The Association between Pediatric NAFLD and Common Genetic Variants
Abstract
:1. Introduction
2. An Overview of the Genetic Variants Associated with NAFLD Identified by GWAS
2.1. PNPLA 3
2.2. GCKR
2.3. TM6SF2
3. Genetic Variants Identified in Candidate Gene Studies
4. Genes Involved in NAFLD Progression
5. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
- Anderson, E.L.; Howe, L.-D.; Jones, H.E.; Higgins, J.P.; Lawlor, D.A.; Fraser, A. The Prevalence of Non-Alcoholic Fatty Liver Disease in Children and Adolescents: A Systematic Review and Meta-Analysis. PLoS ONE 2015, 10, e0140908. [Google Scholar] [CrossRef] [PubMed]
- O’Malley, G.; Santoro, N.; Northrup, V.; D’Adamo, E.; Shaw, M.; Eldrich, S.; Caprio, S. High normal fasting glucose level in obese youth: A marker for insulin resistance and beta cell dysregulation. Diabetologia 2010, 53, 1199–1209. [Google Scholar] [CrossRef] [PubMed]
- Santoro, N.; Amato, A.; Grandone, A.; Brienza, C.; Savarese, P.; Tartaglione, N.; Marzuillo, P.; Perrone, L.; Miraglia Del Giudice, E. Predicting metabolic syndrome in obese children and adolescents: Look, measure and ask. Obes. Facts 2013, 6, 48–56. [Google Scholar] [CrossRef] [PubMed]
- D’Adamo, E.; Santoro, N.; Caprio, S. Metabolic syndrome in pediatrics: Old concepts revised, new concepts discussed. Pediatr. Clin. N. Am. 2011, 58, 1241–1255. [Google Scholar] [CrossRef] [PubMed]
- Makkonen, J.; Pietiläinen, K.H.; Rissanen, A.; Kaprio, J.; Yki-Järvinen, H. Genetic factors contribute to variation in serum alanine aminotransferase activity independent of obesity and alcohol: A study in monozygotic and dizygotic twins. J. Hepatol. 2009, 50, 1035–1042. [Google Scholar] [CrossRef] [PubMed]
- Loomba, R.; Schork, N.; Chen, C.H.; Bettencourt, R.; Bhatt, A.; Ang, B.; Nguyen, P.; Hernandez, C.; Richards, L.; Salotti, J.; et al. Genetics of NAFLD in Twins Consortium. Heritability of Hepatic Fibrosis and Steatosis Based on a Prospective Twin Study. Gastroenterology 2015, 149, 1784–1793. [Google Scholar] [CrossRef] [PubMed]
- Browning, J.D.; Szczepaniak, L.; Dobbins, R.; Nuremberg, P.; Horton, J.D.; Cohen, J.C.; Grundy, S.M.; Hobbs, H.H. Prevalence of hepatic steatosis in an urban population in the United States: Impact of ethnicity. Hepatology 2004, 40, 1387–1395. [Google Scholar] [CrossRef] [PubMed]
- Welsh, J.A.; Karpen, S.; Vos, M.B. Increasing prevalence of nonalcoholic fatty liver disease among United States adolescents, 1988–1994 to 2007–2010. J. Pediatr. 2013, 162, 496–500.e1. [Google Scholar] [CrossRef] [PubMed]
- Romeo, S.; Kozlitina, J.; Xing, C.; Pertsemlidis, A.; Cox, D.; Pennacchio, L.A.; Boerwinkle, E.; Cohen, J.C.; Hobbs, H.H. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 2008, 40, 1461–1465. [Google Scholar] [CrossRef] [PubMed]
- Speliotes, E.K.; Yerges-Armstrong, L.M.; Wu, J.; Hernaez, R.; Kim, L.J.; Palmer, C.D.; Gudnason, V.; Eiriksdottir, G.; Garcia, M.E.; Launer, L.J.; et al. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet. 2011, 7, e1001324. [Google Scholar] [CrossRef] [PubMed]
