Genetic Complexity of Crohn's Disease in Two Large Ashkenazi Jewish Families.
Genetic Complexity of Crohn's Disease in Two Large Ashkenazi Jewish Families.
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DOI：
10.1053/j.gastro.2016.06.040
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发表时间：
2016-10
期刊：
影响因子：
29.4
通讯作者：
Segal AW
中科院分区：
文献类型：
--
作者：
Levine AP;Pontikos N;Schiff ER;Jostins L;Speed D;NIDDK Inflammatory Bowel Disease Genetics Consortium;Lovat LB;Barrett JC;Grasberger H;Plagnol V;Segal AW
克罗恩病（CD）是一种高度遗传性疾病，在德系犹太人中特别常见。我们研究了2个大的德系犹太人家庭，他们有很高的CD患病率，试图确定新的遗传风险变异。从伦敦大学学院医院招募了患有CD和阳性家族史的德系犹太人患者。我们使用全基因组单核苷酸多态性数据来评估常见CD相关风险变异的负担并进行连锁分析。进行外显子组测序，并优先考虑预测为有害的并且在病例中以高频率观察到的罕见变体。我们在一个独立的德系犹太人队列中进行了插补后的家族内关联分析，并评估了候选变异与CD相关的证据。我们研究了DUOX2中的变体对HEK293细胞中过氧化氢产生的影响。我们确定了2个家族（1个>800名成员，1个>200名成员），分别包含54例CD或26例结肠炎病例。这两个家庭有一个显着丰富的以前描述的共同CD相关的风险变异。未观察到全基因组显著连锁。外显子组测序确定了候选变体，包括DUOX2中损害其功能的错义突变和CSF2RB中与德系犹太人个体独立队列中CD相关的移码突变。在一项对2名患有多例CD的大型德系犹太人的研究中，我们发现这种疾病的遗传基础很复杂，常见和罕见的遗传变异都有作用。我们在一个独立的队列中发现了CSF2RB的移码突变。这些发现显示了家族研究的价值和先天免疫系统在CD发病机制中的重要性。
Crohn’s disease (CD) is a highly heritable disease that is particularly common in the Ashkenazi Jewish population. We studied 2 large Ashkenazi Jewish families with a high prevalence of CD in an attempt to identify novel genetic risk variants. Ashkenazi Jewish patients with CD and a positive family history were recruited from the University College London Hospital. We used genome-wide, single-nucleotide polymorphism data to assess the burden of common CD-associated risk variants and for linkage analysis. Exome sequencing was performed and rare variants that were predicted to be deleterious and were observed at a high frequency in cases were prioritized. We undertook within-family association analysis after imputation and assessed candidate variants for evidence of association with CD in an independent cohort of Ashkenazi Jewish individuals. We examined the effects of a variant in DUOX2 on hydrogen peroxide production in HEK293 cells. We identified 2 families (1 with >800 members and 1 with >200 members) containing 54 and 26 cases of CD or colitis, respectively. Both families had a significant enrichment of previously described common CD-associated risk variants. No genome-wide significant linkage was observed. Exome sequencing identified candidate variants, including a missense mutation in DUOX2 that impaired its function and a frameshift mutation in CSF2RB that was associated with CD in an independent cohort of Ashkenazi Jewish individuals. In a study of 2 large Ashkenazi Jewish with multiple cases of CD, we found the genetic basis of the disease to be complex, with a role for common and rare genetic variants. We identified a frameshift mutation in CSF2RB that was replicated in an independent cohort. These findings show the value of family studies and the importance of the innate immune system in the pathogenesis of CD.
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来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
29.4
作者：
Gradel, Kim O.;Nielsen, Hans L.;Nielsen, Henrik
通讯作者：
Nielsen, Henrik
DOI：
10.1073/pnas.1120542109
发表时间：
2012-02-14
影响因子：
11.1
作者：
Gewurz, Benjamin E.;Towfic, Fadi;Kieff, Elliott
通讯作者：
Kieff, Elliott
影响因子：
4.8
作者：
Grasberger, Helmut;Refetoff, Samuel
通讯作者：
Refetoff, Samuel