Raymond Lahaie

Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study

Ulcerative colitis is a chronic inflammatory disease of the colon that presents as diarrhea and gastrointestinal bleeding. We performed a genome-wide association study using DNA samples from 1,052 individuals with ulcerative colitis and preexisting data from 2,571 controls, all of European ancestry. In an analysis that controlled for gender and population structure, ulcerative colitis loci attaining genome-wide significance and subsequent replication in two independent populations were identified on chromosomes 1p36 (rs6426833, combined P = 5.1 × 10−13, combined odds ratio OR = 0.73) and 12q15 (rs1558744, combined P = 2.5 × 10−12, combined OR = 1.35). In addition, combined genome-wide significant evidence for association was found in a region spanning BTNL2 to HLA-DQB1 on chromosome 6p21 (rs2395185, combined P = 1.0 × 10−16, combined OR = 0.66) and at the IL23R locus on chromosome 1p31 (rs11209026, combined P = 1.3 × 10−8, combined OR = 0.56; rs10889677, combined P = 1.3 × 10−8, combined OR = 1.29).

Inflammatory bowel disease characteristics among African Americans, Hispanics, and non-Hispanic Whites: characterization of a large North American cohort.

OBJECTIVES:Inflammatory bowel disease (IBD), comprising primarily of Crohns disease (CD) and ulcerative colitis (UC), is increasingly prevalent in racial and ethnic minorities. This study was undertaken to characterize racial differences in disease phenotype in a predominantly adult population.METHODS:Phenotype data on 830 non-Hispanic white, 127 non-Hispanic African American, and 169 Hispanic IBD patients, recruited from six academic centers, were abstracted from medical records and compiled in the NIDDK-IBD Genetics Consortium repository. We characterized racial differences in family history, disease location and behavior, surgical history, and extraintestinal manifestations (EIMs) using standardized definitions.RESULTS:African American CD patients were more likely than whites to develop esophagogastroduodenal CD (OR = 2.8; 95% CI: 1.4–5.5), colorectal disease (OR = 1.9; 95% CI: 1.1–3.4), perianal disease (OR = 1.7; 95% CI: 1.03–2.8), but less likely to have ileal involvement (OR = 0.55; 95% CI: 0.32–0.96). They were also at higher risk for uveitis (OR = 5.5; 95% CI: 2.3–13.0) and sacroiliitis (OR = 4.0; 95% CI: 1.55–10.1). Hispanics had higher prevalence of perianal CD (OR = 2.9; 95% CI: 1.8–4.6) and erythema nodosum (3.3; 95% CI: 1.7–6.4). Among UC patients, Hispanics had more proximal disease extent. Both African American and Hispanic CD patients, but not UC patients, had lower prevalences of family history of IBD than their white counterparts.CONCLUSIONS:There are racial differences in IBD family history, disease location, and EIMs that may reflect underlying genetic variations and have important implications for diagnosis and management of disease. These findings underscore the need for further studies in minority populations.

Biologics in inflammatory bowel disease: what are the data?

Background Over the last decade, biologics have gained an important place for the treatment of moderate to severe inflammatory bowel disease (IBD), and many randomized control trials have evaluated their efficacy. Aim The goal of this review is to analyze the results of these trials and to highlight the evidence and indications emerging from these studies for their implementation in the management of IBD patients. Methods A PubMed search was realized to screen high-quality clinical trials studying biologic agents currently available in clinics for the treatment of IBD. Words used were: “infliximab,” “adalimumab,” “certolizumab,” “golimumab,” “natalizumab,” “vedolizumab,” “ustekinumab,” “azathioprine,” “methotrexate,” “Crohns disease,” and “ulcerative colitis.” Results In Crohns disease, studies supporting induction and maintenance therapies were documented for infliximab, adalimumab, certolizumab, natalizumab, vedolizumab, and ustekinumab. Infliximab, adalimumab, and certolizumab have evidences for fistulizing Crohns disease and only infliximab and adalimumab have evidences for mucosal healing. In ulcerative colitis, studies supporting induction, maintenance, and mucosal healing were found with infliximab, adalimumab, golimumab, and vedolizumab. Only infliximab was associated with evidences for combination therapy with thiopurine and acute severe colitis in ulcerative colitis. Conclusion Management with biologics in IBD patients is well validated by high-quality clinical trials.

