Gene discoveries in subjects with Crohn's disease of African descent

项目摘要 克罗恩病（CD）是一种破坏性的胃肠道炎症性疾病，影响超过100万美国人，但由于未知原因，不成比例地影响非洲裔美国人（AA）。尽管AA占美国人口的约15%，但他们具有不同程度的严重疾病进展，对抗TNF治疗无反应性，我们已经证明这可能至少部分具有遗传基础。我们的研究小组是NIDDK IBD遗传学联盟（NIDDK IBD-GC）的辅助成员，我们已经成功地解决了许多非洲裔美国人的具体问题。通过NIDDK IBD Genetics Consortium的辅助奖，我们的RO 1奖资助使我们能够完成首个基于GWAS和全基因组测序的IBD AA研究。我们发现了AA IBD中第一个全基因组显著的、多研究重复的基因座，并证明了该基因座（5p13.1，靠近编码前列腺素E2受体的PTGER 4基因）和LACC 1对非洲血统人群中克罗恩病相对于欧洲来源人群的效应量增强。我们还确定了新的基因座，需要复制的影响较小的大小，并证明了非洲特定的影响估计大幅提高非洲衍生人群的多基因风险评估的性能。5p13.1中最强的相关性距离PTGER 4约250 kb，包含22个SNP区块，似乎可以解释非裔美国人人群中CD变异的约3.5%，比欧洲人群的效应大小增加约1.4倍。这促使目前的赠款试图在遗传，分子和功能水平上了解这一区域，同时在与AA患者治疗失败相关的更广泛签名的背景下研究这一位点的具体影响。通过已建立的合作、患者招募网站、样本收集管道和最先进的表观基因组和转录组分析，我们继续推进我们的进展和势头，我们在此提出完成以下目标，以检验我们的假设，即通过分子特征可识别存在疾病进展风险和对抗TNF治疗反应不良的患者，这部分是由单细胞水平上的祖先特异性等位基因效应驱动的。由于CD进展不成比例地影响AA并且可以预防，因此了解生物治疗在肠道中的影响并利用这些信息为干预策略提供信息是一个高度优先事项。因此，在Aim 1中，我们将建立预测AA中CD进展的细胞类型特异性转录谱。在目标2中，我们将确定5p13.1/PTGER 4和LACC 1增加AA风险的分子机制。最后，在目标3中，我们将与NIDDK IBD-GC合作，通过创新的参与和招募方法大幅增加AA IBD队列规模，同时与NIDDK GC合作完成其使命。这些研究的结果对NIH和NIDDK很重要，因为它满足了这些研究患者人群中缺失分子谱的许多未满足的需求。

PROJECT SUMMARY Crohn’s disease (CD) is a devastating inflammatory disorder of the gastrointestinal tract that affects over 1 million Americans, yet disproportionately affects African Americans (AA) for unknown reasons. Although AAs constitute ~15% of the US population, they have disparate levels of severe disease progression, non-responsiveness to anti-TNF treatment, which we have shown is likely to at least in part have a genetic basis. Our research group is an ancillary member of the NIDDK IBD-genetics consortium (NIDDK IBD-GC) and we have been successful in addressing many African American-specific issues. Our RO1 award funding through an ancillary award from the NIDDK IBD Genetics Consortium enabled us to complete the first GWAS and whole genome sequencing based study in AAs with IBD. We have discovered the first genome-wide significant, multi-study replicated, locus in AA IBD, and demonstrated enhanced effect sizes at that locus (5p13.1 near the PTGER4 gene encoding the Prostaglandin E2 Receptor) and LACC1 for Crohn’s disease in African ancestry populations relative to European derived populations. We have also identified novel loci with smaller effect sizes in need of replication, and demonstrated that African-specific effect estimates substantively improve the performance of polygenic risk assessment in African derived populations. The strongest associations in 5p13.1 are approximately 250kb from PTGER4 and contain a 22 SNP block which appears to explain approximately ~3.5% of the variance in CD in the African American population, an approximately 1.4-fold effect size increase over European populations. This motivates the current grant’s attempt to understand this region at the genetic, molecular, and functional levels, while studying this locus’ specific effects within the context of broader signatures associated with treatment failure in AA patients. Moving forward with our progress and momentum through established collaborations, patient recruitment sites, sample collection pipelines and state-of-the-art epigenome and transcriptome analysis, we propose herein to complete the following Aims that will test our hypothesis that patients who are at risk for disease progression and poor response to anti-TNF therapy are identifiable via molecular signatures, driven in part by ancestry-specific allelic effects at the single cell level. Since CD progression disproportionately affects AA and can be prevented, it is a high priority to understand the impact of biologic therapy in the gut and to use this information to inform intervention strategies. Thus, in Aim1, we will establish cell-type specific transcription profiles that predict CD progression in AAs. In Aim 2, we will determine the molecular mechanisms responsible for enhanced risk in AA at 5p13.1/PTGER4 and LACC1. Finally, in Aim3, we will be working with NIDDK IBD-GC to substantially increase the AA IBD cohort size by innovative engagement and recruitment methods, while collaborating with NIDDK GC to fulfil their mission. The outcomes of these studies are important to the NIH and NIDDK as it fulfills many of the unmet needs in missing molecular profiles from these under studied patient populations.