- Adams, L.A.; White, S.W.; Marsh, J.A.; Lye, S.J.; Connor, K.L.; Maganga, R.; Ayonrinde, O.T.; Olynyk, J.K.; Mori, T.A.; Beilin, L.J.; et al. Association between liver-specific gene polymorphisms and their expression levels with nonalcoholic fatty liver disease. Hepatology 2013, 57, 590–600. [Google Scholar] [CrossRef] [PubMed]
- Buch, S.; Stickel, F.; Trépo, E.; Way, M.; Herrmann, A.; Nischalke, H.D.; Brosch, M.; Rosendahl, J.; Berg, T.; Ridinger, M.; et al. A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis. Nat. Genet. 2015, 47, 1443–1448. [Google Scholar] [CrossRef] [PubMed]
- Mancina, R.M.; Dongiovanni, P.; Petta, S.; Pingitore, P.; Meroni, M.; Rametta, R.; Borén, J.; Montalcini, T.; Pujia, A.; Wiklund, O.; et al. The MBOAT7-TMC4 Variant rs641738 Increases Risk of Nonalcoholic Fatty Liver Disease in Individuals of European Descent. Gastroenterology 2016, 150, 1219–1230.e6. [Google Scholar] [CrossRef] [PubMed]
- Wilson, P.A.; Gardner, S.D.; Lambie, N.M.; Commans, S.A.; Crowther, D.J. Characterization of the human patatin-like phospholipase family. J. Lipid Res. 2006, 47, 1940–1949. [Google Scholar] [CrossRef] [PubMed]
- Lake, A.C.; Sun, Y.; Li, J.; Kim, J.E.; Johnson, J.W.; Li, D.; Revett, T.; Shih, H.H.; Liu, W.; Paulsen, J.E.; et al. Expression, regulation, and triglyceride hydrolase activity of Adiponutrin family members. J. Lipid Res. 2005, 46, 2477–2487. [Google Scholar] [CrossRef] [PubMed]
- Huang, Y.; He, S.; Li, J.Z.; Seo, Y.K.; Osborne, T.F.; Cohen, J.C.; Hobbs, H.H. A feed-forward loop amplifies nutritional regulation of PNPLA3. Proc. Natl. Acad. Sci. USA 2010, 107, 7892–7897. [Google Scholar] [CrossRef] [PubMed]
- Huang, Y.; Cohen, J.C.; Hobbs, H.H. Expression and characterization of a PNPLA3 protein isoform (I148M) associated with nonalcoholic fatty liver disease. J. Biol. Chem. 2011, 286, 37085–37093. [Google Scholar] [CrossRef] [PubMed]
- Kumari, M.; Schoiswohl, G.; Chitraju, C.; Paar, M.; Cornaciu, I.; Rangrez, A.Y.; Wongsiriroj, N.; Nagy, H.M.; Ivanova, P.T.; Scott, S.A.; et al. Adiponutrin functions as a nutritionally regulated lysophosphatidic acid acyltransferase. Cell Metab. 2012, 15, 691–702. [Google Scholar] [CrossRef] [PubMed]
- Santoro, N.; Kursawe, R.; D’Adamo, E.; Dykas, D.J.; Zhang, C.K.; Bale, A.E.; Calí, A.M.; Narayan, D.; Shaw, M.M.; Pierpont, B.; et al. A common variant in the patatin-like phospholipase 3 gene (PNPLA3) is associated with fatty liver disease in obese children and adolescents. Hepatology 2010, 52, 1281–1290. [Google Scholar] [CrossRef] [PubMed]
- Romeo, S.; Sentinelli, F.; Cambuli, V.M.; Incani, M.; Congiu, T.; Matta, V.; Pilia, S.; Huang-Doran, I.; Cossu, E.; Loche, S.; et al. The 148M allele of the PNPLA3 gene is associated with indices of liver damage early in life. J. Hepatol. 2010, 53, 335–338. [Google Scholar] [CrossRef] [PubMed]
- Li, J.Z.; Huang, Y.; Karaman, R.; Ivanova, P.T.; Brown, H.A.; Roddy, T.; Castro-Perez, J.; Cohen, J.C.; Hobbs, H.H. Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis. J. Clin. Investig. 2012, 122, 4130–4144. [Google Scholar] [CrossRef] [PubMed]
