CTLA-4 gene polymorphism regulates CTLA-4 mRNA stability and protein level in patients with ulcerative colitis / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To investigate the effect of (AT)n repeat polymorphism of the 3'untranslated region in cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) gene on CTLA-4 mRNA stability and full length (flCTLA-4) and soluble CTLA4 (sCTLA-4) expression in ulcerative colitis (UC).</p><p><b>METHODS</b>flCTLA-4 mRNA in colonic biopsies and sCTLA-4 mRNA stability in peripheral blood mononuclear cells of UC patients were measured by quantitative PCR and half-life, respectively. The protein expression of flCTLA-4 in colonic biopsies and sCTLA-4 in sera of UC patients were determined by immunohistochemistry and enzyme-linked immunosorbent assay, respectively. The polymorphism of CTLA-4 (AT)n repeats in 300 UC and 700 age and sex matched healthy controls was genotyped by fluorescent PCR.</p><p><b>RESULTS</b>Among the UC patients, sCTLA-4 mRNA expression levels were decreased in active disease compared to non-active disease (P= 0.004). Carriers of the longer alleles of the (AT)n repeats expressed lower levels of flCTLA-4 and sCTLA-4 mRNA and sCTLA-4 protein than those of the shorter alleles in UC (all P< 0.01), and mRNA with long (AT)n repeat alleles has shorter half-life than mRNA with short alleles and, hence, are unstable. The frequency of long allele carriers of CTLA-4 (AT)n repeats was significantly higher in UC patients than in the healthy controls (22.0% vs. 6.3%, P< 0.01, OR= 4.21, 95% CI: 2.79-6.33), and associated with extensive colitis (P= 0.008).</p><p><b>CONCLUSION</b>CTLA-4 gene expression levels were associated with (AT)n repeat polymorphisms in UC patients. The expression of CTLA-4 mRNA and protein were decreased in carriers of the longer alleles of the (AT)n repeats of CTLA-4 gene. This study suggests that CTLA-4 plays an important role in genetic risk and pathophysiology for UC in central China.</p>

Association of cytotoxic T lymphocyte antigen-4 promoter C-658T polymorphism with ulcerative colitis in Chinese / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To investigate the association of gene polymorphism of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) with ulcerative colitis (UC) in Chinese.</p><p><b>METHODS</b>One hundred and seventeen patients with UC and 246 healthy controls were genotyped for the polymorphisms of C-658T in the promoter and C61T at the 3' untranslated region of the CTLA-4 gene using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) and polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP), respectively. The genotype and allele frequencies of the two groups were calculated and compared by chi square test.</p><p><b>RESULTS</b>The frequency of TT+CT genotype at the CTLA-4 gene C-658T in the promoter was significantly higher in UC patients than that in healthy controls (P=0.015). The frequency of the T allele at this locus was also significantly higher in UC patients than that in the controls (P=0.033). The frequencies of TT genotype and T allele at the C-658T locus were highly associated with extensive colitis in UC patients (P=0.037, and P=0.0067, respectively).</p><p><b>CONCLUSION</b>The T allele of CTLA-4 promoter C-658T locus was highly associated with UC in Chinese Han of central China.</p>