Jeremy Sanderson

Inflammatory bowel disease (IBD) comprises mainly Crohn’s disease (CD) and Ulcerative Colitis (UC). The Western model suggests that environmental factors, immunological factors, the gut microbiome, and genetic disposition all contribute to the onset and sustained symptoms that define CD, although the pathogenesis of CD remains unresolved. Current studies propose that in individuals who are genetically susceptible, genetic factors linked to immune dysregulation, in combination with environmental exposure, can result in dysbiosis of the gut microbiome and intestinal barrier dysfunction, leading to immune dysregulation. In Malaysia, the incidence of IBD is rising with CD increasing disproportionally compared to UC, and the incidence of CD currently mirrors that of the United Kingdom in the 1930s, which now has one of the highest incidences worldwide. Given the suggested role of Mycobacterium avium subspecies paratuberculosis (MAP) in CD in Western countries, which is subject to some controversy, this review summarises for the first time the current evidence on genetic, environmental, and microbial factors that could contribute to the rise of Crohn’s disease in Malaysia and proposes preventive approaches. We note the increasing reliance of Malaysia on imported cattle and milk products from areas of high Johne’s Disease prevalence to meet increasing demand and changes in milk preferences in the Malaysian population, both key indicators for human-MAP exposure in the Western model. Therefore, should MAP be shown to be associated with CD in Malaysia, some preventative measures are suggested, such as screening imported and native beef and dairy cattle, dairy products and ultimately water, both recreational and potable.

Background: In inflammatory bowel disease (IBD), conventional thiopurine users cease treatment in 60% of cases within 5 years, mostly because of adverse events or nonresponse. In this study, the authors aimed to investigate the role of 6-thioguanine nucleotide (TGN) measurements, geno/phenotyping of thiopurine S-methyltransferase (TPMT), and their mutual relationship with TG therapy in IBD. Methods: An international retrospective, multicenter cohort study was performed at 4 centers in the Netherlands (Máxima Medical Centre) and the United Kingdom (Guy's and St. Thomas' Hospital, Queen Elizabeth Hospital, and East Surrey Hospital). Results: Overall, 526 6-TGN measurements were performed in 316 patients with IBD. The median daily dosage of TG was 20 mg/d (range 10–40 mg/d), and the median duration of TG use was 21.1 months (SD, 28.0). In total, 129 patients (40.8%) had a known TPMT status. In the variant-type and wild-type TPMT genotype metabolism groups, median 6-TGN values were 1126 [interquartile range (IQR) 948–1562] and 467.5 pmol/8 × 10E8 red blood cells (RBCs) (IQR 334–593). A significant difference was observed between the 2 groups (P = 0.0001, t test). For TPMT phenotypes, in the slow, fast, and normal metabolism groups, the median 6-TGN values were 772.0 (IQR 459–1724), 296.0 (IQR 200–705), and 774.5 pmol/8 × 10E8 RBCs (IQR 500.5–981.5), with a significant difference observed between groups (P < 0.001, analysis of variance). Conclusions: Our findings indicated that TPMT measurements at TG initiation can be useful but are not necessary for daily practice. TPMT genotypes and phenotypes are both associated with significant differences in 6-TGN levels between metabolic groups. However, the advantage of TG remains that RBC 6-TGN measurements are not crucial to monitor treatments in patients with IBD because these measurements did not correlate with laboratory result abnormalities. This presents as a major advantage in countries where patients cannot access these diagnostic tests.

Background: Estimates of the risk of developing Crohn's disease (CD) can be made using DNA testing for mutations in the NOD2 (CARD15) gene, family history, and smoking status. Smoking doubles the risk of CD, a risk that is reduced by stopping. CD therefore serves as a timely and novel paradigm within which to assess the utility of predictive genetic testing to motivate behaviour change to reduce the risk of disease. The aim of the study is to describe the impact upon stopping smoking of communicating a risk of developing CD that incorporates DNA analysis. We will test the following main hypothesis: Smokers who are first degree relatives (FDRs) of CD probands are more likely to make smoking cessation attempts following communication of risk estimates of developing CD that incorporate DNA analysis, compared with an equivalent communication that does not incorporate DNA analysis. Methods/design: A parallel groups randomised controlled trial in which smokers who are FDRs of probands with CD are randomly allocated in families to undergo one of two types of assessment of risk for developing CD based on either: i. DNA analysis, family history of CD and smoking status, or ii. Family history of CD and smoking status The primary outcome is stopping smoking for 24 hours or longer in the six months following provision of risk information. The secondary outcomes are seven-day smoking abstinence at one week and six month follow-ups. Randomisation of 470 smoking FDRs of CD probands, with 400 followed up (85%), provides 80% power to detect a difference in the primary outcome of 14% between randomised arms, at the 5% significance level. Discussion: This trial provides one of the strongest tests to date of the impact of communicating DNA-based risk assessment on risk-reducing behaviour change. Specific issues regarding the choice of trial design are discussed. Trial Registration: ISRCTN: ISRCTN21633644