- Giudice, E.M.; 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. [Google Scholar] [CrossRef]
- Viitasalo, A.; Pihlajamaki, J.; Lindi, V.; Atalay, M.; Kaminska, D.; Joro, R.; Lakka, T.A. Associations of I148M variant in PNPLA3 gene with plasma ALT levels during 2-year follow-up in normal weight and overweight children: the PANIC Study. Pediatr. Obes. 2015, 10, 84–90. [Google Scholar] [CrossRef] [PubMed]
- Romeo, S.; Sentinelli, F.; Dash, S.; Yeo, G.S.; Savage, D.B.; Leonetti, F.; Capoccia, D.; Incani, M.; Maglio, C.; Iacovino, M.; et al. Morbid obesity exposes the association between PNPLA3 I148M (rs738409) and indices of hepatic injury in individuals of European descent. Int. J. Obes. (Lond.) 2010, 34, 190–194. [Google Scholar] [CrossRef] [PubMed]
- Santoro, N.; Savoye, M.; Kim, G.; Marotto, K.; Shaw, M.M.; 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, e37827. [Google Scholar] [CrossRef] [PubMed]
- Marzuillo, P.; Grandone, A.; Perrone, L.; del Giudice, E.M. 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. [Google Scholar] [CrossRef] [PubMed]
- Perttilä, J.; Huaman-Samanez, C.; Caron, S.; Tanhuanpää, K.; Staels, B.; Yki-Järvinen, H.; Olkkonen, V.M. PNPLA3 is regulated by glucose in human hepatocytes, and its I148M mutant slows down triglyceride hydrolysis. Am. J. Physiol. Endocrinol. Metab. 2012, 302, E1063–E1069. [Google Scholar] [CrossRef] [PubMed]
- Donati, B.; Motta, B.M.; Pingitore, P.; Meroni, M.; Pietrelli, A.; Alisi, A.; Petta, S.; Xing, C.; Dongiovanni, P.; del Menico, B.; et al. The rs2294918 E434K variant modulates patatin-like phospholipase domain-containing 3 expression and liver damage. Hepatology 2016, 63, 787–798. [Google Scholar] [CrossRef] [PubMed]
- Saxena, R.; Voight, B.F.; Lyssenko, V.; Burtt, N.P.; de Bakker, P.I.; Chen, H.; Roix, J.J.; Kathiresan, S.; Hirschhorn, J.N.; Daly, M.J.; et al. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 2007, 316, 1331–1336. [Google Scholar] [CrossRef] [PubMed]
- Willer, C.J.; Sanna, S.; Jackson, A.U.; Scuteri, A.; Bonnycastle, L.L.; Clarke, R.; Heath, S.C.; Timpson, N.J.; Najjar, S.S.; Stringham, H.M.; et al. Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat. Genet. 2008, 40, 161–169. [Google Scholar] [CrossRef] [PubMed]
- Matschinsky, F.M. Regulation of pancreatic beta-cell glucokinase: From basics to therapeutics. Diabetes 2002, 51 (Suppl. 3), S394–S404. [Google Scholar] [CrossRef] [PubMed]
- Beer, N.L.; Tribble, N.D.; McCulloch, L.J.; Roos, C.; Johnson, P.R.; Orho-Melander, M.; Gloyn, A.L. The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver. Hum. Mol. Genet. 2009, 18, 4081–4088. [Google Scholar] [CrossRef] [PubMed]
- Santoro, N.; Zhang, C.K.; Zhao, H.; Pakstis, A.J.; Kim, G.; Kursawe, R.; Dykas, D.J.; Bale, A.E.; Giannini, C.; Pierpont, B.; et al. Variant in the glucokinase regulatory protein (GCKR) gene is associated with fatty liver in obese children and adolescents. Hepatology 2012, 55, 781–789. [Google Scholar] [CrossRef] [PubMed]