Human basophils interact with memory T cells to augment Th17 responses

Basophils are a rare population of granulocytes that have long been associated with IgE-mediated and Th2-associated allergic diseases. However, the role of basophils in Th17 and/or Th1 diseases has not been reported. In the present study, we report that basophils can be detected in the mucosa of Th17-associated lung and inflammatory bowel disease and accumulate in inflamed colons containing large quantities of IL-33. We also demonstrate that circulating basophils increased memory Th17 responses. Accordingly, IL-3- or IL-33-activated basophils amplified IL-17 release in effector memory T cells (T(EM)), central memory T cells (T(CM)), and CCR6(+) CD4 T cells. More specifically, basophils promoted the emergence of IL-17(+)IFN-γ(-) and IL-17(+)IFN-γ(+), but not IL-17(-)IFN-γ(+) CD4 T cells in T(EM) and T(CM). Mechanistic analysis revealed that the enhancing effect of IL-17 production by basophils in T(EM) involved the ERK1/2 signaling pathway, occurred in a contact-independent manner, and was partially mediated by histamine via H(2) and H(4) histamine receptors. The results of the present study reveal a previously unknown function for basophils in augmenting Th17 and Th17/Th1 cytokine expression in memory CD4 T cells. Because basophils accumulated in inflamed inflammatory bowel disease tissues, we propose that these cells are key players in chronic inflammatory disorders beyond Th2.

Phenotypic and Genotypic Characteristics of Inflammatory Bowel Disease in French Canadians: Comparison With a Large North American Repository

OBJECTIVES:Phenotype characteristics of inflammatory bowel disease (IBD) may differ significantly among ethnic subpopulations. The aim of this study was to characterize the IBD phenotype in French Canadians, the most prominent founder population in North America.METHODS:Using well-characterized phenotype data in the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)-IBD Genetics Consortium repository on patients with IBD, we compared phenotypic characteristics of 202 French Canadians with those of 1,287 other Caucasian patients. These included diagnosis, anatomical location, disease behavior, extraintestinal manifestations, surgical history, and family history of IBD.RESULTS:French-Canadian patients with Crohns disease (CD) were less likely to have stricturing disease (11 vs. 21%, P=0.005; odds ratio (OR): 0.45, 95% confidence interval (95% CI): 0.24–0.85). Using a stringent definition of ethnicity (three out of four grandparents being French Canadians, as opposed to self-report, n=148), French Canadians had a tendency toward developing fistulizing CD (37 vs. 28%, P=0.07), and there was an increased prevalence of sacroiliitis among those with IBD (4 vs. 2%, P=0.045). Among French Canadians, the numbers of current smokers in CD (40 vs. 25%, P=0.006) and former smokers in ulcerative colitis (UC) (35 vs. 20%, P=0.03) were significantly higher. The prevalence of one of the three main variants of nucleotide-binding oligomerization domain containing 2 (NOD2) single-nucleotide polymorphisms (SNPs) among French-Canadian CD patients was 43.2%. The 3020insC SNP correlated with small bowel disease in French Canadians (75 vs. 0%, P=0.006).CONCLUSIONS:French Canadians show an IBD phenotype profile distinct from other Caucasian IBD populations, with an accentuated association between smoking status and IBD. This unique profile may have implications regarding the need for a different approach to the management of IBD in this population.

Helicobacter pylori Antibiotic Resistance: Trends Over Time

Resistance to antibiotics can be a major problem in the treatment of bacterial infections. As the use of antibiotics increases, bacterial resistance to these agents is rising and in many cases is responsible for the failure of treatment regimens. Although the treatment of Helicobacter pylori infection requires the use of more than one antibiotic to obtain adequate eradication rates, the efficacy of the currently used antibiotic combinations has been shown to be decreased by resistance to one of the antibiotics. The use of antibiotics in regiments for the treatment of H pylori is increasing in many countries, including Canada. This increase is both in the use of these antibiotics alone for the treatment of nongastrointestinal infections and in their use in association with proton pump inhibitors for the treatment of H pylori infection. In several European and Asian countries, where resistance to antibiotics is being monitored, it has been demonstrated the H pylori resistance to metronidazole and to clarithromycin increased throughout the 1990s. Thus far, the data available in Canada do not show increased resistance to either of these antibiotics. As for other antibiotics used in the treatment of H pylori infection such as tetracycline and amoxicillin, the rate of resistance to these agents is still very low and does not constitute a significant problem. Because the efficacy of the regimens used in the treatment of H pylori infection is compromised by resistance to the antibiotics used, it is important that H pylori resistance rate in Canada and throughout the world continue to be monitored. Only with such reliable data can the most optimal regimens be recommended.

Bismuth-based quadruple therapy with bismuth subcitrate, metronidazole, tetracycline and omeprazole in the eradication of Helicobacter pylori.

