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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 × 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.

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Acknowledgements

We thank all the study subjects who graciously agreed to participate in the study. We also thank Dr David Greenberg for his continued advice, and NDRI for providing us with human skeletal muscle tissue. We thank the investigators who helped enroll subjects for our studies: Drs Luca Chiovato, Roberto Rocchi and Aldo Pinchera (Pisa, Italy), Sandra McLachlan (Los Angeles, USA), Bernard Rees Smith (Cardiff, Wales, UK), Fred Clark and Eric Young (Newcastle upon Tyne, UK), Meir Berezin (Tel-Hashomer, Israel), George Carayanniotis (Newfoundland, Canada), Rhoda Cobin (New York, NY). This work was supported in part by DK61659, DK067555, and DK073681 from NIDDKD (to YT), and by a research grant from the American Thyroid Association (EMJ).

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Jacobson, E., Huber, A., Akeno, N. et al. A CD40 Kozak sequence polymorphism and susceptibility to antibody-mediated autoimmune conditions: the role of CD40 tissue-specific expression. Genes Immun 8, 205–214 (2007). https://doi.org/10.1038/sj.gene.6364375

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