- Santoro, N.; Caprio, S.; Pierpont, B.; Van Name, M.; Savoye, M.; Parks, E.J. Hepatic De Novo Lipogenesis in Obese Youth Is Modulated by a Common Variant in the GCKR Gene. J. Clin. Endocrinol. Metab. 2015, 100, E1125–E1132. [Google Scholar] [CrossRef] [PubMed]
- Lin, Y.C.; Chang, P.F.; Chang, M.H.; Ni, Y.H. Genetic variants in GCKR and PNPLA3 confer susceptibility to nonalcoholic fatty liver disease in obese individuals. Am. J. Clin. Nutr. 2014, 99, 869–874. [Google Scholar] [CrossRef] [PubMed]
- Kozlitina, J.; Smagris, E.; Stender, S.; Nordestgaard, B.G.; Zhou, H.H.; Tybjærg-Hansen, A.; Vogt, T.F.; Hobbs, H.H.; Cohen, J.C. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 2014, 46, 352–356. [Google Scholar] [CrossRef] [PubMed]
- Grandone, A.; Cozzolino, D.; Marzuillo, P.; Cirillo, G.; Di Sessa, A.; Ruggiero, L.; Di Palma, M.R.; Perrone, L.; Miraglia Del Giudice, E. TM6SF2 Glu167Lys polymorphism is associated with low levels of LDL-cholesterol and increased liver injury in obese children. Pediatr. Obes. 2016, 11, 115–119. [Google Scholar] [CrossRef] [PubMed]
- Liu, Y.L.; Reeves, H.L.; Burt, A.D.; Tiniakos, D.; McPherson, S.; Leathart, J.B.; Allison, M.E.; Alexander, G.J.; Piguet, A.C.; Anty, R.; et al. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nat. Commun. 2014, 5, 4309. [Google Scholar] [CrossRef] [PubMed]
- Sookoian, S.; Castaño, G.O.; Scian, R.; Mallardi, P.; Fernández Gianotti, T.; Burgueño, A.L.; San Martino, J.; Pirola, C.J. 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. [Google Scholar] [CrossRef] [PubMed]
- Goffredo, M.; Caprio, S.; Feldstein, A.E.; D’Adamo, E.; Shaw, M.M.; Pierpont, B.; Savoye, M.; Zhao, H.; Bale, A.E.; Santoro, N. Role of TM6SF2 rs58542926 in the pathogenesis of nonalcoholic pediatric fatty liver disease: A multiethnic study. Hepatology 2016, 63, 117–125. [Google Scholar] [CrossRef] [PubMed]
- Dongiovanni, P.; Petta, S.; Mannisto, V.; Mancina, R.M.; Pipitone, R.; Karja, V.; Maggioni, M.; Kakela, P.; Wiklund, O.; Mozzi, E.; et al. Statin use and non-alcoholic steatohepatitis in at risk individuals. J. Hepatol. 2015, 63, 705–712. [Google Scholar] [CrossRef] [PubMed]
- Dongiovanni, P.; Valenti, L.; Rametta, R.; Daly, A.K.; Nobili, V.; Mozzi, E.; Leathart, J.B.; Pietrobattista, A.; Burt, A.D.; Maggioni, M.; et al. Genetic variants regulating insulin receptor signalling are associated with the severity of liver damage in patients with non-alcoholic fatty liver disease. Gut 2010, 59, 267–273. [Google Scholar] [CrossRef] [PubMed]
- Diez, J.J.; Iglesias, P. The role of the novel adipocyte-derived hormone adiponectin in human disease. Eur. J. Endocrinol. 2003, 148, 293–300. [Google Scholar] [CrossRef] [PubMed]
- Chandran, M.; Phillips, S.A.; Ciaraldi, T.; Henry, R.R. Adiponectin: More than just another fat cell hormone? Diabetes Care 2003, 26, 2442–2450. [Google Scholar] [CrossRef] [PubMed]
- Musso, G.; Gambino, R.; De Michieli, F.; Durazzo, M.; Pagano, G.; Cassader, M. Adiponectin gene polymorphisms modulate acute adiponectin response to dietary fat: Possible pathogenetic role in NASH. Hepatology 2008, 47, 1167–1177. [Google Scholar] [CrossRef] [PubMed]
