Exome sequencing identifies novel compound heterozygous IFNA4 and IFNA10 mutations as a cause of impaired function in Crohn's disease patients.
Exome sequencing identifies novel compound heterozygous IFNA4 and IFNA10 mutations as a cause of impaired function in Crohn's disease patients.
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外显子组测序发现新型化合物杂合 IFNA4 和 IFNA10 突变是克罗恩病患者功能受损的原因
DOI：
10.1038/srep10514
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发表时间：
2015-05-22
影响因子：
4.6
通讯作者：
Guleng B
中科院分区：
文献类型：
--
作者：
Xiao CX;Xiao JJ;Xu HZ;Wang HH;Chen X;Liu YS;Li P;Shi Y;Nie YZ;Li S;Wu KC;Liu ZJ;Ren JL;Guleng B
以前的研究已经强调了遗传易感性在疾病中的作用，有几个基因在克罗恩病(CD)中被确定为重要的。然而，这些基因中的许多很可能是罕见的，与中国CD患者的易感性无关。我们在CD患者中发现了294个相同的变异，其中26个经过Sanger测序验证。两个杂合型干扰素变异(IFNA10 c.60T >； A；IFNA4 c.60A >； T)被鉴定为与CD易感性显著相关。单核苷酸改变使IFNA10中位于信号肽裂解位点前的半胱氨酸变为终止码(TGA)，导致CD患者血清IFNA10水平明显低于对照组。此外，IFNA10和IFNA4突变体可抑制HCVRNA在Huh7细胞中的复制，重组干扰素亚型可通过上调CD4+Treg细胞的表达来恢复DSS诱导的结肠炎。我们通过多中心研究确定杂合的IFNA10和IFNA4变异是导致中国患者功能受损和CD易感基因的原因。这些发现可能为理解CD的遗传异质性提供线索，并导致更好的筛查和改进治疗。
Previous studies have highlighted the role of genetic predispositions in disease, and several genes had been identified as important in Crohn’s disease (CD). However, many of these genes are likely rare and not associated with susceptibility in Chinese CD patients. We found 294 shared identical variants in the CD patients of which 26 were validated by Sanger sequencing. Two heterozygous IFN variants (IFNA10 c.60 T > A; IFNA4 c.60 A > T) were identified as significantly associated with CD susceptibility. The single-nucleotide changes alter a cysteine situated before the signal peptide cleavage site to a stop code (TGA) in IFNA10 result in the serum levels of IFNA10 were significantly decreased in the CD patients compared to the controls. Furthermore, the IFNA10 and IFNA4 mutants resulted in an impairment of the suppression of HCV RNA replication in HuH7 cells, and the administration of the recombinant IFN subtypes restored DSS-induced colonic inflammation through the upregulation of CD4+ Treg cells. We identified heterozygous IFNA10 and IFNA4 variants as a cause of impaired function and CD susceptibility genes in Chinese patients from multiple center based study. These findings might provide clues in the understanding of the genetic heterogeneity of CD and lead to better screening and improved treatment.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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影响因子：
30.8
作者：
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通讯作者：
Schreiber, Stefan
影响因子：
4.8
作者：
Domanski, P;Nadeau, OW;Colamonici, OR
通讯作者：
Colamonici, OR