Jacobson E M, Huber A K, Akeno N, Sivak M, Li C W, Concepcion E, Ho K, Tomer Y
Division of Endocrinology, University of Cincinnati College of Medicine, Vontz Center of Molecular Medicine, Cincinnati, OH 45267, USA.
Genes Immun. 2007 Apr;8(3):205-14. doi: 10.1038/sj.gene.6364375. Epub 2007 Mar 8.
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.
此前，我们和其他人已经证明，CD40的科扎克序列中的一个C/T单核苷酸多态性（SNP）与格雷夫斯病（GD）有关。在此，我们使用一个扩大的患者数据集，证实了CD40 SNP与GD的关联（n = 210，P = 0.002，优势比（OR）= 1.8）。对治疗后甲状腺过氧化物酶（TPO）和/或甲状腺球蛋白（Tg）抗体（Abs）持续升高的患者（TPO/Tg Abs）进行子集分析（n = 126），结果显示该SNP与疾病的关联（P = 5.2 x 10(-5)，OR = 2.5）明显强于甲状腺抗体阴性的GD患者。然而，在健康个体中，CD40 SNP与TPO/Tg Abs无关。接下来，我们测试了CD40 SNP与重症肌无力（MG）的关联，重症肌无力与GD一样，是一种抗体介导的自身免疫性疾病。对81例MG患者的分析发现该SNP与疾病无关联。功能研究表明，CD40 mRNA和蛋白在甲状腺（GD的靶组织）中有显著表达，但在骨骼肌（MG的靶组织）中无表达。综合我们的基因和组织表达数据表明，CD40 Kozak SNP对GD病因中涉及的甲状腺抗体产生具有特异性。由该SNP驱动的CD40甲状腺表达增加可能导致了这种疾病特异性。
