Background: The adiponutrin (PNPLA3) p.I148M and transmembrane 6 superfamily member 2 (TM6SF2) p.E167K variants represent risk factors for non-alcoholic fatty liver disease (NAFLD). In this study, we assessed the effects of caloric restriction on liver phenotypes in NAFLD patients in relation to the PNPLA3 and TM6SF2 genotypes. Methods: We genotyped both variants in 143 individuals with NAFLD (55 females, age 18-74 years) and 180 controls (85 females, age 33-66 years). Liver steatosis was assessed using the ultrasound-based Hamaguchi score. A 4-month dietetic intervention, consisting of restriction of daily caloric intake without changes in physical activity, was performed. Results: Both PNPLA3 (p = 0.002) and TM6SF2 (p = 0.041) variants were associated with NAFLD before intervention. Overall, 88 patients completed the intervention, which led to a significant decrease of steatosis, ALT activities, body mass index, hip and waist circumferences, and waist-hip ratio (all p < 0.0001). Hepatic steatosis and anthropometric traits improved significantly (p < 0.05) in carriers of either PNPLA3 or TM6SF2 risk genotype. The improvement of phenotypic traits, apart from WHR (p = 0.02), was not modified by the presence of PNPLA3 or TM6SF2 variants. Conclusions: The PNPLA3 and TM6SF2 polymorphisms are associated with NAFLD assessed by the Hamaguchi score. Neither PNPLA3 nor TM6SF2 risk alleles impair the response to dietetic intervention in NAFLD.

Blachier M, Leleu H, Peck-Radosavljevic M, Valla DC, Roudot-Thoraval F: The burden of liver disease in Europe: a review of available epidemiological data. J Hepatol 2013;58:593-608.
Loomba R, Sanyal AJ: The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol 2013;10:686-690.
Cortez-Pinto H, Baptista A, Camilo ME, De Moura MC: Nonalcoholic steatohepatitis - a long-term follow-up study: comparison with alcoholic hepatitis in ambulatory and hospitalized patients. Dig Dis Sci 2003;48:1909-1913.
Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, Mullany EC, Biryukov S, Abbafati C, Abera SF, Abraham JP, Abu-Rmeileh NM, Achoki T, AlBuhairan FS, Alemu ZA, Alfonso R, Ali MK, Ali R, Guzman NA, Ammar W, Anwari P, Banerjee A, Barquera S, Basu S, Bennett DA, Bhutta Z, Blore J, Cabral N, Nonato IC, Chang JC, Chowdhury R, Courville KJ, Criqui MH, Cundiff DK, Dabhadkar KC, Dandona L, Davis A, Dayama A, Dharmaratne SD, Ding EL, Durrani AM, Esteghamati A, Farzadfar F, Fay DF, Feigin VL, Flaxman A, Forouzanfar MH, Goto A, Green MA, Gupta R, Hafezi-Nejad N, Hankey GJ, Harewood HC, Havmoeller R, Hay S, Hernandez L, Husseini A, Idrisov BT, Ikeda N, Islami F, Jahangir E, Jassal SK, Jee SH, Jeffreys M, Jonas JB, Kabagambe EK, Khalifa SE, Kengne AP, Khader YS, Khang YH, Kim D, Kimokoti RW, Kinge JM, Kokubo Y, Kosen S, Kwan G, Lai T, Leinsalu M, Li Y, Liang X, Liu S, Logroscino G, Lotufo PA, Lu Y, Ma J, Mainoo NK, Mensah GA, Merriman TR, Mokdad AH, Moschandreas J, Naghavi M, Naheed A, Nand D, Narayan KM, Nelson EL, Neuhouser ML, Nisar MI, Ohkubo T, Oti SO, Pedroza A, Prabhakaran D, Roy N, Sampson U, Seo H, Sepanlou SG, Shibuya K, Shiri R, Shiue I, Singh GM, Singh JA, Skirbekk V, Stapelberg NJ, Sturua L, Sykes BL, Tobias M, Tran BX, Trasande L, Toyoshima H, van de Vijver S, Vasankari TJ, Veerman JL, Velasquez-Melendez G, Vlassov VV, Vollset SE, Vos T, Wang C, Wang X, Weiderpass E, Werdecker A, Wright JL, Yang YC, Yatsuya H, Yoon J, Yoon SJ, Zhao Y, Zhou M, Zhu S, Lopez AD, Murray CJ, Gakidou E: Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2014;384:766-781.
Dyson J, Day C: Treatment of non-alcoholic fatty liver disease. Dig Dis 2014;32:597-604.
Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, Charlton M, Sanyal AJ; American Gastroenterological Association; American Association for the Study of Liver Diseases; American College of Gastroenterology: The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology 2012;142:1592-1609.
