Untitled

Abstract

Objectives: Costimulatory molecules are important factors determining the outcome of transplant. The aim of the present study was to investigate the effect of CTLA-4, CD28, PD-1, and ICOS gene polymorphisms on the outcome of kidney transplant. Materials and Methods: A total of 172 kidney transplant recipients were included in this study. There were 45 recipients (26%) who experienced acute rejection. The CTLA-4, PD-1, ICOS, and CD28 gene polymorphisms were evaluated by polymerase chain reaction and restriction fragment length polymorphism methods. Results: There were no differences between kidney transplant recipients with or without acute rejection in the distribution of genotypes and alleles of studied costimulatory molecules. Significant associations were observed between the AA genotype and the A allele of CTLA-4 1661 (P = .04, P = .05) and also CT and TT genotypes of PD-1.9 in the male compared with female subgroup of patients, with low frequency in the acute rejection group (P = .03; P = .04). Significant associations were observed between the AA genotype and the A allele of CTLA-4 -1661 (P = .02; P = .01) and also GA genotype of PD-1.3 (P = .03) in the male subgroup compared with female subgroup with low frequency of acute rejection. A significant association was observed between TC genotype of CD28 in the female compared with male subgroup of patients with high frequency of acute rejection (P = .05). Conclusions:The above results suggest that genetic polymorphisms of costimulatory molecules function as sex-dependent risk factors for development of acute rejection. Further studies are needed in different populations.

CTLA-4 rs231775 and risk of acute renal graft rejection: an updated meta-analysis with trial sequential analysis

“…After removing of 50 duplicated records, the remaining 101 studies were evaluated by carefully reading of titles, abstracts and full texts. After exclusion of additional 87 not relevant papers, 14 studies describing a total of 15 cohorts were included in the systematic review of association between CTLA-4 rs231775 and risk of acute renal graft rejection 13 – 19 , 29 , 30 , 42 – 46 . The main characteristics of the identified studies are summarized in Table 1 .…”

“…CTLA-4 rs231775 was found in Hardy–Weinberg equilibrium (HWE) in 9 studies 14 – 19 , 30 , 43 – 45 ; it significantly deviated from HWE in three studies 16 , 29 , 42 , while it was not computable in two studies 13 , 46 which reported genotype data as a combined group (AG/AA vs. GG). The distribution of CTLA-4 rs231775 genotypes for each included cohort and timing of AR assessment after kidney transplantation is shown in Table 2 .…”

“…With regard to the study quality, the overall NOS scores ranged from 3 to 9 (median 7) (Table 1 ). Ten studies with a NOS score ≥ 7 were considered of higher quality 13 – 16 , 19 , 29 , 30 , 42 , 45 , 46 . Individual scores for each item of NOS in the identified studies are shown in Supplementary Material, Table S2 .…”

“…In the two most recent meta-analyses 24 , 25 , a higher risk of acute rejection has been reported in kidney transplant recipients under the GG vs. AA/AG model of CTLA-4 rs231775, but only the larger study 25 also detected a higher risk under the G vs. A model contrast. Given the recent publication of two novel primary studies on the risk of acute kidney transplant rejection 29 , 30 , we conducted an updated meta-analysis with trial sequential analysis (TSA) to better estimate the impact of CTLA-4 rs231775 and to determine whether the currently available evidence was sufficient and conclusive. In addition, false-positive report probability (FPRP) analysis was conducted to examine whether the significant findings of the present or previous meta-analyses were noteworthy.…”

“…However, all these studies did not take into account the risk of random errors due to sparse data and multiple meta-analytic up-dates 26 , 27 , which often result in false positive (type-1 error) and false negative (type-2 error) findings. Given that the above-mentioned issues can be addressed by application of trial sequential analysis (TSA) to meta-analytic results 28 and the recent publication of two novel primary studies 29 , 30 , we herein conducted an updated meta-analysis with TSA to assess reliability of the accumulated evidence on the relationship between CTLA-4 rs231775 and acute renal transplant rejection. In addition, noteworthiness of significant pooled estimates from the present and previous meta-analyses was estimated by false positive report probability (FPRP).…”