Genetic Determinants of Outcomes in Diverticular Disease

项目摘要/摘要 基因数据有可能改善对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、寒战和胃肠道不适。对大多数人来说 患者，发作是轻微的和自我限制的，但10%-35%的人继续遭受严重的疾病：多次住院， 结肠穿孔和腹部败血症。每年有数以万计的患者接受大手术 预防严重疾病。然而，目前外科医生没有能力预测哪些患者将患有严重的 疾病。有一个尚未得到满足的临床需求，需要更好地了解疾病和风险分层。 在历史上，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；40-53%的个体憩室炎风险是由遗传引起的。我的前期工作 描述了憩室炎的基因组结构，并确定了42个与该疾病相关的遗传位点。 这项建议建立在前期工作的基础上，以进一步研究憩室病的遗传贡献 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，相互作用 可改变的危险因素--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，包括疝气、脱垂和动脉瘤。 这个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 基因组流行病学。职业发展计划包括完成#年硕士学位 生物信息学，结构化的指导，通过研究的表现来提高技能。我的Main 研究目标是确定患者的遗传背景如何影响糖尿病的发展和进程 憩室病。该项目的主要主题体现在具体目标上：1)生成和验证 使用四个大型生物库对严重憩室炎进行多基因风险评分，2)合并多基因和 通过评估内脏肥胖的相互作用改善憩室炎风险分层的形态测量数据 和遗传风险，3)调查憩室病作为复合连接的常见遗传因果关系 组织退行性特征，检查临床上与憩室炎有关的表型的潜在遗传基础。 这些研究的成功完成将加强我们对基因在憩室炎中的作用的理解， 引导进一步的大规模前瞻性研究，并转化为对患者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.