Effect of PNPLA3, TM6SF2 and MBOAT7 Genetic Variants on Non-alcoholic Fatty Liver Disease Therapeutic Outcome.

Summary

Patatin-like phospholipase domain-containing protein-3 (PNPLA3), the transmembrane 6 superfamily member 2 protein (TM6SF2) and membrane bound O-acyltransferase domain containing 7 (MBOAT7) genes are involved in non-alcoholic fatty liver disease (NAFLD) development and worsening. Following the actual scientific knowledge, some studies have identified the genetic background surrounding NAFLD, counting up to forty different genetic variants that seem to exert also a crucial role in the disease evolution, according to the natural history, until hepatocellular carcinoma onset. However, few data exist regarding their influence on the treatment response. The aim was to explore the effect of 303 mg of silybin-phospholipids complex, 10 mg of vitamin-D and 15 mg of vitamin-E twice a day for six months in NAFLD patients carrying PNPLA3-rs738409, TM6SF2-rs58542926 and MBOAT7-rs641738 genetic variants. The assessed mutations are independently associated with no response to a silybin/vitamin D-based therapy and could be useful therapeutic predictive markers in this context.

Timeline

Start

2017-01-16

Primary completion

2017-10-17

Completion

2018-04-17

Publications

• Background Lu FB, Zheng KI, Rios RS, Targher G, Byrne CD, Zheng MH. Global epidemiology of lean non-alcoholic fatty liver disease: A systematic review and meta-analysis. J Gastroenterol Hepatol. 2020 Dec;35(12):2041-2050. doi: 10.1111/jgh.15156. Epub 2020 Jul 7.
• Background Harris R, West J, Morling JR. Editorial: how widespread and serious is non-alcoholic fatty liver disease in the real world? Aliment Pharmacol Ther. 2020 Jun;51(11):1199-1200. doi: 10.1111/apt.15714. No abstract available.
• Background Dallio M, Masarone M, Errico S, Gravina AG, Nicolucci C, Di Sarno R, Gionti L, Tuccillo C, Persico M, Stiuso P, Diano N, Loguercio C, Federico A. Role of bisphenol A as environmental factor in the promotion of non-alcoholic fatty liver disease: in vitro and clinical study. Aliment Pharmacol Ther. 2018 Mar;47(6):826-837. doi: 10.1111/apt.14499. Epub 2018 Jan 11.
• Background Nicolucci C, Errico S, Federico A, Dallio M, Loguercio C, Diano N. Human exposure to Bisphenol A and liver health status: Quantification of urinary and circulating levels by LC-MS/MS. J Pharm Biomed Anal. 2017 Jun 5;140:105-112. doi: 10.1016/j.jpba.2017.02.058. Epub 2017 Mar 10.
• Background Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, Natale S, Vanni E, Villanova N, Melchionda N, Rizzetto M. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology. 2003 Apr;37(4):917-23. doi: 10.1053/jhep.2003.50161.
• Background Federico A, Dallio M, Caprio GG, Ormando VM, Loguercio C. Gut microbiota and the liver. Minerva Gastroenterol Dietol. 2017 Dec;63(4):385-398. doi: 10.23736/S1121-421X.17.02375-3.
• Background Santoro N, Kursawe R, D'Adamo E, Dykas DJ, Zhang CK, Bale AE, Cali AM, Narayan D, Shaw MM, Pierpont B, Savoye M, Lartaud D, Eldrich S, Cushman SW, Zhao H, Shulman GI, Caprio S. A common variant in the patatin-like phospholipase 3 gene (PNPLA3) is associated with fatty liver disease in obese children and adolescents. Hepatology. 2010 Oct;52(4):1281-90. doi: 10.1002/hep.23832.
• Background Burza MA, Pirazzi C, Maglio C, Sjoholm K, Mancina RM, Svensson PA, Jacobson P, Adiels M, Baroni MG, Boren J, Ginanni Corradini S, Montalcini T, Sjostrom L, Carlsson LM, Romeo S. PNPLA3 I148M (rs738409) genetic variant is associated with hepatocellular carcinoma in obese individuals. Dig Liver Dis. 2012 Dec;44(12):1037-41. doi: 10.1016/j.dld.2012.05.006. Epub 2012 Jun 15.
• Background Santoro N, Savoye M, Kim G, Marotto K, Shaw MM, Pierpont B, Caprio S. Hepatic fat accumulation is modulated by the interaction between the rs738409 variant in the PNPLA3 gene and the dietary omega6/omega3 PUFA intake. PLoS One. 2012;7(5):e37827. doi: 10.1371/journal.pone.0037827. Epub 2012 May 21.
• Background Chalasani N, Guo X, Loomba R, Goodarzi MO, Haritunians T, Kwon S, Cui J, Taylor KD, Wilson L, Cummings OW, Chen YD, Rotter JI; Nonalcoholic Steatohepatitis Clinical Research Network. Genome-wide association study identifies variants associated with histologic features of nonalcoholic Fatty liver disease. Gastroenterology. 2010 Nov;139(5):1567-76, 1576.e1-6. doi: 10.1053/j.gastro.2010.07.057. Epub 2010 Aug 11.
