• S Romeo, F Sentinelli, S Dash, G S H Yeo, D B Savage, F Leonetti, D Capoccia, M Incani, C Maglio, M Iacovino, S O'Rahilly, and M G Baroni.
• Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, UK. sr517@medschl.cam.ac.uk
• Int J Obes (Lond). 2010 Jan 1; 34 (1): 190-4.

ContextThe 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.ObjectiveTo determine whether the PNPLA3 variant alters the susceptibility of morbidly obese subjects to develop liver injury and metabolic sequelae.Participants And MethodsThe 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 MeasuresIndices of liver injury (alanine transaminase (ALT), aspartate transaminase (AST)), glucose tolerance and insulin resistance were measured.ResultsMarkers 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.ConclusionObese Southern Europeans carrying the 148M allele have increased indices of liver damage uncoupled from proxy measures of insulin resistance.

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