Although heterogeneity was addressed statistically by applying a random effect model, we aimed to further investigate its potential sources where possible. Thus, the full dataset was utilized for investigation of heterogeneity by sensitivity analysis. In some studies, NAFLD patients were mostly recruited because of elevated

ALT levels; thus, there was a marked enrichment of patients with NASH and few of them showed simple steatosis. Moreover, potential selection bias when selecting patients for liver biopsy may also explain the heterogeneity. The current meta-analysis is useful to clearly

understand buy Apoptosis Compound Library the magnitude of the effect of rs738409 on the histological severity of NAFLD, which is far beyond the small magnitude observed for common variants on complex traits,29 and may be explained by the nonsynonymous nature of the polymorphism that induces an amino acid change of I for M (missense Ileu (ATC) Met (ATG)) with possible functional consequences.30 A potential limitation of this study is its reliance on two studies,3, 4 which included cases from the Nonalcoholic Steatohepatitis Clinical Research Network Ku-0059436 ic50 (NASH CRN). This fact may limit the research results to liver disease severity. Hence, to circumvent this potential caveat, we performed the whole analysis about all the NAFLD-related phenotypes excluding the smaller study in terms of sample size3 (details in Supporting MCE公司 Table 3). We observed a very similar magnitude in the variant effect on the analyzed phenotypes. Data about a GWAS on NAFLD performed in female adults also from the NASH CRN was not included in this meta-analysis because rs738409 was not captured by the chip.9 Although 15 SNPs in the PNPLA3 were captured by the GWAS and none of them showed

significant association with NAFLD, it is important to note that among five variants, only rs2076211 was in moderate linkage disequilibrium (r2: 0.65) with rs738409 precluding any imputation even assuming access to the complete dataset. An interesting observation about the analysis of the significant association between rs738409 and liver enzymes is the 28% increase in serum levels observed in GG homozygous individuals, a relevant aspect that might be regarded when selecting patients for clinical trials, decision-making on indication of liver biopsy, and evaluation of the magnitude of any treatment response based on serum ALT levels.