BACKGROUND A previous study showed that 14 days of qid bismuth-based triple therapy with tetracycline 500 mg, metronidazole 250 mg and colloidal bismuth subcitrate 120 mg resulted in excellent Helicobacter pylori eradication rates (89.5%). The present study looked at a shorter treatment period by adding omeprazole and by reducing the dose of tetracycline. METHODS One hundred sixty-one patients with H pylori confirmed by histology and (13)carbon urea breath test were included in the study. They were treated for seven days with bismuth subcitrate 120 mg plus metronidazole 250 mg plus tetracycline 250 mg qid plus omeprazole 20 mg bid (OBMT). Patients were 18 to 75 years of age and had dyspepsia with or without a history of peptic ulcer. Patients with irritable bowel syndrome, active ulcer or previous attempt at eradication, or those who had used antibiotics or antiulcer drugs in the previous 30 days were excluded. Eradication was determined by two (13)carbon urea breath tests done one and three months, respectively, after treatment. Strains with minimal inhibitory concentrations of 8 microg/mL or higher were considered to be resistant to metronidazole. RESULTS The overall per protocol eradication rate was 84%-89.5% in metronidazole-sensitive and 70.8% in metronidazole-resistant strains. Modified intent-to-treat analysis resulted in a 80% eradication rate--82.5% in metronidazole-sensitive and 66.7% in metronidazole-resistant strains. Only one patient discontinued treatment because of adverse events. CONCLUSIONS The OBMT regimen used in this study is safe and effective against metronidazole-sensitive H pylori strains.

The Quebec Association of Gastroenterology Position Paper on Colorectal Cancer Screening - 2003

Colorectal cancer is a leading cause of death and the third most common cancer in Canada. Evidence suggests that screening can reduce mortality rates and the cost effectiveness of a program compares favourably with initiatives for breast and cervical cancer. The objectives of the Association des gastro-entérologues du Québec Task Force were to determine the need for a policy on screening for colorectal cancer in Quebec, to evaluate the testing methods available and to propose one or more of these alternatives as part of a formal screening program, if indicated. Fecal occult blood testing (FOBT), endoscopy (including sigmoidoscopy and colonoscopy), barium enema and virtual colonoscopy were considered. Although most clinical efficacy data are available for FOBT and sigmoidoscopy, there are limitations to programs based on these strategies. FOBT has a high false positive rate and a low detection yield, and even a combination of these strategies will miss 24% of cancers. Colonoscopy is the best strategy to both detect and remove polyps and to diagnose colorectal cancer, with double contrast barium enema also being a sensitive detection method. The Task Force recommended the establishment, in Quebec, of a screening program with five- to 10-yearly double contrast barium enema or 10-yearly colonoscopy for individuals aged 50 years or older at low risk. The program should include outcome monitoring, public and professional education to increase awareness and promote compliance, and central coordination with other provincial programs. The program should be evaluated; specific billing codes for screening for colorectal cancer would help facilitate this. Formal feasibility, effectiveness and cost-effectiveness studies in Quebec are now warranted.

Molecular Heterogeneity of Human Motilinlike Immunoreactivity Explained by the Processing of Prepromotilin

Results of studies on the molecular forms of canine motilin suggest that this hormone might be synthesized as a higher molecular weight precursor, as is the case for most other biologically active peptides. Chromatographic analysis of human duodenal mucosa extracts and of human serum, using motilin-specific antibodies, also shows the presence of multiple forms of motilinlike immunoreactivity. Cell free translation of human duodenal messenger ribonucleic acid (mRNA) and immunoprecipitation of nascent peptides with motilin antibodies confirm that motilin is synthesized as a 14-15-kilodalton polypeptide precursor. Sequence of the human intestinal motilin complementary deoxyribonucleic acid (cDNA) demonstrates that this precursor bears a 25-amino acid signal peptide, a single dibasic cleavage site immediately following the 22 amino acids of human motilin, and a 65-amino acid polypeptide (motilin-related peptide) following this dibasic processing site. Southern analysis of human genomic kilobases DNA demonstrates that only one motilin gene is contained within 3.5-4 of human genomic DNA. Northern analysis of human intestinal RNA reveals one species of motilin mRNA of an estimated 700 nucleotides in length. These results suggest that (a) only one gene encodes the synthesis of human motilin in the different tissues where this polypeptide is synthesized; (b) human intestinal motilin is translated from one mRNA species and the resulting precursor is processed within the duodenal mucosa by sequential proteolytic cleavage first at a site within the motilin-related peptide, which results in the liberation of a 6-kilodalton form of motilinlike immunoreactivity, and then at the dibasic amino acid cleavage site, thus freeing motilin 22 from its precursor.

CD47 fusion protein targets CD172a+ cells in Crohn’s disease and dampens the production of IL-1β and TNF

CD172a+ cells producing IL-1β and TNF are increased in inflamed tissues in Crohn’s disease and can be targeted by CD47 fusion protein.