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

项目总结 克罗恩病(CD)是一种破坏性的胃肠道炎症性疾病，影响100多万美国人，但不成比例地影响非裔美国人(AA)，原因不明。尽管AA约占美国人口的15%，但他们的严重疾病进展程度不同，对抗肿瘤坏死因子治疗无反应，我们已经表明，这可能至少部分有遗传基础。我们的研究小组是NIDDK IBD-遗传学联合会(NIDDK IBD-GC)的辅助成员，我们已经成功地解决了许多非裔美国人特有的问题。我们的RO1奖通过NIDDK IBD遗传学联盟的辅助奖资助，使我们完成了第一个基于GWAS和全基因组测序的IBD AAS研究。我们已经在AA IBD中发现了第一个全基因组显著的、多项研究重复的基因座，并显示出该基因座(编码前列腺素E2受体的PTGER4基因附近的5p13.1)和LACC1在非洲血统人群中对克罗恩病的作用大小相对于欧洲派生人群有所增强。我们还确定了需要复制的具有较小效应大小的新的基因座，并证明了非洲特有的效应估计实质上改善了非洲衍生人群的多基因风险评估的性能。5p13.1中最强的关联大约是来自PTGER4的250kb，包含一个22个SNP块，似乎可以解释非裔美国人CD大约3.5%的变异，大约是欧洲人的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该区域，同时在与再生障碍性贫血患者治疗失败相关的更广泛签名的背景下研究该基因座的特定影响。随着我们的进展和势头，通过建立合作、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，我们在此建议完成以下目标，这些目标将检验我们的假设，即处于疾病进展风险和抗肿瘤坏死因子治疗反应差的患者可以通过分子签名识别，部分是由单细胞水平上祖先特有的等位基因效应驱动的。由于CD进展对再生障碍性贫血的影响是不成比例的，而且是可以预防的，因此了解生物疗法对肠道的影响并利用这些信息为干预策略提供信息是当务之急。因此，在Aim1中，我们将建立预测AAS中CD进展的细胞类型特异性转录图谱。在目标2中，我们将确定5p13.1/PTGER4和LACC1的AA风险增加的分子机制。最后，在Aim3中，我们将与NIDDK IBD-GC合作，通过创新的参与和招聘方法大幅增加AA IBD的队伍规模，同时与NIDDK GC合作完成他们的使命。这些研究的结果对NIH和NIDDK很重要，因为它满足了这些正在研究的患者群体中缺失的分子图谱中许多未得到满足的需求。

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.