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.
Highlights
Population, those loci were estimated to explain only 23.2% of the observed heritability[11], indicating that a large number of Crohn’s disease (CD) susceptibility loci have not yet been identified[12]
genome-wide association studies (GWASs) have identified susceptibility loci that are triggered by environmental factors, resulting in disturbed innate and adaptive immune responses toward a reduced diversity of commensal microbiota[26]
Epidemiological studies suggest that genetic factors play a significant role in CD patients and the clinical characteristics[27]
Summary
After filtering out the genes for which the variants were not validated by Sanger sequencing or were not cloned by PCR, a total of 26 genes were confirmed and represented in all four affected individuals (Supplementary Table 6). Our results indicated that the serum level of IFNA10 was significantly decreased in the CD patients compared to the healthy controls (Fig. 2C, 117.9 ± 5 .17 vs 99.4 ± 6.54, P < 0 .05). The total CD3+ inflammatory cells in the lamina propria were decreased, and CD4+ CD25+ and CD4+ Foxp3+ Treg cells were significantly increased in the IFNA subtype treatment groups compared to the control mice, indicating that different IFNA subtypes control acute colitis through the induction of Treg cells
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