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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Genome-wide association study identifies NRG1 as a susceptibility locus for Hirschsprung's disease
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Genome-wide association study identifies NRG1 as a susceptibility locus for Hirschsprung's disease

机译：全基因组关联研究确定NRG1为Hirschsprung病的易感基因座

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摘要

Hirschsprung's disease (HSCR), or aganglionic megacolon, is a congenital disorder characterized by the absence of enteric ganglia in variable portions of the distal intestine. RET is a well-established susceptibility locus, although existing evidence strongly suggests additional loci contributing to sporadic HSCR. To identify these additional genetic loci, we carried out a genome-wide association study using the Affymetrix 500K marker set. We successfully genotyped 293,836 SNPs in 181 Chinese subjects with sporadic HSCR and 346 ethnically matched control subjects. The SNPs most associated with HSCR were genotyped in an independent set of 190 HSCR and 510 control subjects. Aside from SNPs in RET, the strongest overall associations in plausible candidate genes were found for 2 SNPs located in intron 1 of the neuregulin 1 gene (NRG1) on 8p12, with rs16879552 and rs7835688 yielding odds ratios of 1.68[CI_(95)%:(1.40,2.00),P= 1.80 × 10~(-8)]and 1.98;CI_(95%).(1.59,2.47), P= 1.12 × 10~(-9)], respectively, for the heterozygous risk genotypes under an additive model. There was also a significant interaction between RET and NRG1 (P = 0.0095), increasing the odds ratio 2.3-fold to 19.53 for the RET rs2435357 risk genotype (TT) in the presence of the NRG1 rs7835688 heterozygote, indicating that NRG1 is a modifier of HSRC penetrance. Our highly significant association findings are backed-up by the important role of NRG1 as regulator of the development of the enteric ganglia precursors. The identification of NRG1 as an additional HSCR susceptibility locus not only opens unique fields of investigation into the mechanisms underlying the HSCR pathology, but also the mechanisms by which a discrete number of loci interact with each other to cause disease.
机译：Hirschsprung病（HSCR）或神经节性巨结肠是一种先天性疾病，其特征是在远端肠的可变部分中没有肠神经节。 RET是一个公认的易感基因座，尽管现有证据强烈表明其他基因位点可导致散发性HSCR。为了鉴定这些额外的遗传基因座，我们使用Affymetrix 500K标记集进行了全基因组关联研究。我们成功地对了181例散发HSCR的中国受试者和346例种族匹配的对照受试者进行了293,836个SNP的基因分型。在一组独立的190名HSCR和510名对照受试者中对与HSCR最相关的SNP进行了基因分型。除了RET中的SNP外，还发现了8p12位于神经调节蛋白1基因（NRG1）内含子1上的2个SNP的可能候选基因中最强的整体关联，rs16879552和rs7835688的比值比为1.68 [CI_（95）％： （1.40,2.00），P = 1.80×10〜（-9）]和1.98; CI_（95％）。（1.59,2.47），P = 1.12×10〜（-9）]，分别为杂合风险加性模型下的基因型。在存在NRG1 rs7835688杂合子的情况下，RET rs2435357风险基因型（TT）的RET rs2435357风险基因型（TT）的比值比增加2.3倍，至19.53，RET与NRG1之间也存在显着相互作用（P = 0.0095）。 HSRC渗透率。 NRG1作为肠神经节前体发育的调节剂的重要作用支持了我们高度重要的关联研究结果。将NRG1鉴定为额外的HSCR易感性位点，不仅为HSCR病理基础的机制打开了独特的研究领域，而且为离散数量的基因座彼此相互作用导致疾病的机制提供了独特的研究领域。

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    Maria-Merce Garcia-Barcelo; Clara Sze-man Tang; Elly Sau-wai Ngan; Vincent Chi-hang Lui; Yan Chen; Man-ting So; Thomas Yuk-yu Leon; Xiao-ping Miao; Cathy Ka-yee Shum; Feng-qin Liu; Ming-yiu Yeung; Zhen-wei Yuan; Wei-hong Guo; Lei Liu; Xiao-bing Suns; Liu-ming Huang; Jin-fa Tou; You-qiang Song; Danny Chan; Kenneth M. C. Cheung; Kenneth Kak-yuen Wong; Stacey S. Cherny; Pak-chung Sham; Paul Kwong-hang Tam;

  • 作者单位

    Departments of Surgery University of Hong Kong Departments of Centre for Reproduction, Development, and Growth, University of Hong Kong;

    Department of Psychiatry Genome Research Centre University of Hong Kong;

    Departments of Surgery University of Hong Kong Departments of Centre for Reproduction, Development, and Growth, Departments of 'Biochemistry University of Hong Kong;

    Departments of Surgery University of Hong Kong Departments of Centre for Reproduction, Development, and Growth, Departments of 'Biochemistry University of Hong Kong;

    Departments of Surgery University of Hong Kong;

    Departments of Surgery University of Hong Kong;

    Departments of Surgery University of Hong Kong;

    Departments of Surgery University of Hong Kong Department of Surgery, Shenzhen Children's Hospital, Shenzhen, China;

    Departments of Surgery University of Hong Kong;

    Departments of Surgery University of Hong Kong;

    Department of Psychiatry, University of Hong Kong;

    Department of Paediatric Surgery, Shengjing Hospital, China Medical University, Shenyang, China;

    Department of Surgery, Beijing Children's Hospital, Beijing, China;

    Department of Psychiatry, University of Hong Kong;

    Department of Pediatric Surgery, Shandong Medical University, Shandong, China;

    Department of Surgery, Shenzhen Children's Hospital, Shenzhen, China;

    Department of Surgery, Zhejiang Children's Hospital, Zhejiang, China;

    Departments of Biochemistry, University of Hong Kong;

    Departments of Biochemistry, University of Hong Kong;

    Departments of Orthopaedics and Traumatology of the Li Ka Shing Faculty of Medicine, University of Hong Kong;

    Departments of Surgery, University of Hong Kong;

    Department of Psychiatry, University of Hong Kong Department of Genome Research Centre, University of Hong Kong;

    Department of Psychiatry, University of Hong Kong Departments of Centre for Reproduction, Development, and Growth, University of Hong Kong;

    Departments of Surgery University of Hong Kong Departments of Centre for Reproduction, Development, and Growth, University of Hong Kong;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    GWA; RET;

    机译：GWA;RET;

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