TP53 codon 72 Arg/Arg polymorphism is associated with a higher risk for inflammatory bowel disease development

AIM: To investigate the association between tumor protein 53(TP53) codon 72 polymorphisms and the risk for inflammatory bowel disease(IBD) development.METHODS: Numerous genetic and epigenetic drivers have been identified for IBD including the TP53 gene. Pathogenic mutations in TP53 gene have only been reported in 50% of colorectal cancer(CRC) patients. A single nucleotide polymorphism(SNP) in the TP53 gene resulting in the presence of either arginine(Arg)or proline(Pro) or both at codon 72 was shown to alter TP53 tumor-suppressor properties. This SNP has been investigated as a risk factor for numerous cancers,including CRC. In this study we analyzed TP53 codon 72 polymorphism distribution in 461 IBD,181 primary sclerosing cholangitis patients and 62 healthy controls. Genotyping of TP53 was performed by sequencing and restriction fragment length polymorphism analysis of genomic DNA extracted from peripheral blood. RESULTS: The most frequent TP53 genotype in IBD patients was Arg/Arg occurring in 54%-64% of cases(and in only 32% of controls). Arg/Pro was the most prevalent genotype in controls(53%) and less common in patients(31%-40%). Pro/Pro frequency was not significantly different between controls and IBD patients. CONCLUSION: The data suggests that the TP53 codon 72 Arg/Arg genotype is associated with increased risk for IBD development.

Understanding of chemoprophylaxis and concordance in inflammatory bowel disease

AIM:To assess patients' understanding for the reasons for taking 5-aminosalicylic acid or ursodeoxycholic acid as chemoprophylaxis against colorectal carcinoma associated with in? ammatory bowel disease (IBD). METHODS: A questionnaire-based study using a 5 point opinion scale was performed. One hundred and ninety-two patients with colitis only and 74 patients with primary sclerosing cholangitis and IBD were invited to take part. RESULTS: Overall response rate was 58%. Sixtyfour percent of patients claimed full concordance with chemoprophylaxis for maintenance of remission. Eightyfour percent of patients considered daily concordance during remission to be very important. Seventy-five percent stated they understood the reasons for taking the drugs. However, only 50% of the patients were aware of any link of their condition to bowel cancer. Seventy-nine percent of patients felt their concordance and understanding would be improved if they were informed of the chemoprophylactic potential of the medication.

Clinical predictors of thiopurine-related adverse events in Crohn's disease

AIM: To determine the incidence and predictors of thiopurine-related adverse events. METHODS: Subjects with Crohn's disease who were followed in the Alberta Inflammatory Bowel Disease Consortium patient database registry were identified. Retrospective chart review was conducted between August 5th, 2010 and June 1st, 2012. We collected data on: age at diagnosis; sex; disease location and behaviour at time of prescribing thiopurine; perianal fistulising disease at or prior to thiopurine prescription; smoking status at time of thiopurine prescription, use of corticosteroid within 6 mo of diagnosis; dosage, age at onset, and cessation of 5-aminosalicyclic acid(5-ASA); anti-tumour necrosis factor medication exposure and intestinal resection before thiopurine prescription. The primary outcome of interest was the first adverse event that led to discontinuation of the first thiopurine medication used. Logistic regression models were used to associate clinical characteristics with outcomes after adjusting for potential confounders. Risk estimates were presented as odds ratios(OR) with 95% CI. Effect modification by age and sex were explored.RESULTS: Our cohort had a median follow-up duration of 5.8 years [interquartile range(IQR 25th-75th) 2.7-9.1]. Thiopurine therapy was discontinued in 31.3% of patients because of: hypersensitivity reactions(7.1%), acute pancreatitis(6.2%), gastrointestinal intolerance(5.4%), leucopenia(3.7%), hepatotoxicity(3.4%), infection(1.1%) and other reasons(4.3%). A higher incidence of thiopurine withdrawal was observed in patients over the age of 40(39.4%, P = 0.007). A sexby-age interaction(P = 0.04) was observed. Females older than 40 years of age had an increased risk of thiopurine discontinuation due to an adverse event(age above 40 vs age below 40, adjusted OR = 2.8; 95%CI: 1.4-5.6). In contrast, age did not influence thiopurine withdrawal in males(age above 40 vs below 40, adjusted OR = 0.9; 95%CI: 0.4-2.1). Other clinical variables(disease location and phenotype, perianal disease, smoking history, history of intestinal resection and prior 5-ASA or corticosteroid use) were not associated with an increased risk an adverse event leading to therapy cessation. CONCLUSION: Thiopurine withdrawal due to adverse events is commoner in women over the age of 40 at prescription. These findings need to be replicated in other cohorts.