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

Abstract

Abstract. Wang XB, Pirskanen R, Giscombe R, Lefvert AK (Shanghai University of TCM, Shanghai, China; and Karolinska University Hospital and Karolinska Institutet, Stockholm; Sweden). Two SNPs in the promoter region of the CTLA-4 gene affect binding of transcription factors and are associated with human myasthenia gravis. J Intern Med 2008; 263: 61-69.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.

Association of functional genetic variants of CTLA4 with reduced serum CTLA4 protein levels and increased risk of idiopathic recurrent miscarriages

“…It has been shown that there may be a correlation between CTLA4 gene variants and alternative splicing (39). The expression of alternatively spliced flCTLA4 and sCTLA4 isoforms are influenced by the CTLA4 5 0 -upstream regulatory region and 3 0 -untranslated region gene polymorphisms (37,40,41).…”

“…The noncoding region variants of CTLA4 gene may result in abnormal alternative splicing. It has been shown that the noncoding region SNPs of CTLA4 that present in the 5 0 -upstream regulatory region may cause abnormal alternative splicing and affect gene expression; hence, they may be associated with disease susceptibility (39).…”

Transcriptional control of the human glucocorticoid receptor: identification and analysis of alternative promoter regions

“…A third generation human haplotype map catalogues from 1.3 to 4.1 million SNPs depending on ethnicity (Altshuler et al 2010). Polymorphisms within gene promoter regions can have profound effects on transcriptional efficiency of genes (Blank et al 2005;Myers et al 2007;Wang et al 2008) and may contribute to disease susceptibility of complex inherited traits. For example, a SNP in the interleukin-1 promoter region was reportedly associated with rheumatoid arthritis (Harrison et al 2008) and an E-cadherine160 C/A promoter polymorphism was associated with increased susceptibility and altered disease progression of pancreatic carcinoma in Chinese patients (Fei et al 2010).…”

Ctla-4 Gene Polymorphism in Relation to Thyroid Disorders in Patients With Chronic Hepatitis C Under Interferon Alpha Therapy

“…The first of these reports was made by Yanagawa et al (1995), who found a significant association between variation in the (AT) dinucleotide repeat within the 3'-untranslated region of the CTLA-4 gene and the presence of Grave's Disease (GD). Subsequent to these findings, many others have reported associations between SNPs within and around the CLTA-4 region and rheumatoid arthritis (Lei et al, 2005), celiac disease (Hunt et al, 2005), type I diabetes (Jung et al, 2009), myasthenia gravis (Wang et al, 2008) and autoimmune pancreatitis (Chang et al, 2007). Furthermore, the CTLA-4 gene has also been implicated in other autoimmune disorders like Hoshimoto's Thyroiditis (HT) (Kotsa et al, 1997), Addison's disease (Vaidya et al, 2002) and Multiple sclerosis (Kouki et al, 2000).…”