Despite the specific pathological mechanism of NAFLD still needs to be explored. Nevertheless, research increasingly revealed that genetic predisposition plays an crucial intrinsic role in the occurrence and development of NAFLD. In addition, SNPs in human might be one of the critical steps to disclose the genetic factor for NAFLD pathogenesis. With further research, GSTs genes as a genetic factor have obtained increasing attention over current years. So far, the present researches have been implemented concerning the relationship of GSTM1, GSTT1 and GSTP1 genes polymorphism and the NAFLD vulnerability with inconsistent conclusions. This inconsistency might be caused by factors like limited sample sizes, confounding factors, as well as clinical heterogeneity of NAFLD. Therefore, we collected the existing evidence and looked into the associations of GSTs genes SNPs and the NAFLD vulnerability via meta-analysis, which could combine data from individual studies, examine and explain the heterogeneity, and increase the statistical power. In conclusion, the merged data suggested a significant correlation between GSTM1, GSTT1 and GSTP1 genes SNPs and the NAFLD vulnerability. Of note, the recalculated P-value, ORs and 95%CIs did not change substantially after the omission of an individual study.
In a word, we performed a meta-analysis of 7 case-control studies that satisfied the inclusion criteria. It should be noted that the current comprehensive analysis was more necessary and meaningful owing to the conclusions of qualified case-control studies are conflicting and contradictory. In this work, it demonstrated that the frequency of GSTM1 null, GSTT1 null and GSTP1-Val allele genotypes in NAFLD patients was remarkably higher than that in healthy subjects. Namely, these genotypes have a significantly increased risk for NAFLD. Furthermore, the outcomes of the meta-analysis were considered to be statistically robust and reliable according to the sensitivity analysis.
GSTs are enzymes in the second-stage detoxification system, which can not only catalyze reduced glutathione sulfhydryl groups, but also neutralize lipid and DNA oxidation products, and have protective effects against endogenous oxidative stress and exogenous toxins [25–26]. Among them, GSTT1, GSTM1 and GSTP1 have garnered considerable attention from various research teams around the world in the recent decade . Several investigations have disclosed that homozygous deletion of GSTM1 and GSTT1 genes (GSTM1 null and GSTT1 null) were connected with lack of relevant GST isoenzyme synthesis and augmented the susceptibility of genetic damage [28–29]. Furthermore, the double null genotypes of GSTT1 and GSTM1 genes could decline the activity of sulfhydryl binding so as to induce insufficient activity of detoxification in the body [30, 31]. GSTP1 gene polymorphism is the outcome of a single nucleotide substitution of A to G, which leads to valine instead of isoleucine in the binding site of GSTP1 and alters catalytic activity of enzyme [32, 33]. Previous reports also suggested that GSTM1/GSTT1 null or GSTP1-Val genotypes were remarkably associated with the vulnerability of hepatis B virus, hepatocellular carcinoma, alcoholic cirrhosis, and NAFLD [34–39]. Moreover, the GSTM1 null genotype was reported to be more common in NAFLD patients than in controls, and GSTP1-Val was proved to be a hazard for NAFLD vulnerability in the Iranian population .
Up to now, this is the first synthetical study on the relationship between GSTs polymorphisms and NAFLD vulnerability. There were several strengths in this study. First, to gather a maximum amount of relevant literature, a comprehensive search strategy was adopted to retrieve eligible studies in both English and Chinese databases. Besides, the methodological quality of studies was evaluated via NOS, which allowed for the judgment of potential risk of bias. According to the NOS, all eligible studies were of high methodological quality. Furthermore, sensitivity analyses were carried out in this study, which guaranteed the reliability of the findings.
Nevertheless, there still existed several drawbacks should be acknowledged. First, only seven studies were included, the statistical power was limited, and subgroup analyses were not carried out because of the limited degree of freedom. Second, the absence of HWE in individual studies may lead to information bias. Third, We ignored the synergistic effect of polymorphism at other sites of NAFLD because only three loci in the GST gene were studied in association with susceptibility to NAFLD. Thus, interactions between these loci and genes may result in concealing or amplifying the actual function of individual loci or genes. Leave aside these drawbacks, this study is the first to provide a more accurate and powerful evidence on the association between GSTM1, GSTT1 and GSTP1 genes polymorphisms and NAFLD vulnerability.