特发性扩张型心肌病CTLA-4基因外显子A/G多态性与sCTLA4及Th1/Th2偏离的相关性研究

目的探讨细胞毒性T淋巴细胞相关抗原4(CTLA4)基因外显子1A49→G多态性与特发性扩张型心肌病(IDC)遗传易感性的关系。方法采用聚合酶链反应限制性片段长度多态性(PCRRFLP)分析IDC(48例)及正常对照(50名)CTLA4基因外显子49位点A→G多态性;ELISA检测血清sCTLA4,IFNγ及IL4水平,以IFNγ/IL4比值作为Th1/Th2偏离指标。结果IDC组GG基因型和G等位基因频率显著高于对照组(P=0.012,P=0.008);IDC组与对照组相比sCTLA4水平较高(1.87μg/L±1.06μg/L,0.54μg/L±0.19μg/L,P<0.05);IFNγ水平较低(16ng/L±6ng/L,30ng/L±10ng/L,P<0.05);IFNγ/IL4比值较低(1.63±0.50,3.01±0.89,P<0.05);两组间IL4差异无统计学意义。IDC组GG基因型及G等位基因频率与sCTLA4水平(r=0.57,P=0.021)及IFNγ/IL4比值(r=0.42,P=0.028)相关。结论CTLA4基因外显子A49→G多态性与IDC易感性相关。

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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.