential to improve the care of patients with the common colorectal disease diverticulitis. Every year over 200,000 people are hospitalized with diverticulitis in the United States. Attacks of diverticulitis are characterized by abdominal pain, fevers, chills, and gastrointestinal distress. For most patients, attacks are mild and self-limited, but 10-35% go on to suffer severe disease: multiple hospitalizations, colon perforation, and abdominal sepsis. Tens of thousands of patients undergo major surgery every year to prevent severe disease. Currently, however, surgeons have no ability to predict which patients will have severe disease. There is an unmet clinical need for improved understanding of the disease and risk stratification. Historically, diverticulitis was considered an environmental disease related to diet, but data show clear evidence of heritability; 40-53% of individual risk of diverticulitis is due to genetics. My preliminary work described the genomic architecture of diverticulitis and identified 42 genetic loci associated with the disease. This proposal builds on that preliminary work to further investigate the genetic contribution to diverticular disease. My central hypothesis is that genetic risk factors can predict severity of diverticulitis, interact with modifiable risk factors – such as visceral adiposity, and may manifest themselves as diverticulitis or as other clinically-associated connective tissue traits including hernia, prolapse, and aneurysm. The overall goal of this application is to support my training and development as an independent investigator in genomic epidemiology. The career development plan includes completion of a master’s degree in bioinformatics, structured mentorship, and enhancement of skills through performance of research. My main research goal is to determine how a patient’s genetic background influences the development and course of diverticular disease. The major themes of this project are reflect in the Specific Aims: 1) Generate and validate a polygenic risk score for severe diverticulitis using four large biobanks, 2) Incorporate polygenic and morphometric data to improve diverticulitis risk stratification by assessing the interaction of visceral adiposity and genetic risk, 3) Investigate a common genetic causality for diverticular disease as a composite connective tissue degenerative trait, examining an underlying genetic basis for phenotypes clinically linked to diverticulitis. Successful completion of these studies will enhance our understanding of the role of genetics in diverticulitis, lead to further large scale prospective research, and translate into meaningful genomic tools for patients with diverticulitis.