Recent studies have reported an association between cytokine gene polymorphisms and GC risk. However, results are inconsistent among studies from different geographic regions and ethnic groups. Our goal was to evaluate the influence of Helicobacter pylori (H. pylori) infection and host genetic factors on GC susceptibility in a population of Spanish white GC patients. DNA from 404 unrelated patients with GC and 404 sex- and age-matched healthy controls was typed for several functional polymorphisms in pro- (IL-1B, TNFA, LTA, IL-12p40) and anti-inflammatory (IL-4, IL-1RN, IL-10, TGFB1) genes by PCR, RFLP, and TaqMan assays. H. pylori infection and CagA/VacA antibody status were also determined by western blot serology. Logistic regression analysis identified H. pylori infection with cagA strains (OR 2.54, 95% CI 1.77-3.66), smoking habit (OR 1.91, 95% CI 1.25-2.93), and positive family history of GC (OR 3.67, 95% CI 2.01-6.71) as independent risk factors for GC. None of the cytokine gene polymorphisms analyzed in this study were associated with susceptibility to GC development, whether GC patients were analyzed as a group or categorized according to anatomic location or histological subtype. Some simultaneous combinations of proinflammatory genotypes reportedly associated with greater GC risk yielded no significant differences between patients and controls. Our results show that, at least in some white populations, the contribution of the cytokine gene polymorphisms evaluated in this study (IL-1B, IL-1RN, IL-12p40, LTA, IL-10, IL-4, and TGF-B1) to GC susceptibility may be less relevant than previously reported.

André R. A. Marques, Mina Mirzaian, Hisako Akiyama, Patrick Wisse, Maria J. Ferraz, Paulo Gaspar, Karen Ghauharali-van der Vlugt, Rianne Meijer, Pilar Giraldo, Pilar Alfonso, Pilar Irún, Maria Dahl, Stefan Karlsson, Elena V. Pavlova, Timothy M. Cox, Saskia Scheij, Marri Verhoek, Roelof Ottenhoff, Cindy P. A. A. van Roomen, Navraj S. Pannu, Marco van Eijk, Nick Dekker, Rolf G. Boot, Herman S. Overkleeft, Edward Blommaart, Yoshio Hirabayashi, Johannes M. Aerts

Impaired function of NPC1 or NPC2 lysosomal proteins leads to the intracellular accumulation of unesterified cholesterol, the primary defect underlying Niemann-Pick type C (NPC) disease. In addition, glycosphingolipids (GSLs) accumulate in lysosomes as well. Intralysosomal lipid accumulation triggers the activation of a set of genes, including potential biomarkers. Transcript levels of Gpnmb have been shown to be elevated in various tissues of an NPC mouse model. We speculated that Gpnmb could serve as a marker for visceral lipid accumulation in NPC disease. We report that Gpnmb expression is increased at protein level in macrophages in the viscera of Npc1^nih/nih mice. Interestingly, soluble Gpnmb was also found to be increased in murine and NPC patient plasma. Exposure of RAW264.7 macrophages to the NPC-phenotype-inducing drug U18666A also upregulated Gpnmb expression. Inhibition of GSL synthesis with the glucosylceramide synthase (GCS) inhibitor N-butyl-1-deoxynojirimycin prevented U18666A-induced Gpnmb induction and secretion. In summary, we show that Gpnmb is upregulated in NPC mice and patients, most likely due to GSL accumulation.

Chronic inflammation takes part in the pathogenesis of some malignancies of the gastrointestinal tract including colorectal (CRC), gastric, and esophageal cancers. The use of ω3 polyunsaturated fatty acid (ω3-PUFA) supplements for chemoprevention or adjuvant therapy of gastrointestinal cancers is being investigated in recent years. Most evidence has been reported in CRC, although their protective role has also been reported for Helicobacter pylori-induced gastric cancer or Barrett's esophagus-derived adenocarcinoma. Studies based on ω3-PUFA supplementation in animal models of familial adenomatous polyposis (FAP) and CRC revealed positive effects on cancer prevention, reducing the number and size of tumors, down-regulating arachidonic acid-derived eicosanoids, upregulating anti-oxidant enzymes, and reducing lipid peroxidation, whereas contradictory results have been found in induced colitis and colitis-associated cancer. Beneficial effects have also been found in FAP and ulcerative colitis patients. Of special interest is their positive effect as adjuvants on radio- and chemo-sensitivity, specificity, and prevention of treatment complications. Some controversial results obtained in CRC might be justified by different dietary sources, extraction and preparation procedures of ω3-PUFAs, difficulties on filling out food questionnaires, daily dose and type of PUFAs, adenoma subtype, location of CRC, sex differences, and genetic factors. Studies using animal models of inflammatory bowel disease have confirmed that exogenous administration of active metabolites derived from PUFAs called pro-resolving mediators like lipoxin A4, arachidonic acid-derived, resolvins derived from eicosapentaenoic (EPA), docosahexaenoic (DHA), and docosapentaenoic (DPA) acids as well as maresin 1 and protectins DHA- and DPA-derived improve disease and inflammatory outcomes without causing immunosuppression or other side effects.

Gaucher disease (GD) is due to deficiency of the glucocerebrosidase enzyme. It is panethnic, but its presentation reveals ethnicity-specific characteristics.