A Study On The Associations Of Ulcerative Colitis With The Polymorphisms Of Histo-Blood Group Antigens Genes

Objective:Inflammatory bowel diseases (IBDs), mainly comprising ulcerative colitis (UC) and Crohn's disease (CD), are a group of chronic intestinal disorders with unknown etiology. The imbalance of intestinal microbiota has been suggested to play a key role in the pathogenesis of IBD. Histo-blood group antigens act as binding sites for some intestinal microbes. It has been demonstrated that the expression of HBGA is modulated by Fucosyltransferases (FUTs) encoding genes FUT2and FUT3. In recent years, several studies linked several single nucleotide polymorphisms (SNPs) of FUT2gene to the constitutions of intestinal microbiota as well as the predisposition of type1diabetes and primary sclerosing cholangitis. Furthermore, FUT2gene has been suggested to be one of the susceptibility genes of CD. However, the impact of FUT2gene polymorphisms on UC is still uncertain. Moreover, few studies to date have been performed on the relationship between FUT3and UC. Since FUT2and FUT3exert a synergistic effect on the expression of ABO and Lewis antigens, the present study aimed to simultaneously investigate associations of UC with the polymorphisms and haplotypes of FUT2and FUT3genes in Zhejiang Han population, and then provided evidence for unveiling the genetic pathogenesis of UC.Methods:From May2008to May2013, a total of233inpatients and outpatients with UC were recruited from the principal hospitals in Wenzhou city, Zhejiang Province of Southeast China, including The Second and The First Affiliated Hospitals of Wenzhou Medical University as well as The Central Hospital of Wenzhou City. The diagnosis of UC was in accord with "The guideline of diagnosis and treatment of Inflammatory bowel diseases" in2012conducted by the Chinese Society of Digestive Diseases, Chinese Medical Association. At the same period,292age-, and sex-matched healthy controls were recruited at the Health Examination Center of The Second Affiliated Hospital of Wenzhou Medical University. Approximately5ml of peripheral blood was collected from each study individual into tubes containing EDTA. Genomic DNA was extracted from peripheral blood, and then multiplex PCR amplification was carried out. Genotyping of FUT2and FUT3were conducted using multiplex SNaPshot assays of ABI (Applied Biosystems, California, USA). The six single nucleotide polymorphisms of FUT2(C357T, A385T and G428A) and FUT3gene (T59G, G508A and T1067A) were detected. The Hardy-Weinberg equilibrium rule for each of the studied polymorphisms as well as the genotypic and allelic distributions were evaluated by the ?2test. The linkage disequilibrium (LD) and haplotype analysis were carried out by Haploview4.2software. Moreover, the multifactor dimensionality reduction was used to analyze the interaction between FUT2and FUT3genes and several environmental factors, such as smoking.Results:By duplicate detection and direct sequencing, the accuracy of SNaPshot genotyping method was proved to be100%. The genotypic distributions of the six polymorphic loci in the controls were in accordance with HWE. The allelic and genotypic frequencies of FUT2and FUT3genes did not statistically differ between UC patients and the controls (all P>0.05). Nor did FUT2C357T, G428A and FUT3G508A(all p>0.05). Using unconditional Logistic regression analysis, however, we found that the variant allele G and genotype GG+GT of FUT3at T59G site were significantly decreased in patients with extensive colitis compared to the others[17.5%(35/200) vs25.9%(69/266), P=0.022, OR=0.530,95%CI:0.308-0.914;31.0%(31/100) vs45.9%(61/133), P=0.030, OR=0.606,95%CI:0.384-0.956, respectively]. The C357T and A385T two polymorphic loci of FUT2gene were in LD(D'=0.935, r2=0.106). The same result was drawn for the T59Q G508A and T1067A three polymorphic sites of FUT3:T1067A/G508A(D'=1.0, r2=0.017), T1067A/T59G (D'=0.932r2=0.29), G508A/T59G (D'=0.966, r2=0.471). However, none of the haplotypes statistically differ between UC patients and the controls (all P>0.05). In addition, there were no interactional effects between FUT2and FUT3genes as well as smoking on the predisposition of UC.Conclusions:The polymorphisms and haplotypes of FUT2gene were not significantly related to UC. The mutation of FUT3T59G, nevertheless, might have impact on the locations of UC.