Promrat K, Kleiner DE, Niemeier HM, Jackvony E, Kearns M, Wands JR, Fava JL, Wing RR: Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology 2010;51:121-129.
Harrison SA, Fecht W, Brunt EM, Neuschwander-Tetri BA: Orlistat for overweight subjects with nonalcoholic steatohepatitis: a randomized, prospective trial. Hepatology 2009;49:80-86.
Sookoian S, Pirola CJ: Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology 2011;53:1883-1894.
Anstee QM, Day CP: The genetics of NAFLD. Nat Rev Gastroenterol Hepatol 2013;10:645-655.
Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, Boerwinkle E, Cohen JC, Hobbs HH: Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008;40:1461-1465.
Krawczyk M, Grünhage F, Zimmer V, Lammert F: Variant adiponutrin (PNPLA3) represents a common fibrosis risk gene: non-invasive elastography-based study in chronic liver disease. J Hepatol 2011;55:299-306.
Yki-Jarvinen H: Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome. Lancet Diabetes Endocrinol 2014;2:901-910.
Krawczyk M, Portincasa P, Lammert F: PNPLA3-associated steatohepatitis: toward a gene-based classification of fatty liver disease. Semin Liver Dis 2013;33:369-379.
Sevastianova K, Kotronen A, Gastaldelli A, Perttilä J, Hakkarainen A, Lundbom J, Suojanen L, Orho-Melander M, Lundbom N, Ferrannini E, Rissanen A, Olkkonen VM, Yki-Järvinen H: Genetic variation in PNPLA3 (adiponutrin) confers sensitivity to weight loss-induced decrease in liver fat in humans. Am J Clin Nutr 2011;94:104-111.
Marzuillo P, Grandone A, Perrone L, del Giudice EM: Weight loss allows the dissection of the interaction between abdominal fat and PNPLA3 (adiponutrin) in the liver damage of obese children. J Hepatol 2013;59:1143-1144.
Kempinska-Podhorodecka A, Krawczyk M, Klak M, Blatkiewicz M, Lammert F, Milkiewicz P, Milkiewicz M: Healthy PNPLA3 risk allele carriers present with unexpected body fat composition. A study of one thousand subjects. J Gastrointestin Liver Dis 2014;23:33-37.
Kozlitina J, Smagris E, Stender S, Nordestgaard BG, Zhou HH, Tybjaerg-Hansen A, Vogt TF, Hobbs HH, Cohen JC: Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2014;46:352-356.
Liu YL, Reeves HL, Burt AD, Tiniakos D, McPherson S, Leathart JB, Allison ME, Alexander GJ, Piguet AC, Anty R, Donaldson P, Aithal GP, Francque S, Van Gaal L, Clement K, Ratziu V, Dufour JF, Day CP, Daly AK, Anstee QM: TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nat Commun 2014;5:4309.
Sookoian S, Castano GO, Scian R, Mallardi P, Fernandez Gianotti T, Burgueno AL, San Martino J, Pirola CJ: Genetic variation in transmembrane 6 superfamily member 2 and the risk of nonalcoholic fatty liver disease and histological disease severity. Hepatology 2015;61:515-525.
Dongiovanni P, Petta S, Maglio C, Fracanzani AL, Pipitone R, Mozzi E, Motta BM, Kaminska D, Rametta R, Grimaudo S, Pelusi S, Montalcini T, Alisi A, Maggioni M, Kärjä V, Borén J, Käkelä P, Di Marco V, Xing C, Nobili V, Dallapiccola B, Craxi A, Pihlajamäki J, Fargion S, Sjöström L, Carlsson LM, Romeo S, Valenti L: Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. Hepatology 2015;61:506-514.
Milano M, Aghemo A, Mancina RM, Fischer J, Dongiovanni P, De Nicola S, Fracanzani AL, D'Ambrosio R, Maggioni M, De Francesco R, Fargion S, Berg T, Stickel F, Hampe J, Romeo S, Colombo M, Valenti L: Transmembrane 6 superfamily member 2 gene E167K variant impacts on steatosis and liver damage in chronic hepatitis C patients. Hepatology 2015;62:111-117.
Scorletti E, West AL, Bhatia L, Hoile SP, McCormick KG, Burdge GC, Lillycrop KA, Clough GF, Calder PC, Byrne CD: Treating liver fat and serum triglyceride levels in NAFLD, effects of PNPLA3 and TM6SF2 genotypes: results from the WELCOME trial. J Hepatol 2015;pii:S0168-8278(15)00539-5.
