2. Academic Validation
  3. 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

  • Sci Rep. 2015 May 22;5:10514. doi: 10.1038/srep10514.
Chuan-Xing Xiao 1,  Jing-Jing Xiao 2,  Hong-Zhi Xu 1,  Huan-Huan Wang 1,  Xu Chen 1,  Yuan-Sheng Liu 1,  Ping Li 1,  Ying Shi 1,  Yong-Zhan Nie 3,  Shao Li 4,  Kai-Chun Wu 3,  Zhan-Ju Liu 5,  Jian-Lin Ren 1,  Bayasi Guleng 6
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Zhongshan Hospital affiliated to Xiamen University, 201 Hubin South Road, Xiamen, Fujian Province, 361004, China.
  • 2 BGI-Shenzhen, Shenzhen, Guangdong, 518083, China.
  • 3 State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, West Changle Road 15, Xi'an, 710032, China.
  • 4 MOE Key Laboratory of Bioinformatics and Bioinformatics, Tsinghua University, Beijing, 100084, China.
  • 5 Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China.
  • 6 1] Department of Gastroenterology, Zhongshan Hospital affiliated to Xiamen University, 201 Hubin South Road, Xiamen, Fujian Province, 361004, China [2] Faculty of Clinical Medicine, Medical College of Xiamen University, 168 University Road, Xiamen, Fujian Province, 361005, China [3] State Key Laboratory of Cellular Stress Biology, Xiamen University, 168 University Road, Xiamen, Fujian Province, 361005, China.
PMID: 26000985 DOI: 10.1038/srep10514
Abstract

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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