14 A P value equal to or less than 0.05 was considered statistically significant. All calculations were performed using the Comprehensive Meta-Analysis computer program (Biostat, Englewood, NJ). We evaluated 16 studies that met the selection criteria and that were identified using the search strategy described in Supporting Fig. 1. Studies characteristics are shown in Table 1. Data from one study that fulfilled the eligibility criteria was included after personal contact with the investigators15; data on one further study was unavailable because in the article the authors did not disclose the raw data and our attempts to contact the authors were unsuccessful.16 All the studies scored well in

terms of adequate descriptions of selection criteria and reference JQ1 solubility dmso test, blind assessment of the reference test, and the availability of clinical data. A general critique concerns the observation that information about

genotype counts per evaluated phenotype was scarcely found across the studies. Eleven studies were hospital-based case-control studies,2-6, 15, 17-21 and the other five were population-based case-control studies,1, 22-24 or family-based studies.25 Information about liver biopsy was available in six studies,2-6, 17 and data about disease severity was analyzed in 2,651 patients with NAFLD; ALT levels according to the rs738409 genotypes were available in 11 studies.1, 2, 5, 6, 15, 17-21, 24 Genotyping for rs738409 was carried out across studies using Taqman assay in 111, 5, http://www.selleckchem.com/products/KU-60019.html 6, 17-24 studies, by allele-specific oligonucleotides in two studies,2, 15 and by Sequenom MassARRAY iPLEX Gold platform (Sequenom, San Diego, CA) in the remaining three studies.3, 4, 25 Data regarding fatty liver disease as a disease trait extracted from 11 studies included 5,100 individuals,2-4, 6, 15, 17, 18, 20, 23-25 and, as expected, the analysis showed a significant association between fatty liver and the rs738409 variant either in the fixed or the random model (P < 1 × 10−9) (Fig. 1a); details of the association stratified by age are shown in Supporting Fig. 2. At any rate, we did not observe heterogeneity

among studies aminophylline as assessed by the Q statistic (P = 0.33), I2: 11.97. From the Begg and Mazumdar’s rank correlation test (two-tailed P = 0.15), it seems that there was no publication bias. The evaluation of the risk associated with heterozygosity for the variant and fatty liver as a dichotomic variable also showed a significant association with the G allele. Interestingly, this analysis suggests that rs738409 exerts an additive effect on the susceptibility to develop NAFLD (Fig. 7); the details of the association analysis results for NAFLD and the CG versus CC genotypes are given in Supporting Table 1. In addition, we found five homogeneous reports (P = 0.22, I2: 27.5) that reported retrieval data about the measurement of liver fat content (determined using hydrogen magnetic resonance spectroscopy [H-MRS]) according to the rs738409 genotypes.