Hamaguchi M, Kojima T, Itoh Y, Harano Y, Fujii K, Nakajima T, Kato T, Takeda N, Okuda J, Ida K, Kawahito Y, Yoshikawa T, Okanoue T: The severity of ultrasonographic findings in nonalcoholic fatty liver disease reflects the metabolic syndrome and visceral fat accumulation. Am J Gastroenterol 2007;102:2708-2715.
Krawczyk M, Stachowska E, Lammert F, Milkiewicz P, Milkiewicz M: Reduction of caloric intake improves liver steatosis and overrides the prosteatotic effect of the PNPLA3 p.I148 M variant. Z Gastroenterol 2014;52:KG128.
Hosker JP, Matthews DR, Rudenski AS, Burnett MA, Darling P, Bown EG, Turner RC: Continuous infusion of glucose with model assessment: measurement of insulin resistance and beta-cell function in man. Diabetologia 1985;28:401-411.
Arslanow A, Stokes CS, Weber SN, Grünhage F, Lammert F, Krawczyk M: The common PNPLA3 variant p.I148M is associated with liver fat contents as quantified by controlled attenuation parameter (CAP). Liver Int 2015.
Krawczyk M, Grünhage F, Lammert F: Identification of combined genetic determinants of liver stiffness within the SREBP1c-PNPLA3 pathway. Int J Mol Sci 2013;14:21153-21166.
Shen J, Wong GL, Chan HL, Chan RS, Chan HY, Chu WC, Cheung BH, Yeung DK, Li LS, Sea MM, Woo J, Wong VW: PNPLA3 gene polymorphism and response to lifestyle modification in patients with nonalcoholic fatty liver disease. J Gastroenterol Hepatol 2015;30:139-146.
Stojkovic IA, Ericson U, Rukh G, Riddestråle M, Romeo S, Orho-Melander M: The PNPLA3 Ile148Met interacts with overweight and dietary intakes on fasting triglyceride levels. Genes Nutr 2014;9:388.
Giudice EM, Grandone A, Cirillo G, Santoro N, Amato A, Brienza C, Savarese P, Marzuillo P, Perrone L: The association of PNPLA3 variants with liver enzymes in childhood obesity is driven by the interaction with abdominal fat. PLoS One 2011;6:e27933.
Tai CM, Huang CK, Tu HP, Hwang JC, Chang CY, Yu ML: PNPLA3 genotype increases susceptibility of nonalcoholic steatohepatitis among obese patients with nonalcoholic fatty liver disease. Surg Obes Relat Dis 2015;11:888-894.
Zampino R, Coppola N, Cirillo G, Boemio A, Pisaturo M, Marrone A, Macera M, Sagnelli E, Perrone L, Adinolfi LE, Miraglia del Giudice E: Abdominal fat interacts with PNPLA3 I148M, but not with the APOC3 variant in the pathogenesis of liver steatosis in chronic hepatitis C. J Viral Hepat 2013;20:517-523.
Pingitore P, Pirazzi C, Mancina RM, Motta BM, Indiveri C, Pujia A, Montalcini T, Hedfalk K, Romeo S: Recombinant PNPLA3 protein shows triglyceride hydrolase activity and its I148M mutation results in loss of function. Biochim Biophys Acta 2014;1841:574-580.
Kumari M, Schoiswohl G, Chitraju C, Paar M, Cornaciu I, Rangrez AY, Wongsiriroj N, Nagy HM, Ivanova PT, Scott SA, Knittelfelder O, Rechberger GN, Birner-Gruenberger R, Eder S, Brown HA, Haemmerle G, Oberer M, Lass A, Kershaw EE, Zimmermann R, Zechner R: Adiponutrin functions as a nutritionally regulated lysophosphatidic acid acyltransferase. Cell Metab 2012;15:691-702.
Sevastianova K, Santos A, Kotronen A, Hakkarainen A, Makkonen J, Silander K, Peltonen M, Romeo S, Lundbom J, Lundbom N, Olkkonen VM, Gylling H, Fielding BA, Rissanen A, Yki-Järvinen H: Effect of short-term carbohydrate overfeeding and long-term weight loss on liver fat in overweight humans. Am J Clin Nutr 2012;96:727-734.
Mancina RM, Matikainen N, Maglio C, Söderlund S, Lundbom N, Hakkarainen A, Rametta R, Mozzi E, Fargion S, Valenti L, Romeo S, Taskinen MR, Borén J: Paradoxical dissociation between hepatic fat content and de novo lipogenesis due to PNPLA3 sequence variant. J Clin Endocrinol Metab 2015;100:E821-E825.
Smagris E, BasuRay S, Li J, Huang Y, Lai KM, Gromada J, Cohen JC, Hobbs HH: Pnpla3I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis. Hepatology 2015;16:108-118.
You do not currently have access to this content.