Evaluation of polymorphism, hypermethylation and expression pattern of CTLA4 gene in a sample of Iranian patients with schizophrenia

Abstract

The cytotoxic T lymphocyte-associated antigen 4 gene (CTLA4) has a crucial role in regulation of T cell proliferation and mediates T cell apoptosis by encoding the T cell receptor. Schizophrenia (SCZ) patients often have abnormalities in terms of the function and development of the immune system. The aim of the present study was to investigate promoter variation and expression profile of the CTLA4 gene in patients with SCZ. We isolated genomic DNA from peripheral blood of 94 individuals with SCZ and 99 healthy control subjects. Genotypic analysis of CTLA4 (-318) was done by Tetra-ARMS-PCR. Methylation-specific polymerase chain reaction (MS-PCR) was used to estimate promoter hypermethylation of the CTLA4 gene. In addition, we investigated CTLA4 mRNA levels in 34 blood samples from cases and healthy controls using real-time reverse transcription PCR. The CT genotype of CTLA4 has a significantly protective effect on the risk to SCZ (OR=0.44; 95% CI 0.18-1.06, P=0.007) in comparison with the wild CC genotype. Promoter methylation of the CTLA4 gene increased the risk of disease statistically (OR=3.82, 95% CI 1.34-10.9, P=0.015) in cases when compared to healthy controls in blood samples. The mRNA expression level results showed statistically significant differences (P<0.0001) between cases (n=17) and healthy controls (n=17). To the best of our knowledge, this is the first evidence showing that promoter methylation of the CTLA4 gene along with transition of C to T was linked to a significantly higher expression of CTLA4 mRNA levels in patients with SCZ.

Gene expression profiling in peripheral blood mononuclear cells of early-onset schizophrenia

“…Among the 84 DE genes listed above, SLC18A1 has been reported to be associated with SZ [7] , [8] . In addition, CTLA4 was also identified showing a high expression level in SZ [9] which is consistent with the results from our study. Through our description above, we believe that this dataset will be useful for the exploration of SZ's pathogenesis in the future.…”

Genomics and epigenomics in novel schizophrenia drug discovery: translating animal models to clinical research and back

“…Brain tissue Saliva 5-HTT Hypermethylation of 5-HTT promoter [83] 94/99 Peripheral blood CTLA4 Hypermethylation [84] 11/12 Prefrontal cortex SOX10 Hypermethylation [85] 31/31 Brain tissue GABRB2 Epigenetic regulation of GABRB2 observably disrupted in schizophrenia [86] 36/36 Prefrontal cortex GAD1 H3K4 hypomethylation due to mixed-lineage leukemia 1-regulated gene dysfunction [87] 28/26 Peripheral blood leukocytes Global DNA methylation No difference between schizophrenia patients and control [88] 20 pairs of discordant twins 8 pairs of concordant twins Peripheral blood Global DNA methylation RELN SOX10…”

DNA methylation patterns of protein coding genes and long noncoding RNAs in female schizophrenic patients

“…Epigenetic alterations can reflect the interaction between genetic factors and environmental ones in the development of SCZ [Abdolmaleky and Thiagalingam, 2011]. As the major component of epigenetic regulation, DNA methylation of GAD, RELN, COMT, SOX10, BDNF, and CTLA4 genes have been reported to be correlated with the risk of SCZ [Abdolmaleky et al, 2005[Abdolmaleky et al, , 2006Abdolmaleky and Thiagalingam, 2011;Grayson et al, 2005;Ikegame et al, 2013;Iwamoto et al, 2005;Kordi-Tamandani et al, 2013;Nohesara et al, 2011;Pun et al, 2011;Sharma et al, 2008;Tolosa et al, 2010].…”