Clinical Significance of Multidrug Resistant 1 Gene Polymorphism C3435T in Ulcerative Colitis

Abstract

Ulcerative colitis (UC) is a chronic disease that is characterized by diffuse inflammation of the mucosa of the colon and rectum. The main clinical symptom of UC is bloody diarrhea. The clinical course is characterized by exacerbations and remissions and may occur spontaneously or in response to intercurrentillnesses or treatment changes (da Silva et al., 2014). Previous studies suggested that the occurrence of UC have involved multiple factors including infection, environmental, psychologyical, immunological, and genetic factors. In recent years, studies attempted to evaluate the association of genetic polymorphisms and UC susceptibility, disease severity as well as corticosteroid response(Cao et al., 2015). MDR1 gene is located in chromosome 7; it includes 28 exons and codes 1280 amino acid residues.It encodes P-gp, which is closely related to bowel diseases(Cao et al., 2015).The MDR1 gene contains over 50 SNPs, in which only C3435T at 26 exon and C1236T at12 exon are synonymous mutations and the frequencies of their alleles vary greatly in different populations(Liu et al., 2008 andCao et al., 2015). The present study investigated the clinical utility of the MDR1 gene (C3435T) in patients with UC. For this purpose, samples were collected from 50 patients diagnosed as UC according to clinical, endoscopic and histopathological examinations (Group I) and 50 age and sex- matched apparently healthy controls (Group II). Patients were subclassifiedaccording to disease severity into mild, moderate and severe UC patients. They were also subdivided according to the response to GC therapy into GC responders and GC non-responders. All individuals in the study were subjected to full history including present history, family history and past history, general clinical examination, biopsy for site of disease determination by sigmoidoscopy or full colonoscopy, general laboratory investigations including CBC, serum sodium, potassium and albumin, CRP and ESR and assay of MDR1 gene polymorphism C3435T by PCR amplification and restriction analysis. The study revealed: - MDR1 genotype (3435TT) and T allele could be a risk factor for developing UC. - The homozygous type (3435TT) was associated with increased disease severity compared to wild type (3435CC). - The wild type (3435CC) was more frequently present in GC responders compared to non-responders, however, TT genotype was more frequently associated with GC non responders. - No difference was detected between male and female UC patients. In conclusion, the present study supports the hypothesis that SNP rs1045642 of MDR1 gene (C3435T) is involved in UC predisposition. In addition, the TT genotypeand the T allele were associated with disease severity as well asno response to GC therapy.