Morbid obesity exposes the association between PNPLA3 I148M (rs738409) and indices of hepatic injury in individuals of European descent

Context:The PNPLA3 I148M variant (rs738409) is robustly associated with hepatic steatosis. Intriguingly, initial findings in cohorts with a mean body mass index (BMI) of 30 kg m 2 also suggested that it is associated with elevated liver enzymes but not with insulin resistance and dyslipidaemia. Objective: To determine whether the PNPLA3 variant alters the susceptibility of morbidly obese subjects to develop liver injury and metabolic sequelae.Participants and methods:The study was carried out in 678 obese Italians (mean BMI41 kg m 2) who were genotyped for the I148M variant. All participants provided fasting blood samples and then underwent oral glucose tolerance tests.Main outcome measures:Indices of liver injury (alanine transaminase (ALT), aspartate transaminase (AST)), glucose tolerance and insulin resistance were measured.Results:Markers of hepatic injury such as ALT and AST were significantly higher in carriers of the 148M allele (P2.2 × 10 5 and 0.001, respectively). In all, 50% of 148M risk allele homozygotes had pathological levels of ALT (40 U l 1) compared with 25% of 148I allele homozygotes (P0.005). Glucose tolerance and insulin sensitivity were similar in all three genotypes.Conclusion:Obese Southern Europeans carrying the 148M allele have increased indices of liver damage uncoupled from proxy measures of insulin resistance.