title: 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 ± 2.43 U/ml) as compared to controls (mean ± SEM; 21.06 ± 3.89 U/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.
authors.affiliation: Department of Medical genetics, Sanjay Gandhi Post-graduate Institute of Medical Sciences, Lucknow, India; Department of Anatomy, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India.
authors.forename: M K
authors.initials: MK
authors.lastname: Misra
authors.forename: S
authors.initials: S
authors.lastname: Prakash
authors.forename: R
authors.initials: R
authors.lastname: Kapoor
authors.forename: S K
authors.initials: SK
authors.lastname: Pandey
authors.forename: R K
authors.initials: RK
authors.lastname: Sharma
authors.forename: S
authors.initials: S
authors.lastname: Agrawal
mesh_terms: D064591:Allografts / Q000378:metabolism*; D020029:Base Pairing / Q000235:genetics; D003586:Cytomegalovirus Infections / Q000150:complications / Q000235:genetics; D003710:Demography; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006084:Graft Rejection / Q000150:complications / Q000235:genetics*; D059951:HLA-G Antigens / Q000235:genetics*; D006801:Humans; D054643:INDEL Mutation / Q000235:genetics*; D053208:Kaplan-Meier Estimate; D007676:Kidney Failure, Chronic / Q000150:complications / Q000235:genetics*; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012995:Solubility
chemical_list: D059951:HLA-G Antigens
keywords: HLA-G 14-bp insertion/deletion; HLA-G 5′ URR; acute allograft rejection; cytomegalovirus infection; end-stage renal disease; soluble HLA-G