- Tokushige, K.; Hashimoto, E.; Noto, H.; Yatsuji, S.; Taniai, M.; Torii, N.; Shiratori, K. Influence of adiponectin gene polymorphisms in Japanese patients with non-alcoholic fatty liver disease. J. Gastroenterol. 2009, 44, 976–982. [Google Scholar] [CrossRef] [PubMed]
- Hsieh, C.J.; Wang, P.W.; Hu, T.H. Association of adiponectin gene polymorphism with nonalcoholic fatty liver disease in Taiwanese patients with type 2 diabetes. PLoS ONE 2015, 10, e0127521. [Google Scholar] [CrossRef] [PubMed]
- Wang, Z.L.; Xia, B.; Shrestha, U.; Jiang, L.; Ma, C.W.; Chen, Q.; Chen, H.; Hu, Z.G. Correlation between adiponectin polymorphisms and nonalcoholic fatty liver disease with or without metabolic syndrome in Chinese population. J. Endocrinol. Investig. 2008, 31, 1086–1091. [Google Scholar] [CrossRef] [PubMed]
- Zhang, W.; Zhu, L.Q.; Huo, X.L.; Qin, J.; Yuan, G.Y. Association between adiponectin gene T45G polymorphism and nonalcoholic fatty liver disease risk: A meta-analysis. Genet. Mol. Res. 2016, 15. [Google Scholar] [CrossRef] [PubMed]
- Phillips, C.M.; Goumidi, L.; Bertrais, S.; Field, M.R.; Ordovas, J.M.; Cupples, L.A.; Defoort, C.; Lovegrove, J.A.; Drevon, C.A.; Blaak, E.E.; et al. Leptin receptor polymorphisms interact with polyunsaturated fatty acids to augment risk of insulin resistance and metabolic syndrome in adults. J. Nutr. 2010, 140, 238–244. [Google Scholar] [CrossRef] [PubMed]
- Lu, H.; Sun, J.; Sun, L.; Shu, X.; Xu, Y.; Xie, D. Polymorphism of human leptin receptor gene is associated with type 2 diabetic patients complicated with non-alcoholic fatty liver disease in China. J. Gastroenterol. Hepatol. 2009, 24, 228–232. [Google Scholar] [CrossRef] [PubMed]
- Zain, S.M.; Mohamed, Z.; Mahadeva, S.; Cheah, P.L.; Rampal, S.; Chin, K.F.; Mahfudz, A.S.; Basu, R.C.; Tan, H.L.; Mohamed, R. Impact of leptin receptor gene variants on risk of non-alcoholic fatty liver disease and its interaction with adiponutrin gene. J. Gastroenterol. Hepatol. 2013, 28, 873–879. [Google Scholar] [CrossRef] [PubMed]
- Guerre-Millo, M.; Gervois, P.; Raspé, E.; Madsen, L.; Poulain, P.; Derudas, B.; Herbert, J.M.; Winegar, D.A.; Willson, T.M.; Fruchart, J.C.; et al. Peroxisome proliferator-activated receptor alpha activators improve insulin sensitivity and reduce adiposity. J. Biol. Chem. 2000, 275, 16638–16642. [Google Scholar] [CrossRef] [PubMed]
- Gastaldelli, A.; Harrison, S.A.; Belfort-Aguilar, R.; Hardies, L.J.; Balas, B.; Schenker, S.; Cusi, K. Importance of changes in adipose tissue insulin resistance to histological response during thiazolidinedione treatment of patients with nonalcoholic steatohepatitis. Hepatology 2009, 50, 1087–1093. [Google Scholar] [CrossRef] [PubMed]
- Chen, S.; Li, Y.; Li, S.; Yu, C. A Val227Ala substitution in the peroxisome proliferator activated receptor alpha (PPAR alpha) gene associated with non-alcoholic fatty liver disease and decreased waist circumference and waist-to-hip ratio. J. Gastroenterol. Hepatol. 2008, 23, 1415–1418. [Google Scholar] [CrossRef] [PubMed]
