Serum Analyte Profiles Associated With Crohn's Disease and Disease Location

Background Crohn's disease (CD) can affect any segment of the digestive tract but is most often localized in the ileal, ileocolonic, and colorectal regions of the intestines. It is believed that the chronic inflammation in CD is a result of an imbalance between the epithelial barrier, the immune system, and the intestinal microbiota. The aim of the study was to identify circulating markers associated with CD and/or disease location in CD patients. Methods We tested 49 cytokines, chemokines, and growth factors in serum samples from 300 patients with CD and 300 controls. After quality control, analyte levels were tested for association with CD and disease location. Results We identified 13 analytes that were higher in CD patients relative to healthy controls and that remained significant after conservative Bonferroni correction (P < 0.0015). In particular, CXCL9, CXCL1, and interleukin IL-6 had the greatest effect and were highly significant (P < 5 x 10(-7)). We also identified 9 analytes that were associated with disease location, with VEGF, IL-12p70, and IL-6 being elevated in patients with colorectal disease (P < 3 x 10(-4)). Conclusions Multiple serum analytes are elevated in CD. These implicate the involvement of multiple cell types from the immune, epithelial, and endothelial systems, suggesting that circulating analytes reflect the inflammatory processes that are ongoing within the gut. Moreover, the identification of distinct profiles according to disease location supports the existence of a biological difference between ileal and colonic CD, consistent with previous genetic and clinical observations

Genetic predisposition for beta cell fragility underlies type 1 and type 2 diabetes

none29noneDooley, James; Tian, Lei; Schonefeldt, Susann; Delghingaro-Augusto, Viviane; Garcia-Perez, Josselyn E.; Pasciuto, Emanuela; Di Marino, Daniele; Carr, Edward J.; Oskolkov, Nikolay; Lyssenko, Valeriya; Franckaert, Dean; Lagou, Vasiliki; Overbergh, Lut; Vandenbussche, Jonathan; Allemeersch, Joke; Chabot-Roy, Genevieve; Dahlstrom, Jane E.; Laybutt, D. Ross; Petrovsky, Nikolai; Socha, Luis; Gevaert, Kris; Jetten, Anton M.; Lambrechts, Diether; Linterman, Michelle A.; Goodnow, Chris C.; Nolan, Christopher J.; Lesage, Sylvie; Schlenner, Susan M.; Liston, AdrianDooley, James; Tian, Lei; Schonefeldt, Susann; Delghingaro-Augusto, Viviane; Garcia-Perez, Josselyn E.; Pasciuto, Emanuela; Di Marino, Daniele; Carr, Edward J.; Oskolkov, Nikolay; Lyssenko, Valeriya; Franckaert, Dean; Lagou, Vasiliki; Overbergh, Lut; Vandenbussche, Jonathan; Allemeersch, Joke; Chabot-Roy, Genevieve; Dahlstrom, Jane E.; Laybutt, D. Ross; Petrovsky, Nikolai; Socha, Luis; Gevaert, Kris; Jetten, Anton M.; Lambrechts, Diether; Linterman, Michelle A.; Goodnow, Chris C.; Nolan, Christopher J.; Lesage, Sylvie; Schlenner, Susan M.; Liston, Adria

Genetic predisposition for beta cell fragility underlies type 1 and type 2 diabetes

Type 1 (T1D) and type 2 (T2D) diabetes share pathophysiological characteristics, yet mechanistic links have remained elusive. T1D results from autoimmune destruction of pancreatic beta cells, whereas beta cell failure in T2D is delayed and progressive. Here we find a new genetic component of diabetes susceptibility in T1D non-obese diabetic (NOD) mice, identifying immune-independent beta cell fragility. Genetic variation in Xrcc4 and Glis3 alters the response of NOD beta cells to unfolded protein stress, enhancing the apoptotic and senescent fates. The same transcriptional relationships were observed in human islets, demonstrating the role of beta cell fragility in genetic predisposition to diabetes.status: publishe