title: Exome sequencing identifies novel compound heterozygous IFNA4 and IFNA10 mutations as a cause of impaired function in Crohn's disease patients.
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.
authors.affiliation: Department of Gastroenterology, Zhongshan Hospital affiliated to Xiamen University, 201 Hubin South Road, Xiamen, Fujian Province, 361004, China.
authors.forename: Chuan-Xing
authors.initials: CX
authors.lastname: Xiao
authors.affiliation: BGI-Shenzhen, Shenzhen, Guangdong, 518083, China.
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Xiao
authors.affiliation: Department of Gastroenterology, Zhongshan Hospital affiliated to Xiamen University, 201 Hubin South Road, Xiamen, Fujian Province, 361004, China.
authors.forename: Hong-Zhi
authors.initials: HZ
authors.lastname: Xu
authors.affiliation: Department of Gastroenterology, Zhongshan Hospital affiliated to Xiamen University, 201 Hubin South Road, Xiamen, Fujian Province, 361004, China.
authors.forename: Huan-Huan
authors.initials: HH
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Zhongshan Hospital affiliated to Xiamen University, 201 Hubin South Road, Xiamen, Fujian Province, 361004, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology, Zhongshan Hospital affiliated to Xiamen University, 201 Hubin South Road, Xiamen, Fujian Province, 361004, China.
authors.forename: Yuan-Sheng
authors.initials: YS
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, Zhongshan Hospital affiliated to Xiamen University, 201 Hubin South Road, Xiamen, Fujian Province, 361004, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Gastroenterology, Zhongshan Hospital affiliated to Xiamen University, 201 Hubin South Road, Xiamen, Fujian Province, 361004, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Shi
authors.affiliation: State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, West Changle Road 15, Xi'an, 710032, China.
authors.forename: Yong-Zhan
authors.initials: YZ
authors.lastname: Nie
authors.affiliation: MOE Key Laboratory of Bioinformatics and Bioinformatics, Tsinghua University, Beijing, 100084, China.
authors.forename: Shao
authors.initials: S
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, West Changle Road 15, Xi'an, 710032, China.
authors.forename: Kai-Chun
authors.initials: KC
authors.lastname: Wu
authors.affiliation: Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China.
authors.forename: Zhan-Ju
authors.initials: ZJ
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, Zhongshan Hospital affiliated to Xiamen University, 201 Hubin South Road, Xiamen, Fujian Province, 361004, China.
authors.forename: Jian-Lin
authors.initials: JL
authors.lastname: Ren
authors.affiliation: 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.
authors.forename: Bayasi
authors.initials: B
authors.lastname: Guleng
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000818:Animals; D044466:Asian People / Q000235:genetics; D001483:Base Sequence; D015704:CD4 Antigens / Q000378:metabolism; D016022:Case-Control Studies; D002460:Cell Line; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D002648:Child; D002681:China; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D003424:Crohn Disease / Q000235:genetics* / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D059472:Exome / Q000235:genetics*; D005260:Female; D016174:Hepacivirus / Q000235:genetics / Q000502:physiology; D006579:Heterozygote; D006801:Humans; D016898:Interferon-alpha / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D010957:Plasmids / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014779:Virus Replication; D055815:Young Adult
chemical_list: D015704:CD4 Antigens; D018925:Chemokines; D016207:Cytokines; C469326:IFNA10 protein, human; C554159:IFNA4 protein, human; D016898:Interferon-alpha; D034741:RNA, Small Interfering