一个来自美国和加拿大的研究团队之前于Science期刊上发表了一篇重要的的文章，提出了参与调控炎症和克罗恩病的关键细胞受体基因，现在，该研究小组又有了新的研究成果。
根据这篇发表于Nature Genetics的研究性文章指出，研究小组另外发现了几个遗传变异，可以增加克罗恩病患病风险的变异。这些与克罗恩病相关的遗传变异的发现，让研究者更进一步了解，与发炎有关的重要生物信号路径。
之前的研究发现了与克罗恩病密切相关的两个基因：CARD15和IL23R。但是，这两个基因的突变并未包含所有的遗传学变异。
在新研究报告中，作者发现了三个重要的基因，它们的突变会明显增加克罗恩病的患病风险：PHOX2B, NCF4和ATG16L1。文章表示自噬作用和宿主细胞对细胞内微生物的反应，在克罗恩病的发病过程中有着重要的地位。
对于这些路径的理解，可能有助于我们开发出更有效的治疗方法。
(资料来源 : Bio.com)
英文原文:
Scientists Find Major Susceptibility Genes for Crohn's Disease
04/16/07 -- A consortium of Canadian and American researchers led by Dr. John D. Rioux, PhD, Associate Professor of Medicine at the Montreal Heart Institute and the Universit? de Montr?al, report in the April 15 online edition of Nature Genetics the results from a search of the entire human genome for genetic risk factors leading to the development of Crohn's disease. Specifically, using a novel approach, the authors identified that the PHOX2B, NCF4 and ATG16L1 genes constitute genetic risk factors for Crohn's disease. In addition, their study identified two regions of the genome where genetic risk factors are located but no known genes were implicated ? further work will be necessary to identify the causal genes in these regions.
More than 1 million Americans and some 170,000 Canadians have Crohn's or colitis, known collectively as inflammatory bowel disease (IBD). The study's authors represent the IBD Genetics Consortium, which is funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health. In addition to the Montreal Heart Institute and Universit? de Montr?al, the Consortium's member institutions include the Cedars-Sinai Medical Center in Los Angeles, the University of Chicago, the Johns Hopkins University, the University of Pittsburgh, the University of Toronto, and Yale University.
Because IBD tends to run in families and is more frequent in certain ethnic populations, especially Ashkenazi Jews, scientists have long suspected a significant genetic component. Although previous genetic studies found a link between Crohn's disease and mutations in a gene known as CARD15, those mutations alone are not considered to account for the entire genetic component of disease. To identify additional genes that are associated with IBD, the international team of researchers scanned the genome?all of 22,000 or so genes? by testing more than 300,000 single nucleotide polymorphisms, or SNPs, in people with Crohn's disease and in healthy controls. The comparison of these SNPs (common genetic variants) between patient and control groups identified multiple SNPs that were strongly associated with Crohn's disease. These findings were then tested in two additional sets of patients and healthy controls in order to confirm their results.
According to the corresponding author John D. Rioux, the findings highlight numerous biological pathways not previously thought to play a role in Crohn's disease. "The identification of the PHOX2B gene in this study, for example, may implicate a role for neuroendocrine cells of the intestinal epithelium as having a role to play in Crohn's Disease. In addition, the identification of the NCF4 gene indicates that altered reactive oxygen species (ROS) production, important in the generation of an effective anti-microbial response, may lead to increased risk to developing Crohn's disease". The fact that the authors also found strong association of the ATG16L1 gene provides further evidence that an individual's response to microbes has an influence on susceptibility to Crohn's disease.
Specifically, in addition to demonstrating its association to disease, these authors have shown that ATG16L1 is essential for the normal autophagic process used to degrade worn-out cellular components and help eliminate some pathogenic bacteria. "We propose that genetic variation in the ATG16L1 gene leads to alterations in how the body uses autophagy and therefore may result in increased persistence of both cellular and bacterial components, leading to inappropriate immune activation and increased risk of Crohn's disease" adds Dr. Rioux.
The findings reported in this study are expected to not only improve on the biological understanding of disease but should also have a long-term impact on clinical practice. According to Dr. Edmond-Jean Bernard, co-author and gastroenterologist at the Hotel Dieu Hospital in Montreal and the Universit? de Montr?al "the multiple genetic risk factors we've identified provide important molecular targets for current functional studies aimed at understanding the disease and important targets for drug development to improve therapy of Crohn's disease in the future." Dr. Stephen P. James, M.D., director of the Division of Digestive Diseases and Nutrition at the National Institutes of Health's NIDDK continued by saying that "these important discoveries not only offer new hope for better therapies for patients with Crohn's disease, they also highlight the promise of the human genome project and subsequent investments by the NIH in large scale, collaborative research projects to unravel the causes of, and hopefully better treatments for complex, enigmatic diseases".
Source: University of Montreal
