Relationship of CTLA-4 exon 1 A49-->G polymorphism with sCTLA-4 and Th1/Th2 bias in idiopathic dilated cardiomyopathy

Abstract

To investigate the association of cytotoxic T lymphocyte associated antigen-4 (CTLA-4) gene exon 1 A49-->G polymorphism with the genetic susceptibility to idiopathic dilated cardiomyopathy (IDC) in Chinese Han nationality. Peripheral blood samples were collected from 48 patients with IDC, 31 males and 17 females, and 50 sex- and age-matched normal controls. ELISA was used to examine the cytokines: sCTLA-4, gamma-interferon (IFN-gamma), and interleukin-4 (IL-4)with the ratio of IFN-gamma/IL-4 as an indicator for Th1/Th2 bias. PCR-RFLP was used to analyze the A/G polymorphism of CTLA-4 exon 1 A49-->G. The relationship of CTLA-4 genotype and alleles frequencies with sCTLA-4, IFN-gamma and IFN-gamma/IL-4 was evaluated by linear regression analysis. Compared with the normal controls, the frequencies of GG genotype (0.6042 and 0.7396, P = 0.012) and the G allele (0.36 and 0.56, P = 0.008) were significantly increased in the patients with IDC. Increased serum sCTLA-4 was found in the IDC group compared with the controls (1.87 microg/L +/- 1.06 microg/L vs. 0.54 microg/L +/- 0.19 microg/L, P < 0.05). IFN-gamma was significantly lower in the IDC group than in the control group (16 ng/L +/- 6 ng/L vs. 30 ng/L +/- 10 ng/L, P < 0.05). The ratio of IFN-gamma/IL-4 was significantly in the IDC group than in the control group (1.63 +/- 0.50 vs. 3.01 +/- 0.89, P < 0.05). No statistically difference was found in the IL-4 level between the two groups. Linear regression analysis manifested significant interrelationship between the GG genotype, G allele frequencies and serum sCTLA-4 (r = 0.57, P = 0.021), IFN-gamma/IL-4 ratio (r = 0.42, P = 0.028) in the IDC group. While no correlation was found for AA, AG genotype and the A allele frequency. CTLA-4 gene exon 1 A49-->G substitution is associated with an increased IDC genetic susceptibility, which implicates that the CTLA-4 gene may have a significant role in IDC, possibly via a Thr-->Ala change in CTLA-4 signal peptide, with a result of functional change of sCTLA-4. The bias of Th1/Th2 paradigm is associated with the increased sCTLA-4 level under certain background of immunogenicity.