Showing papers by "Jean-Paul Achkar published in 2016"
TL;DR: Infliximab is not superior to placebo in preventing clinical recurrence after CD-related resection, however, infliximab does reduce endoscopic recurrence.
233 citations
Broad Institute1, Amgen2, Montreal Heart Institute3, University of Kiel4, Cedars-Sinai Medical Center5, Karolinska Institutet6, Casa Sollievo della Sofferenza7, Katholieke Universiteit Leuven8, University Medical Center Groningen9, Örebro University10, University of Helsinki11, Harvard University12, Wellcome Trust Sanger Institute13, Peninsula College of Medicine and Dentistry14, Johns Hopkins University15, University of Pittsburgh16, Mount Sinai Hospital, Toronto17, Yale University18, Torbay Hospital19, University of Nottingham20, Wellcome Trust Centre for Human Genetics21, University of Edinburgh22, Newcastle University23, Guy's Hospital24, Ninewells Hospital25, Manchester Academic Health Science Centre26, John Radcliffe Hospital27, Norfolk and Norwich University Hospital28, University of Oxford29, Royal Hospital for Sick Children30, Cleveland Clinic31, University of Toronto32, Emory University33, University of Chicago34, Icahn School of Medicine at Mount Sinai35
TL;DR: Targeted sequencing is used to conduct a search for protein-truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants associated with the same disease and demonstrates that the truncated protein exhibits reduced expression and altered subcellular localization, suggesting the protective mechanism may reside in the loss of an interaction or function via mislocalization and/or loss of
Abstract: Protein-truncating variants protective against human disease provide in vivo validation of therapeutic targets. Here we used targeted sequencing to conduct a search for protein-truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants associated with the same disease. Through replication genotyping and imputation we found that a predicted protein-truncating variant (rs36095412, p.R179X, genotyped in 11,148 ulcerative colitis patients and 295,446 controls, MAF=up to 0.78%) in RNF186, a single-exon ring finger E3 ligase with strong colonic expression, protects against ulcerative colitis (overall P=6.89 × 10(-7), odds ratio=0.30). We further demonstrate that the truncated protein exhibits reduced expression and altered subcellular localization, suggesting the protective mechanism may reside in the loss of an interaction or function via mislocalization and/or loss of an essential transmembrane domain.
53 citations
TL;DR: A possible association between low IgG/G1 levels and poor outcomes in CD including surgery is demonstrated and future implications include using immunoglobulin levels in IBD patients as a prognostic indicator or boosting humoral immunity as a treatment in this subset.
Abstract: Inflammatory bowel diseases (IBDs) are considered immune-mediated disorders with dysregulated innate and adaptive immunities. Secondary immunogloblin deficiency can occur in IBD and its impact on the disease course of IBD is not clear. We sought to determine associations between low IgG/G1 levels and poor clinical outcomes in IBD patients. This historic cohort study was performed on IBD patients with obtained IgG/IgG1 levels. The primary outcome was defined as any IBD-related bowel resection surgery and/or hospitalization. Subgroup analyses assessed particular surgical outcomes in Crohn’s disease (CD), ulcerative colitis (UC) or indeterminate colitis (IC), and ileal pouch–anal anastomosis (IPAA). The secondary outcomes included IBD drug escalations and C. difficile or cytomegalovirus infections. A total of 136 IBD patients had IgG/G1 levels checked and adequate follow-up, 58 (42.6 %) with normal IgG/G1 levels and 78 (57.4 %) having low levels. A total of 49 patients (62.8 %) with low immunoglobulin levels had IBD-related surgeries or hospitalizations, compared to 33 patients (56.9 %) with normal levels [odds ratio (OR) 1.28, 95 % confidence interval (CI) 0.64–2.56; p = 0.49]. Low IgG/G1 levels were associated with IBD-related surgery in CD in univariate analysis [hazard ratio (HR) 4.42, 95 % CI 1.02–19.23; p = 0.048] and in Kaplan–Meier survival curve analysis (p = 0.03), with a trend toward significance on multivariate analysis (HR 3.07, 95 % CI 0.67–14.31; p = 0.15). IBD patients with low IgG/G1 levels required more small bowel resections (12.8 vs. 1.7 %, p = 0.024) and 5-aminosalicylate initiations (28.2 vs. 13.8 %, p = 0.045). Our study demonstrated a possible association between low IgG/G1 levels and poor outcomes in CD including surgery. Future implications include using immunoglobulin levels in IBD patients as a prognostic indicator or boosting humoral immunity as a treatment in this subset.
12 citations