Cargnin Sarah, Galli Ubaldina, Lee Kwang Seob, Shin Jae Il, Terrazzino Salvatore
Department of Pharmaceutical Sciences and Interdepartmental Research Center of Pharmacogenetics and Pharmacogenomics (CRIFF), University of Piemonte Orientale, Largo Donegani 2, Novara 28100, Italy.
Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Novara, Italy.
Transplant Rev (Orlando). 2020 Jul;34(3):100548. doi: 10.1016/j.trre.2020.100548. Epub 2020 May 11.
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.
在本研究中，我们系统地重新分析了荟萃分析和全基因组关联研究（GWAS）的结果，以评估肾移植中与急性排斥风险的遗传关联的可信度。截至2019年7月，在PubMed、Web of Knowledge、Cochrane图书馆和Open Grey上进行了全面的文献检索。系统荟萃分析的方法学质量通过AMSTAR工具进行评估。通过采用威尼斯标准和两种贝叶斯统计方法，即假阳性报告概率（FPRP）和贝叶斯假发现概率（BFDP），评估遗传关联的可信度。16项系统荟萃分析，质量评分中等偏高（AMSTAR评分中位数：9，范围：6-11），1项GWAS符合纳入标准。总体而言，我们的系统重新分析已确定8个基因（ACE、CD28、CTLA-4、CYP3A5、IFNG、TNF-α、PTPRO和CCDC67）中的9个多态性变体为急性肾移植排斥的潜在危险因素。在预先设定的先验概率为0.001时，GWAS鉴定的2个单核苷酸多态性（SNP，rs7976329和rs10765602）在FPRP或BFDP下没有显示出值得注意的证据，表明存在假阳性关联的可能性。将威尼斯标准与FPRP和BFDP应用于系统荟萃分析的结果后，IFNG +874 T/A的TT/AT与AA达到了中等的流行病学可信度，而所有其他基因比较均发现关联证据较弱。仍需要设计良好的GWAS和进行更新的荟萃分析的大型重复研究，以确定急性肾移植排斥的可靠遗传预测指标。
