The TargetScan database [37] was used to provide mRNA target predictions for each miRNA in the miRNA-mRNA analysis, here using predicted and conserved targets. TargetScan prediction was accessed through the R-package targetscan.Hs.eg.db (version 0.2.0). 248 of the miRNAs we have profiled have predicted conserved targets, for each one of these we assessed if there was an association with their target mRNAs. We defined an overall association through a statistical gene set test using the mean-rank gene set enrichment method (MR-GSE) [36]. We started with modelling the association between each miRNA and the full set of mRNAs profiled using a linear fixed-effects model with one mRNA as response variable, and the miRNA together with gender, age, metabolic syndrome case/control status, and batch as covariates. The mRNAs were ranked by their miRNA-associated t-statistic, in this case we were performing an one-sided test to assess if there were evidence for anti-correlated enrichment (i.e. negative t-statistic). The null hypothesis in the MR-GSE test is that the set of predicted target mRNAs are randomly chosen from the full set (i.e. all mRNAs profiled), p-values were
