title: The cannabinoid receptor type 2 Q63R variant increases the risk of celiac disease: implication for a novel molecular biomarker and future therapeutic intervention.
abstract: Celiac disease (CD) is a chronic inflammatory disease of the small bowel that occurs with the ingestion of gluten, found in several grains products. Although HLA-DQ2 variant is required for the gluten-derived peptide gliadin presentation by antigen-presenting cells to T-cells, non-HLA genetic factors account for the majority of heritable risk. Several genome-wide association studies have identified susceptibility loci for CD on chromosome 1. Cells of the immune system express the cannabinoid receptor type 2 (CB2), a plasma-membrane receptor activated by both endogenous and exogenous cannabinoids. Consistent data evidence that CB2 is linked to a variety of immune functional events and that, in the course of an inflammatory process, an increased number of receptors becomes available for activation. The cannabinoid receptor type 2 gene (CNR2; GeneID1269) maps on 1p36.11. In order to investigate the possible involvement of CB2 in CD establishment, immunohistochemistry toward CB2 receptor and CD4+ cells in small bowel biopsies from celiac children and association analysis, through TaqMan assay, of a CNR2 common missense variant, rs35761398 (CAA/CGG), resulting in the aminoacidic substitution of Glutamine at codon 63 with Arginine (Q63R), in a cohort of 327 South Italian children have been performed. We observed in this study that CB2 is up-regulated in CD small bowel biopsies and CNR2 rs35761398 is significantly associated with CD (χ(2) = 37.064; d.f. 1; p = 1.14 × 10(-9)). Our findings suggest a role of CB2 in CD. The Q63R variant, increasing more than six-fold the risk for CD susceptibility, might eventually represent a novel molecular biomarker for CD risk stratification. Indeed, we provide here further evidence that CB2 receptor plays a critical role in autoimmunity susceptibility and indicates that it represents a molecular target to pharmacologically modulate the immune components in CD.
authors.affiliation: Department of Pediatrics, Second University of Naples, 80138 Naples, Italy. fra.rossi76@liberto.it
authors.forename: Francesca
authors.initials: F
authors.lastname: Rossi
authors.forename: Giulia
authors.initials: G
authors.lastname: Bellini
authors.forename: Carlo
authors.initials: C
authors.lastname: Tolone
authors.forename: Livio
authors.initials: L
authors.lastname: Luongo
authors.forename: Silvia
authors.initials: S
authors.lastname: Mancusi
authors.forename: Alfonso
authors.initials: A
authors.lastname: Papparella
authors.forename: Craig
authors.initials: C
authors.lastname: Sturgeon
authors.forename: Alessio
authors.initials: A
authors.lastname: Fasano
authors.forename: Bruno
authors.initials: B
authors.lastname: Nobili
authors.forename: Laura
authors.initials: L
authors.lastname: Perrone
authors.forename: Sabatino
authors.initials: S
authors.lastname: Maione
authors.forename: Emanuele Miraglia
authors.initials: EM
authors.lastname: del Giudice
mesh_terms: D000293:Adolescent; D000704:Analysis of Variance; D001706:Biopsy; D018791:CD4 Lymphocyte Count; D016022:Case-Control Studies; D002446:Celiac Disease / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D016009:Chi-Square Distribution; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007421:Intestine, Small / Q000737:chemistry / Q000276:immunology; D007558:Italy; D008297:Male; D020125:Mutation, Missense; D016017:Odds Ratio; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction; D043885:Receptor, Cannabinoid, CB2 / Q000032:analysis / Q000235:genetics*; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: D005819:Genetic Markers; D043885:Receptor, Cannabinoid, CB2