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 BMI = 41 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 (P = 2.2 x 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 (P = 0.005). 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.