Is Crohn's Disease the Price to Pay Today for Having Survived the Black Death?
Is Crohn's Disease the Price to Pay Today for Having Survived the Black Death?
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DOI：
10.1093/ecco-jcc/jjz062
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发表时间：
2019-10-01
影响因子：
8
通讯作者：
Hugot, Jean-Pierre
中科院分区：
文献类型：
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作者：
Dumay, Anne;Gergaud, Olivier;Hugot, Jean-Pierre
背景和目的：核苷酸寡聚化结构域 2 [NOD2] 是先天免疫的关键基因，参与宿主对病原体的防御。多种 NOD2 功能丧失突变与克罗恩病相关 [CD]。它们在欧洲血统人群中的高频率表明了一种平衡选择的模型。由于 NOD2 缺陷与小鼠对假结核耶尔森氏菌的抵抗力相关，因此我们假设在过去的鼠疫爆发期间，由于密切相关的鼠疫耶尔森氏菌而选择了 NOD2 突变。 方法：通过 PubMed 搜索从 60 项研究中收集了在欧洲和地中海国家的健康人群中测量的主要 CD 相关 NOD2 突变 [R702W、G908R 和 1007fs] 的当代频率。鼠疫暴露程度是根据 1346 年至 1860 年欧洲和地中海盆地爆发的数据集计算得出的。建立鼠疫指数来捕捉所研究地理区域鼠疫暴露的强度。结果：NOD2 突变频率与过去鼠疫暴露相关。最常见的突变 [R702W，p = 0.03] 和合并的三个突变 [p = 0.023] 获得了统计显着性。当考虑到假定的人口统计学偏差时，这种关联仍然显着。结论：这一结果支持鼠疫爆发对 CD 相关 NOD2 突变的选择，并进一步质疑暴露于肠道致病性耶尔森菌在 CD 中的作用。
Background and Aims: Nucleotide Oligomerisation Domain 2 [NOD2] is a key gene of innate immunity which participates in the host defence against pathogens. Several loss-of-function NOD2 mutations are associated with Crohn's disease [CD]. Their high frequencies in populations of European ancestry suggest a model of balancing selection. Because NOD2 deficiency has been associated with a resistance to Yersinia pseudotuberculosis in mice, we hypothesised that NOD2 mutations have been selected during past plague outbreaks due to the closely related bacterium Yersinia pestis.Methods: Contemporary frequencies of the main CD-associated NOD2 mutations [R702W, G908R, and 1007fs], measured in healthy people from European and Mediterranean countries, were collected from 60 studies via a PubMed search. Plague exposure was calculated from a dataset providing outbreaks from 1346 to 1860 in Europe and the Mediterranean Bassin. A plague index was built to capture the intensity of plague exposure in the studied geographical areas.Results: NOD2 mutation frequencies were associated with the past exposure to plague. Statistical significance was obtained for the most frequent mutation [R702W, p = 0.03] and for the pooled three mutations [p = 0.023]. The association remained significant when putative demographic biases were considered.Conclusions: This result argues for a selection of CD-associated NOD2 mutations by plague outbreaks and further questioned the role of exposure to enteropathogenic Yersinia species in CD.