Abstract
Contrasting results exist on the association between CTLA-4 rs231775 and acute rejection in kidney transplant recipients. We herein conducted an updated systematic review with meta-analysis and trial sequential analysis (TSA) to clarify this relationship and to establish whether the current evidence is sufficient to draw firm conclusions. In addition, noteworthiness of significant pooled odds ratios (ORs) was estimated by false positive report probability (FPRP). A comprehensive search was performed through PubMed, Web of Knowledge, Cochrane Library and Open Grey up to October 2019. Fifteen independent cohorts, including a total of 5,401 kidney transplant recipients, were identified through the systematic review. Overall, no association was detected with the allelic (OR 1.07, 95% CI 0.88–1.30, P = 0.49), dominant (OR 0.94, 95% CI 0.73–1.22, P = 0.66) or the recessive (OR 1.18, 95% CI 0.97–1.43, P = 0.096) model of CTLA-4 rs231775. In each genetic model, the cumulative Z-curve in TSA crossed the futility boundary and entered the futility area. In addition, none of the significant genetic comparisons detected in the subsequent and sensitivity analyses or in previously reported meta-analyses were found to be noteworthy by FPRP. In conclusion, this study provides strong evidence that CTLA-4 rs231775 is not a clinically-relevant genetic risk determinant of acute rejection after renal transplantation.
Highlights
Contrasting results exist on the association between CTLA-4 rs231775 and acute rejection in kidney transplant recipients
CTLA-4 exerts its immunosuppressive function through a variety of mechanisms which include competition with the co-stimulatory CD28 molecule for binding to their shared B7 ligands (CD80/CD86) on the antigenpresenting cells (APC)[2], and interference with TCR-mediated signal transduction[3]
After exclusion of additional 87 not relevant papers, studies describing a total of cohorts were included in the systematic review of association between CTLA-4 rs231775 and risk of acute renal graft
Summary
Contrasting results exist on the association between CTLA-4 rs231775 and acute rejection in kidney transplant recipients. We conducted an updated systematic review with meta-analysis and trial sequential analysis (TSA) to clarify this relationship and to establish whether the current evidence is sufficient to draw firm conclusions. Noteworthiness of significant pooled odds ratios (ORs) was estimated by false positive report probability (FPRP). Fifteen independent cohorts, including a total of 5,401 kidney transplant recipients, were identified through the systematic review. None of the significant genetic comparisons detected in the subsequent and sensitivity analyses or in previously reported metaanalyses were found to be noteworthy by FPRP. This study provides strong evidence that CTLA-4 rs231775 is not a clinically-relevant genetic risk determinant of acute rejection after renal transplantation. Given the key role of CTLA4 on regulation of allograft rejection and t olerance[4,5], a great attention has been focused on the relationship between
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