Gene polymorphisms and risk of acute renal graft rejection: A field synopsis of meta-analyses and genome-wide association studies

In the present study we systematically re-analyzed results from meta-analyses and genome-wide association studies (GWASs) to assess the credibility of genetic associations with acute rejection risk in renal transplantation. A comprehensive literature search was performed on PubMed, Web of Knowledge, Cochrane library, and Open Grey up to July 2019. Methodological quality of systematic meta-analyses was assessed by the AMSTAR tool. Credibility of genetic associations was assessed by employing the Venice criteria and two Bayesian statistical approaches, the false positive report probability (FPRP) and the Bayesian false discovery probability (BFDP). Sixteen systematic meta-analyses, with a moderate-high quality score (median AMSTAR score: 9, range: 6–11) and 1 GWAS fulfilled the inclusion criteria. Overall, our systematic re-analysis has identified 9 polymorphic variants in 8 genes (ACE, CD28, CTLA-4, CYP3A5, IFNG, TNF-α, PTPRO and CCDC67) as potential risk factors for acute renal graft rejection. At the pre-specified prior probability of 0.001, the 2 SNPs identified by the GWAS (rs7976329 and rs10765602) showed no evidence of noteworthiness under FPRP or BFDP, indicating the possibility of false-positive associations. After applying the Venice criteria in combination with FPRP and BFDP to results from systematic meta-analyses, TT/AT vs AA of IFNG +874 T/A reached moderate epidemiological credibility, while weak evidence of association was found for all the other genetic comparisons. Well-designed GWASs and large replication studies with updated meta-analyses are still needed to identify reliable genetic predictors of acute renal graft rejection.