• Background 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 Apr;46(4):352-6. doi: 10.1038/ng.2901. Epub 2014 Feb 16.
• Background 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 Jun 30;5:4309. doi: 10.1038/ncomms5309.
• Background Mancina RM, Dongiovanni P, Petta S, Pingitore P, Meroni M, Rametta R, Boren J, Montalcini T, Pujia A, Wiklund O, Hindy G, Spagnuolo R, Motta BM, Pipitone RM, Craxi A, Fargion S, Nobili V, Kakela P, Karja V, Mannisto V, Pihlajamaki J, Reilly DF, Castro-Perez J, Kozlitina J, Valenti L, Romeo S. The MBOAT7-TMC4 Variant rs641738 Increases Risk of Nonalcoholic Fatty Liver Disease in Individuals of European Descent. Gastroenterology. 2016 May;150(5):1219-1230.e6. doi: 10.1053/j.gastro.2016.01.032. Epub 2016 Feb 2.
• Background Federico A, Dallio M, Masarone M, Gravina AG, Di Sarno R, Tuccillo C, Cossiga V, Lama S, Stiuso P, Morisco F, Persico M, Loguercio C. Evaluation of the Effect Derived from Silybin with Vitamin D and Vitamin E Administration on Clinical, Metabolic, Endothelial Dysfunction, Oxidative Stress Parameters, and Serological Worsening Markers in Nonalcoholic Fatty Liver Disease Patients. Oxid Med Cell Longev. 2019 Oct 15;2019:8742075. doi: 10.1155/2019/8742075. eCollection 2019.
• Background Forouhi NG, Luan J, Cooper A, Boucher BJ, Wareham NJ. Baseline serum 25-hydroxy vitamin d is predictive of future glycemic status and insulin resistance: the Medical Research Council Ely Prospective Study 1990-2000. Diabetes. 2008 Oct;57(10):2619-25. doi: 10.2337/db08-0593. Epub 2008 Jun 30.
• Background Barchetta I, De Bernardinis M, Capoccia D, Baroni MG, Fontana M, Fraioli A, Morini S, Leonetti F, Cavallo MG. Hypovitaminosis D is independently associated with metabolic syndrome in obese patients. PLoS One. 2013 Jul 31;8(7):e68689. doi: 10.1371/journal.pone.0068689. Print 2013.
• Background Boursier J, Zarski JP, de Ledinghen V, Rousselet MC, Sturm N, Lebail B, Fouchard-Hubert I, Gallois Y, Oberti F, Bertrais S, Cales P; Multicentric Group from ANRS/HC/EP23 FIBROSTAR Studies. Determination of reliability criteria for liver stiffness evaluation by transient elastography. Hepatology. 2013 Mar;57(3):1182-91. doi: 10.1002/hep.25993. Epub 2013 Feb 4.
• Background Sasso M, Miette V, Sandrin L, Beaugrand M. The controlled attenuation parameter (CAP): a novel tool for the non-invasive evaluation of steatosis using Fibroscan. Clin Res Hepatol Gastroenterol. 2012 Feb;36(1):13-20. doi: 10.1016/j.clinre.2011.08.001. Epub 2011 Sep 15.
• Background Uchida D, Takaki A, Oyama A, Adachi T, Wada N, Onishi H, Okada H. Oxidative Stress Management in Chronic Liver Diseases and Hepatocellular Carcinoma. Nutrients. 2020 May 28;12(6):1576. doi: 10.3390/nu12061576.
• Background Loguercio C, Andreone P, Brisc C, Brisc MC, Bugianesi E, Chiaramonte M, Cursaro C, Danila M, de Sio I, Floreani A, Freni MA, Grieco A, Groppo M, Lazzari R, Lobello S, Lorefice E, Margotti M, Miele L, Milani S, Okolicsanyi L, Palasciano G, Portincasa P, Saltarelli P, Smedile A, Somalvico F, Spadaro A, Sporea I, Sorrentino P, Vecchione R, Tuccillo C, Del Vecchio Blanco C, Federico A. Silybin combined with phosphatidylcholine and vitamin E in patients with nonalcoholic fatty liver disease: a randomized controlled trial. Free Radic Biol Med. 2012 May 1;52(9):1658-65. doi: 10.1016/j.freeradbiomed.2012.02.008. Epub 2012 Feb 15.
• Background Federico A, Trappoliere M, Tuccillo C, de Sio I, Di Leva A, Del Vecchio Blanco C, Loguercio C. A new silybin-vitamin E-phospholipid complex improves insulin resistance and liver damage in patients with non-alcoholic fatty liver disease: preliminary observations. Gut. 2006 Jun;55(6):901-2. doi: 10.1136/gut.2006.091967. No abstract available.
• Background Trappoliere M, Caligiuri A, Schmid M, Bertolani C, Failli P, Vizzutti F, Novo E, di Manzano C, Marra F, Loguercio C, Pinzani M. Silybin, a component of sylimarin, exerts anti-inflammatory and anti-fibrogenic effects on human hepatic stellate cells. J Hepatol. 2009 Jun;50(6):1102-11. doi: 10.1016/j.jhep.2009.02.023. Epub 2009 Apr 5.
• Dallio M, Masarone M, Romeo M, Tuccillo C, Morisco F, Persico M, Loguercio C, Federico A. PNPLA3, TM6SF2, and MBOAT7 Influence on Nutraceutical Therapy Response for Non-alcoholic Fatty Liver Disease: A Randomized Controlled Trial. Front Med (Lausanne). 2021 Oct 8;8:734847. doi: 10.3389/fmed.2021.734847. eCollection 2021.

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Indications