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Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease

机译：宿主与微生物的相互作用塑造了炎症性肠病的遗传结构

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摘要

Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases5. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.
机译：克罗恩氏病和溃疡性结肠炎是炎症性肠病（IBD）的两种常见形式，影响了250万欧洲血统的人，其他人群的患病率也在上升。全基因组关联研究和作为独立表型的这两种疾病的后续荟萃分析已暗示了其发病机理中先前未曾怀疑的机制，例如自噬，并表明某些IBD基因座与其他炎性疾病共有5。在这里，我们通过进行克罗恩氏病和溃疡性结肠炎全基因组关联扫描的荟萃分析，然后通过对重要发现的广泛验证，总共对超过75,000例病例和对照进行分析，从而扩展了相关途径的知识。我们确定71个新的协会，共163个IBD基因座，满足全基因组重要性阈值。大多数基因座对这两种表型都有贡献，并且方向性（在人类历史过程中始终偏向一个等位基因）和平衡（偏向于在人群中保留两个等位基因）的选择效果是显而易见的。许多IBD基因座也与其他免疫介导的疾病有关，最明显的是强直性脊柱炎和牛皮癣。我们还观察到IBD易感基因座和分枝杆菌感染之间有相当大的重叠。基因共表达网络分析强调了这种关系，宿主对分枝杆菌的反应与IBD易感者之间共有途径。

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  • 来源
    《Nature》 |2012年第7422期|p.119-124|共6页
  • 作者

    Luke Jostins; Stephan Ripke; Rinse K. Weersma; Richard H. Duerr; Dermot P. McGovem; et al;

  • 作者单位

    Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK;

    Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA;

    Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen 9700 RB, The Netherlands;

    Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania 15261, USA;

    F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Los Angeles, California 90048, USA Medical Genetics Institute, Cedars-Sinai Med ical Center, Los Angeles, California 90048, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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