Association of functional genetic variants of transcription factor Forkhead Box P3 and Nuclear Factor-κB with end-stage renal disease and renal allograft outcome

• FOXP3 SNPs rs2232365 and rs3761548 showed 3- to 3.5-folds risk for ESRD and ARE
• NF-kB1 SNPs rs28362491 and rs696 showed 2- to 4-folds risk for ESRD and ARE
• MDR analysis (six factor) revealed 6-folds risk for ESRD and 23-folds risk for ARE
• rs2232365, rs3761548, rs28362491 and rs696 SNPs showed lowest overall survival
• Moderate LD exists between rs2232365, rs3761548, rs5902434 and rs2294021 tag-SNPs

BackgroundThe transcription factor FOXP3 and NF-κB regulates the expression of various genes that play an important role in the regulation of renal inflammation. We investigated the association of FOXP3 (rs2232365, rs3761548, rs5902434 and rs2294021) and NF-κB1 (rs28362491 and rs696) gene variants in susceptibility and prognosis of end stage renal disease (ESRD) and renal allograft outcome.MethodsWe genotyped four common polymorphisms of FOXP3 and two-tag SNPs of NF-κB1 genes in 350 ESRD cases and 350 controls. Single marker analysis and SNP–SNP interaction model (one to six way combinations) was used for determination of clinical outcome of ESRD and acute rejection episode (ARE).ResultsWe observed significantly higher occurrence of mutant genotypes of tag-SNPs of FOXP3 namely; rs2232365 and rs3761548 along with NF-kB1 namely; rs28362491 and rs696 in ESRD and ARE cases, suggested a risk association for ESRD and ARE. Interestingly, multifactor dimension reduction analysis suggested an increased risks of nearly 6-folds for ESRD and 23-folds for ARE cases under the six factors model which consists of tag-SNPs of FOXP3 (rs2232365, rs3761548, rs5902434 and rs2294021) and NF-kB1 (rs28362491 and rs696). Kaplan–Meier survival analysis showed the lowest overall survival for mutant genotypes compared with wild and heterozygous genotypes of rs2232365 and rs3761548 tag SNPs of FOXP3 as well as NF-kB1 tag-SNPs rs28362491 and rs696 in renal allograft recipients. The crude and adjusted hazard ratios in univariate and multivariate Cox regression models showed almost 2-folds to 3-folds risk for overall survival against mutant genotypes of tag-SNPs of FOXP3 (rs2232365 and rs3761548) and NF-kB1 (rs28362491 and rs696) genes.ConclusionsThese results suggest that variants of transcription factor FOXP3 and NF-kB1 might be associated with increased risk to the clinical outcome of ESRD and renal allograft survival.