Association of CTLA-4 Gene Polymorphism with End-Stage Renal Disease and Renal Allograft Outcome

Abstract

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is upregulated in effector-T-cells after activation that may alter signal transduction and subsequently cytokine production. The present study was designed to investigate the impact of CTLA-4+49 A>G (rs231775), -318 C>T (rs5742909), -658 C>T (rs11571317), -1147 C>T (rs16840252), -1661 A>G (rs4553808), +6230 A>G (rs3087243) SNPs, and microsatellite (AT)n repeat polymorphism among end-stage renal disease (ESRD), acute allograft rejection (AR), and delayed graft function (DGF) cases. In this regard, 350 ESRD patients and 350 controls were included. Polymerase chain reaction (PCR)-restriction fragment length polymorphism analysis method was used for genotyping of CTLA-4 SNPs, while PCR-polyacrylamide gel electrophoresis method was adopted for studying CTLA4 (AT)n polymorphism. The mutant genotype GG of CTLA-4+49A>G,+6230 A>G, and longer alleles of (AT)n repeats polymorphisms were risk associated with ESRD, AR, and DGF cases. The distribution of haplotype+49G:+6230G and GCTTGG (constructed by using 6 studied SNPs) showed risk association for ESRD, DGF, and AR cases. Further, linkage analysis demonstrated strong to moderate linkage disequilibrium in our study populations. The meta-analysis also revealed risk associations for AR cases against GG genotype of CTLA-4+49A>G SNP, while CTLA-4 -318C>T polymorphism showed no correlation against TT genotype among AR cases. Subsequently, no correlation was established against the CTLA-4 -318C>T, -658 C>T, -1147 C>T, and -1661 A>G SNPs in the promoter region. Survival analysis revealed risk associations against GG genotype of CTLA-4+49A>G, +6230 A>G SNP's with overall survival (OS), and higher hazard for the OS. These results suggested that CTLA-4 variants might be involved in susceptibility to ESRD, AR, and DGF.