title: A CD40 Kozak sequence polymorphism and susceptibility to antibody-mediated autoimmune conditions: the role of CD40 tissue-specific expression.
abstract: Previously, we and others have demonstrated the association of a C/T single nucleotide polymorphism (SNP), in the Kozak sequence of CD40, with Graves' disease (GD). Here, using an expanded data set of patients, we confirm the association of the CD40 SNP with GD (n=210, P=0.002, odds ratio (OR)=1.8). Subset analysis of patients with persistently elevated thyroid peroxidase (TPO) and/or thyroglobulin (Tg) antibodies (Abs), (TPO/Tg Abs), after treatment (n=126), revealed a significantly stronger association of the SNP with disease (P=5.2 x 10(-5), OR=2.5) than in GD patients who were thyroid antibody-negative. However, the CD40 SNP was not associated with TPO/Tg Abs in healthy individuals. Next, we tested the CD40 SNP for association with Myasthenia Gravis (MG), which, like GD is an antibody-mediated autoimmune condition. Analysis of 81 MG patients found no association of the SNP with disease. Functional studies revealed significant expression of CD40 mRNA and protein in the thyroid (target tissue in GD) but not in skeletal muscle (target tissue in MG). Combined, our genetic and tissue expression data suggest that the CD40 Kozak SNP is specific for thyroid antibody production involved in the etiology of GD. Increased thyroidal expression of CD40 driven by the SNP may contribute to this disease specificity.
authors.affiliation: Division of Endocrinology, University of Cincinnati College of Medicine, Vontz Center of Molecular Medicine, Cincinnati, OH 45267, USA. Eric.Jacobson@UC.edu
authors.forename: E M
authors.initials: EM
authors.lastname: Jacobson
authors.forename: A K
authors.initials: AK
authors.lastname: Huber
authors.forename: N
authors.initials: N
authors.lastname: Akeno
authors.forename: M
authors.initials: M
authors.lastname: Sivak
authors.forename: C W
authors.initials: CW
authors.lastname: Li
authors.forename: E
authors.initials: E
authors.lastname: Concepcion
authors.forename: K
authors.initials: K
authors.lastname: Ho
authors.forename: Y
authors.initials: Y
authors.lastname: Tomer
mesh_terms: D020121:5' Untranslated Regions; D000293:Adolescent; D000328:Adult; D000368:Aged; D001323:Autoantibodies / Q000097:blood; D001324:Autoantigens / Q000276:immunology; D001483:Base Sequence; D019013:CD40 Antigens / Q000235:genetics*; D016022:Case-Control Studies; D017931:DNA Primers / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006111:Graves Disease / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D007453:Iodide Peroxidase / Q000276:immunology; D033862:Iron-Binding Proteins / Q000276:immunology; D008297:Male; D008875:Middle Aged; D018448:Models, Immunological; D009157:Myasthenia Gravis / Q000235:genetics / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D020121:5' Untranslated Regions; D001323:Autoantibodies; D001324:Autoantigens; D019013:CD40 Antigens; D017931:DNA Primers; D033862:Iron-Binding Proteins; D012333:RNA, Messenger; C006606:anti-thyroglobulin; C056658:TPO protein, human; D007453:Iodide Peroxidase