Identification of Two Additional Susceptibility Loci for Inflammatory Bowel Disease in a Chinese Populationy

Abstract

Background/Aims: To investigate the associations between the rs1250569 (zinc finger MIZ-type containing 1, ZMIZ1), rs1042522 (tumour protein p53, TP53), and rs10114470 (tumour necrosis factor-like cytokine 1A, TL1A) polymorphisms and the development of inflammatory bowel disease (IBD) in a Chinese (Han) population. We analysed the expression of genes that predispose patients to Crohn’s disease (CD) and ulcerative colitis (UC). Methods: A total of 381 IBD patients and 517 healthy controls were recruited into our study. Polymorphisms at the three loci were genotyped using polymerase chain reaction-ligation detection reactions (PCR-LDR). Genotype-phenotype correlations were analysed. Blood and gut samples were obtained and analysed using quantitative real-time PCR (qRT-PCR), western blot analysis, and immunohistochemistry to investigate the mRNA and protein levels and in situ expression of genes found to predispose patients to IBD. Furthermore, the expression of susceptible genes was further verified using a mouse dextran sulphate sodium (DSS)-induced acute colitis model. Results: No significant association was detected between rs1250569 and rs1042522 genotypes and CD or UC susceptibility. However, the frequency of allele A of rs1250569 was much higher in CD patients than that in healthy controls (55.03% vs. 48.48%, respectively; p = 0.044). The mutation rates at rs10114470 were dramatically lower at both the genotype and allele level in patients than those in healthy controls (p = 0.002 at both the genotype and allele level). Additionally, increased ZMIZ1 and TL1A levels were detected in intestinal samples obtained from both IBD patients and DSS-treated mice. Conclusion: rs1250569 (ZMIZ1) and rs10114470 (TL1A) are two novel loci that indicate susceptibility to IBD in Han-Chinese patients. Consistent with previous studies, TL1A expression levels were higher in Chinese Han IBD patients and DSS-treated mice. Most importantly, we found that ZMIZ1 expression was markedly higher in both IBD patients and mice with experimentally induced colitis, suggesting that ZMIZ1 plays important roles in the pathogenesis of IBD.

Multifaceted death receptor 3 signaling—promoting survival and triggering death

“…Anti‐TNF treatment diminishes intestinal TL1A expression in CD patients, which is in agreement with a recent study that reported regulation of TL1A expression in CD through mucosa‐derived factors including TNF . Associations between TL1A gene polymorphism and development of CD in European, Korean, Japanese, and Chinese populations have been assessed by several Genome Wide Association Studies (GWAS) and in sum strengthen the role of TL1A as driver of inflammatory bowel diseases (IBD) . Remarkably, the link between TL1A gene polymorphisms and CD was confirmed in different ethnical groups and in patients of almost all ages, which distinguishes TL1A from a variety of other genes associated with CD.…”

Gene polymorphisms and serum levels of TL1A in patients with rheumatoid arthritis

“…Lan et al demonstrated no significant association between rs1250569 and rs1042522 genotypes and Crohn's disease (CD) or UC susceptibility. However, the frequency of allele A of rs1250569 was much higher in CD patients than that in healthy controls in a Chinese population (Lan et al, ). Li et al showed a significantly decreased frequency of the TT genotype in rs3810936 in acute anterior uveitis patients (Li et al, ).…”

TL1A (TNFSF15) and DR3 (TNFRSF25): A Co-stimulatory System of Cytokines With Diverse Functions in Gut Mucosal Immunity

“…Other studies have also proposed that certain Tnfsf15 alleles may bear prognostic value for the severity of IBD. In the Chinese population, the T allele of SNP rs10114470 was associated with increased probability of developing stricturing, penetrating, or perianal complications (27). In the same notion, Pernat Dobrez et al identified the SNP rs4263839 as a possible marker for disease progression.…”