PSC Resource Of Genetic Risk, Environment and Synergy Studies (PROGRESS)

PSC 遗传风险、环境和协同研究资源（进展）

• 批准号: 8035823
• 负责人: KONSTANTINOS N LAZARIDIS
• 金额: $ 83.41万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8035823
• 关键词: PSC; Resource; Genetic; Risk; Environment

DESCRIPTION (provided by applicant): Primary sclerosing cholangitis (PSC) is a progressive liver disease strongly associated with inflammatory bowel disease (IBD). About 75% of PSC patients are diagnosed with IBD, most commonly ulcerative colitis (UC) and conversely, 5-7% of IBD patients develop PSC. Life expectancy of PSC patients is reduced due to lack of medical therapy, advancement to end-stage liver disease and an increased risk of colon cancer and cholangiocarcinoma (CCA). Thus, while rare in the population, PSC is a notable threat to patients with IBD. Like IBD, PSC is thought to arise as the result of interacting genetic and environmental risk factors. Taken further, the IBD-PSC relationship may be one of overlapping risk capable of prompting both liver and gut involvement, with distinct mechanisms further influencing organ specific disease development. Yet, comprehensive studies focused on the dissection of the genetic and environmental risks in PSC, and its relationship with UC, have not been performed. To this end, we created the PSC Resource of Genetic Risk, Environment and Synergy Studies (PROGRESS). This resource currently comprises 618 PSC patients and 779 primary clinic-based controls; the largest of its kind in North America. Moreover, we have established collaborations between PROGRESS and the Norwegian PSC Research Center (NOPSC), UK PSC Consortium (UKPSC) and IBD Genetics Consortium (IBDGC) to share resources in pursuit of our common goals. In this application, we propose to test the hypothesis that genetic variants and/or environmental mediators contribute to PSC susceptibility and its association with UC. To achieve this, we propose three Specific Aims. In Aim 1, we will expand PROGRESS through continued recruitment of PSC patients at Mayo Clinic and seven other participating medical centers across North America. In Aim 2, we will perform 2 genome wide association studies (GWAS) to identify genetic variants for: (a) susceptibility to PSC- discovery study: 2000 PSC patients and 5000 controls; replication study: 1900 PSC patients and 3000 controls; and, (b) susceptibility to PSC in UC- discovery study: 1400 PSC patients with UC and 1000 UC patients without PSC; replication group: 1330 PSC patients with UC and 1000 UC patients without PSC. In Aim 3, we will determine environmental risk factors for PSC using validated, self-administered questionnaires collected from PROGRESS participants (1000 PSC patients and 1000 controls). This study will begin to identify the genetic variants and environmental factors associated with PSC and its relationship with UC. These findings will serve as foundation for future risk assessment and disease prevention strategies as well as for basic research studies looking for implicated mechanisms and potentially leading to novel therapies for PSC. PUBLIC HEALTH RELEVANCE: The goals of this study are to identify genetic susceptibility to and environmental risks for Primary Sclerosing Cholangitis (PSC) and to embark on dissecting its strong association with inflammatory bowel disease (IBD). To achieve these objectives, we established the PSC Resource Of Genetic Risk, Environment and Synergy Studies (PROGRESS) and formed collaborations with national and international consortia of IBD and PSC. If successfully performed, this study will improve our knowledge of PSC and IBD pathogenesis, which could advance the prognosis and therapy of these disorders.

描述（由申请人提供）：原发性硬化性胆管炎（PSC）是一种与炎症性肠病（IBD）密切相关的进行性肝病。约75%的PSC患者被诊断患有IBD，最常见的是溃疡性结肠炎（UC），相反，5-7%的IBD患者发展为PSC。PSC患者的预期寿命由于缺乏药物治疗、进展为终末期肝病以及结肠癌和胆管癌（CCA）风险增加而缩短。因此，虽然在人群中罕见，但PSC对IBD患者是一个显著的威胁。与IBD一样，PSC被认为是遗传和环境风险因素相互作用的结果。进一步说，IBD-PSC关系可能是能够促使肝脏和肠道受累的重叠风险之一，具有进一步影响器官特异性疾病发展的独特机制。然而，全面的研究集中在PSC的遗传和环境风险的解剖，及其与UC的关系，还没有进行。为此，我们创建了遗传风险，环境和协同研究PSC资源（PROGRESS）。该资源目前包括618名PSC患者和779名主要临床对照;这是北美同类中最大的。此外，我们还与挪威PSC研究中心（NOPSC）、英国PSC联盟（UKPSC）和IBD遗传学联盟（IBDGC）建立了合作关系，以共享资源，实现我们的共同目标。在本申请中，我们提出测试遗传变异和/或环境介质有助于PSC易感性及其与UC的关联的假设。为此，我们提出了三个具体目标。在目标1中，我们将通过在马约诊所和北美其他七个参与医疗中心继续招募PSC患者来扩大PROGRESS。在目标2中，我们将进行2个全基因组关联研究（GWAS）以鉴定以下的遗传变体：（a）对PSC的易感性-发现研究：2000名PSC患者和5000名对照;复制研究：1900名PSC患者和3000名对照;和（B）UC中对PSC的易感性-发现研究：1400名患有UC的PSC患者和1000名没有PSC的UC患者;复制组：1330例PSC伴UC患者和1000例UC不伴PSC患者。在目标3中，我们将使用从PROGRESS参与者（1000名PSC患者和1000名对照）中收集的经过验证的自我管理问卷来确定PSC的环境风险因素。本研究将开始鉴定PSC相关的遗传变异和环境因素及其与UC的关系。这些发现将为未来的风险评估和疾病预防策略以及寻找相关机制的基础研究奠定基础，并可能导致PSC的新疗法。 公共卫生关系：本研究的目的是确定原发性硬化性胆管炎（PSC）的遗传易感性和环境风险，并着手剖析其与炎症性肠病（IBD）的密切联系。为了实现这些目标，我们建立了PSC遗传风险、环境和协同研究资源（PROGRESS），并与IBD和PSC的国家和国际财团建立了合作关系。如果成功进行，这项研究将提高我们对PSC和IBD发病机制的认识，这可能会促进这些疾病的预后和治疗。