1. ¹Division of Endocrinology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
2. ²Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA
3. ³Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA
4. ⁴Cincinnati VA Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA

Correspondence: Dr EM Jacobson, Division of Endocrinology, University of Cincinnati College of Medicine, Vontz Center of Molecular Medicine, 3125 Eden Ave., ML 0547, Cincinnati, OH 45267, USA. E-mail: Eric.Jacobson@UC.edu

Received 28 September 2006; Revised 5 January 2007; Accepted 8 January 2007; Published online 8 March 2007.

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 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.