ORIGINAL ARTICLE Morbid obesity exposes the association between PNPLA3 I148M (rs738409) and indices of hepatic injury in individuals of European descent S Romeo 1,2 , F Sentinelli 2 , S Dash 1 , GSH Yeo 1 , DB Savage 1 , F Leonetti 3 , D Capoccia 3 , M Incani 2 , C Maglio 3 , M Iacovino 4 , S O’Rahilly 1 and MG Baroni 2 1 Institute of Metabolic Science, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK; 2 Department of Medical Sciences, Endocrinology and Metabolism, University of Cagliari, Cagliari, Sardinia, Italy; 3 Department of Clinical Sciences, University of Rome La Sapienza, Rome, Italy and 4 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA 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 ¼ 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 ¼ 2.2  10 5 and 0.001, respectively). In all, 50% of 148M risk allele homozygotes had pathological levels of ALT (440 U l 1 ) compared with 25% of 148I allele homozygotes (P ¼ 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. International Journal of Obesity advance online publication, 20 October 2009; doi:10.1038/ijo.2009.216 Keywords: non-alcoholic fatty liver disease (NAFLD); patatin-like phospholipase domain containing 3 (PNPLA3); insulin resistance Introduction Non-alcoholic fatty liver disease (NAFLD) is a burgeoning health problem in Western countries. It has been estimated that 30% of the population in the United States has hepatic steatosis. 1 A body of evidence shows that NAFLD is highly related to obesity and its metabolic consequences such as insulin resistance and dyslipidaemia. 2 In addition to altering metabolic risk, hepatic steatosis is also associated with significant liver disease in some patients. As many as 10–20% of patients with NAFLD develop steatohepatitis 2 and approximately 5% proceed to liver cirrhosis within 10 years of diagnosis. 3 The biological determinants of disease progression are currently poorly understood. We recently identified 4 a nonsynonymous sequence variation I148M (rs738409) in the PNPLA3 gene. It was strongly associated with increased hepatic fat content in three ethnic groups (African, European Americans and Hispanics, P ¼ 5.9  10 10 ) of the Dallas Heart Study, with the largest effect found in the Hispanics. PNPLA3 is a 481-residue protein with lipase activity in vitro 5,6 and it is highly expressed in the liver. 6 Moreover, the frequency of the risk allele (148M) mirrored the prevalence of cirrhosis in the three ethnic groups, with highest prevalence again in Hispanics followed by European Americans and African Americans. 4 When alanine transaminase (ALT), a marker of hepatic injury, was evaluated in these populations, an Received 28 May 2009; revised 18 August 2009; accepted 23 August 2009 Correspondence: Dr S Romeo, Institute of Metabolic Science, University of Cambridge, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK. E-mail: sr517@medschl.cam.ac.uk International Journal of Obesity (2009) 1–5 & 2009 Macmillan Publishers Limited All rights reserved 0307-0565/09 $32.00 www.nature.com/ijo