Genetic and genomic approaches to better understand the clinical heterogeneity in inflammatory bowel diseases

炎症性肠病（IBD）、克罗恩病（CD）和溃疡性结肠炎（UC）是 发病的重要原因，最近的估计表明，有超过300万 患有IBD的美国人对美国经济造成非常严重的经济负担。200多 增加IBD易感性的遗传基因座已经被鉴定， 对IBD分子结构的理解将改善患者的预后。 然而，要实现这一目标仍然存在重大挑战，本提案旨在 解决其中一些关键问题。1)大多数进展都是在欧洲取得的。 我们的目标是继续努力招募和研究非欧洲人， 我们必须努力使所有人都能从这些进步中受益。2)我们将解决 通过专注于两个领域的基因发现来满足未满足的医疗需求：肛门瘘CD， 与生活质量差、发病率高和治疗反应差相关;以及 对抗TNF治疗无应答，这发生在大多数IBD受试者中。这 随着新的治疗选择变得越来越重要， 可用于治疗IBD。3)许多IBD相关基因座位于基因间（“垃圾”DNA） 区域及其功能后果仍不清楚。使用创新的基因组 我们提出的方法与最先进的生物信息学策略一起， 这些过程受到我们已经确定的易感基因座的影响。4)最后我们会 扩展了我们以前的观察，即潘氏细胞表型是一个重要的读出， 基因环境相互作用，以及一个重要的临床生物标志物，在CD到人群 来自不同的种族和地理位置。总的来说，这些方法将 进一步了解IBD的根本原因，并确定其他生物标志物， 在临床实践中的应用，并突出了IBD的新的潜在治疗途径。

The inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), are significant causes of morbidity with recent estimates suggesting there are more than 3 million Americans with IBD with very significant financial burden to the US economy. More than 200 genetic loci that increase susceptibility to IBD have been identified with the anticipation that an understanding of the molecular architecture of IBD will lead to improved outcomes for patients. However, there are significant challenges remaining to achieve this and this proposal seeks to address some of these key issues. 1) The majority of advances have been made in European ancestry populations and we aim to continue our efforts to recruit and study non European populations to extend the benefits of these advances to all parts of society. 2) We will address unmet medical needs by focusing on genetic discovery in two areas: peri anal fistulizing CD is associated with poor quality of life, significant morbidity, and poor response to treatment; and non response to anti TNF therapy which happens in the majority of subjects with IBD. This latter phenotype is increasingly important to define as new therapeutic options become available for treating IBD. 3) Many of the IBD associated loci fall in intergenic ('junk' DNA) regions and their functional consequences remain unclear. Using innovative genomic approaches together with state of the art bioinformatics strategies we propose to identify the processes that are influenced by the susceptibility loci we have identified. 4) And finally we will extend our previous observations that Paneth cell phenotypes are an important readout of gene environment interactions, as well as an important clinical biomarker, in CD to populations from a variety of ethnicities and geographical locations. Collectively, these approaches will shed additional insights into the underlying causes of IBD as well as identify additional biomarkers for use in clinical practice and highlight novel potential therapeutic pathways for IBD.