Association of HLA-G promoter and 14-bp insertion-deletion variants with acute allograft rejection and end-stage renal disease

Abstract

The aim of this study was to investigate the HLA-G 14-bp insertion/deletion (I/D) polymorphism among end-stage renal disease (ESRD) patients. Cytomegalovirus (CMV) infection, acute allograft rejection (AR) and overall survival after renal transplantation was investigated in 300 ESRD patients and 302 age, sex and ethnicity-matched controls. Sequencing was performed to evaluate the impact of HLA-G promoter region single-nucleotide polymorphisms (SNPs) whereas semi-quantitative PCR method was used to determine the probable HLA-G expression pattern among ESRD and AR cases. Further, soluble human leukocyte antigen (HLA)-G (sHLA-G) expression levels were compared in AR vs non-AR cases in the light of HLA-G 14-bp I/D polymorphism. Increased risk was found for 14-bp D/D (deletion-DD) genotype and 14-bp D allele [DD: odds ratio (OR)=1.46, 95% confidence interval (CI)=1.03-2.06, P value=0.0358; D: OR=1.29, 95% CI=1.03-1.62, P value=0.0277], respectively for ESRD and CMV infection (DD: OR=2.70, 95% CI=1.45-5.05, P value=0.0021; D: OR=1.94, 95% CI=1.22-3.08, P value=0.0052). Nearly fourfold (OR = 3.62, 95%CI=1.61-8.14, p=0.0039) risk was observed for 14-bp I/I (insertion-II) genotype for AR. Survival analysis showed increased overall survival (OS) (AR or death) for 14-bp D/D genotype. HLA-G promoter region sequencing was carried out among 60 ESRD patients and 100 normal controls which showed increased risk for -964 G>A, -725 C>G/T and -486 A>C SNPs. -964 G>A and -725 C>G/T SNPs showed risk association for AR patients. High level of HLA-G transcripts was observed among non-AR patients. Further soluble HLA-G (sHLA-G) showed increased levels in ESRD patients (mean±SEM; 62.16±2.43U/ml) as compared to controls (mean±SEM; 21.06±3.89U/ml) (P=<0.0001). The 14-bp I/I, 14-bp I/D and 14-bp D/D genotypes showed significantly higher levels of sHLA-G among non-AR as compared to AR patients. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.