Two SNPs in the promoter region of the CTLA-4 gene affect binding of transcription factors and are associated with human myasthenia gravis

Objectives. The molecular mechanisms underlying the regulation of the CD152 (CTLA-4) gene are largely unknown. Two single nucleotide polymorphisms (SNPs) located in the promoter region are suspected to contribute to the pathogenesis of myasthenia gravis (MG) through regulation of gene expression. Setting, Subjects and Design. One hundred and sixty-five unrelated Swedish-Caucasian patients with MG (103 females and 62 males, age 17 to 92 years) and 148 ethnically matched healthy individuals were studied. Gene typing of two SNPs (T/C-1772 and A/G(-1661)) and quantification of soluble CD152 were performed in the patients. Besides the association studies, the function of these two SNPs is characterized. Results. We present new genetic associations of two SNPs in the CD152 gene with human MG. These SNPs located in the promoter region are involved in transcriptional binding activity for Nuclear Factor I (NF-1) and c/ EBPbeta, as demonstrated using chromatin immunoprecipitation and electromobility shift assay. MG patients with the T/C-1772 polymorphism have elevated levels of sCD152 in sera. Conclusions. The two SNPs in the promoter region are associated with MG and might cause abnormal alternative splicing and affect the expression of CD152, thereby contributing to the pathogenesis of MG.