Cytotoxic T‐lymphocyte antigen 4 gene +49A/G polymorphism significantly associated with susceptibility to primary biliary cirrhosis: A meta‐analysis

Abstract

OBJECTIVE:To evaluate comprehensively the association of cytotoxic T-lymphocyte antigen 4 (CTLA-4) +49A/G polymorphism with susceptibility to primary biliary cirrhosis (PBC). METHODS:PubMed was used to search for the relevant published articles. The risk of PBC association with the CTLA-4 +49A/G polymorphism was estimated for each study in a random-effects model. Odds ratio (OR) and 95% confidence interval (CI) were estimated for each study. Risks to PBC were estimated by stratified analysis in patients with different ethnicity and antimitochondrial antibody (AMA) status, as well as histological stages. RESULTS:A total of 12 articles were included in the study. An association between PBC and CTLA-4 G allele was found, overall OR = 1.20, 95% CI 1.03-1.41 (P = 0.02). However, stratification by ethnicity indicated a significant association between the G allele and PBC in Asians (OR = 1.36, 95% CI 1.12-1.65, P = 0.002), but not in Caucasians (OR = 1.15, 95% CI 0.95-1.39, P = 0.15). Moreover, AMA positive patients carrying G allele were more susceptible to PBC compared with AMA negative patients (OR = 1.23, 95% CI 1.06-1.43, P = 0.007; OR = 0.98, 95% CI 0.71-1.34, P = 0.88, respectively). CONCLUSIONS:Polymorphism in exon 1 of CTLA-4 gene at position 49 may act as a candidate of susceptibility locus to PBC. However, larger studies with participants of varying ethnicity and stratified by clinical and laboratory characteristics are needed to validate our findings.KEY WORDS: cytotoxic T-lymphocyte antigen 4, single nucleotide polymorphism, primary biliary cirrhosis, meta-analysis. INTRODUCTIONPrimary biliary cirrhosis (PBC) is an autoimmune disease characterized by female preponderance and destruction of intrahepatic bile ducts that often results in cirrhosis and hepatic failure. [1][2][3][4] Twin and family aggregated data suggest that there is a significant genetic predisposition for PBC, and the complex features in etiology are thought to be resulted from the interaction between multiple genetic and environmental factors. 2011; 12; 428-435 doi: 10.1111/j.1751-2980.2011.00537.x 428 Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative regulator of T-cell immune response and is expressed predominantly in activated regulatory T-cells. [6][7][8] The absence of gene in knockout or CTLA-4-deficient mice leads to massive lymphoproliferative disorders, fatal multi-organ destruction and early death. Journal of Digestive Diseases2,3 The apparent association between pathological T-cell response and the development of PBC 9,10 suggests that CTLA-4 might be an attractive and candidate facilitator of the PBC susceptibility gene. Variants in the gene encoding immunoregulatory CTLA-4 were examined for the candidate susceptibility loci for PBC.CTLA-4 gene is located on chromosome 2q33; the adjacent gene encoding another two immunoregulatory proteins: inducible co-stimulator and its stimulatory counterpart (CD28).11 Significant amino-acid replacement resulted from single nucleotide polymorphisms (SNPs) has been described. For ...

Genetic Polymorphisms of Cytotoxic T-Lymphocyte Antigen 4 in Primary Biliary Cholangitis: A Meta-Analysis

“…For patients in cases, the frequencies of allele and genotype in rs231775 and rs231725 were increased more significantly than those in controls. As to allele, the results of rs231775 were similar to the results of five published meta-analyses by Eskandari-Nasab et al [39], Huang et al [23], Miyake et al [24], Li et al [25], and Chen et al [14]. Li and Miyake indicated that the G allele might be connected with PBC as a risk factor.…”

“…Recent study showed that PBC was significantly associated with some concrete gene polymorphisms [14]. Since PBC displays characteristics of autoimmunity, more and more studies concentrated in associations between genetic polymorphism and variations of autoimmunity.…”

High Levels of Soluble Ctla-4 Are Present in Anti-Mitochondrial Antibody Positive, but Not in Antibody Negative Patients with Primary Biliary Cirrhosis

“…First of all, they are reminiscent of similar observations reported by a number of research groups, including our own, in other autoimmune diseases (both systemic and organ-specific) [26]–[31], [33], [34], and in other immunological or haematological disorders, such as IgE-mediated reaction to hymenoptera venom [35], or acute lymphoblastic leukemia (ALL) in paediatric patients [36]. In some of these conditions, sCTLA-4 concentrations appeared to be somehow correlated with disease activity or outcome (e.g.…”

“…Finally, there is still a debate about the spliced/shaded nature of the soluble variant of CTLA-4 [27], [34], [36], [39]. Moreover, the relationship between CTLA-4 polymorphism(s) described associated with autoimmune diseases (including PBC) [33] and the ability to produce the spliced soluble form of the molecule has been not yet elucidated.…”

A Literature Review of Concomitant Primary Biliary Cirrhosis and GravesÂ’ Disease

“…Although some studies have reported that the PTPN22 polymorphism C1858T is associated with GD, it has not been observed to influence the risk of PBC in previous studies [28,29]. However, some studies have suggested that polymorphism in exon 1 of the CTLA-4 gene at position 49 (+49A/G, rs231775) may influence the risk of GD [27,30] and also the risk of PBC [31][32][33]. Therefore, genetic factors such as CTLA-4 may be a candidate for a susceptibility locus driving concomitant cases of PBC and GD, although further investigations to identify common genetic factors in both PBC and GD are warranted.…”