- Domenici, F.A.; Brochado, M.J.; Martinelli Ade, L.; Zucoloto, S.; da Cunha, S.F.; Vannucchi, H. Peroxisome proliferator-activated receptors alpha and gamma2 polymorphisms in nonalcoholic fatty liver disease: A study in Brazilian patients. Gene 2013, 529, 326–331. [Google Scholar] [CrossRef] [PubMed]
- Dongiovanni, P.; Rametta, R.; Fracanzani, A.L.; Benedan, L.; Borroni, V.; Maggioni, P.; Maggioni, M.; Fargion, S.; Valenti, L. Lack of association between peroxisome proliferator-activated receptors alpha and gamma2 polymorphisms and progressive liver damage in patients with non-alcoholic fatty liver disease: A case control study. BMC Gastroenterol. 2010, 10, 102. [Google Scholar] [CrossRef] [PubMed]
- Leone, T.C.; Lehman, J.J.; Finck, B.N.; Schaeffer, P.J.; Wende, A.R.; Boudina, S.; Courtois, M.; Wozniak, D.F.; Sambandam, N.; Bernal-Mizrachi, C.; et al. PGC-1alpha deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis. PLoS Biol. 2005, 3, e101. [Google Scholar] [CrossRef] [PubMed]
- Hara, K.; Tobe, K.; Okada, T.; Kadowaki, H.; Akanuma, Y.; Ito, C.; Kimura, S.; Kadowaki, T. A genetic variation in the PGC-1 gene could confer insulin resistance and susceptibility to Type II diabetes. Diabetologia 2002, 45, 740–743. [Google Scholar] [CrossRef] [PubMed]
- Yoneda, M.; Hotta, K.; Nozaki, Y.; Endo, H.; Uchiyama, T.; Mawatari, H.; Iida, H.; Kato, S.; Hosono, K.; Fujita, K.; et al. Association between PPARGC1A polymorphisms and the occurrence of nonalcoholic fatty liver disease (NAFLD). BMC Gastroenterol. 2008, 8, 27. [Google Scholar] [CrossRef] [PubMed]
- Lin, Y.C.; Chang, P.F.; Chang, M.H.; Ni, Y.H. A common variant in the peroxisome proliferator-activated receptor-γ coactivator-1α gene is associated with nonalcoholic fatty liver disease in obese children. Am. J. Clin. Nutr. 2013, 97, 326–331. [Google Scholar] [CrossRef] [PubMed]
- Yang, H.; Li, Y.-Y.; Nie, Y.-Q.; Sha, W.-H.; Du, Y.-L.; Lai, X.-B.; Zhou, Y.J. Effect of peroxisome proliferator-activated receptors-γand co-activator-1α genetic polymorphisms on plasma adiponectin levels and susceptibility of non-alcoholic fatty liver disease in Chinese people. Liver Int. 2008, 28, 385–392. [Google Scholar] [CrossRef]
- van Dijk, K.W.; Rensen, P.C.; Voshol, P.J.; Havekes, L.M. The role and mode of action of apolipoproteins CIII and AV: Synergistic actors in triglyceride metabolism? Curr. Opin. Lipidol. 2004, 15, 239–246. [Google Scholar] [CrossRef] [PubMed]
- Guettier, J.M.; Georgopoulos, A.; Tsai, M.Y.; Radha, V.; Shanthirani, S.; Deepa, R.; Gross, M.; Rao, G.; Mohan, V. Polymorphisms in the fatty acid-binding protein 2 and apolipoprotein C-III genes are associated with the metabolic syndrome and dyslipidemia in a South Indian population. J. Clin. Endocrinol. Metab. 2005, 90, 1705–1711. [Google Scholar] [CrossRef] [PubMed]
- Petersen, K.F.; Dufour, S.; Feng, J.; Befroy, D.; Dziura, J.; Dalla Man, C.; Cobelli, C.; Shulman, G.I. Increased prevalence of insulin resistance and nonalcoholic fatty liver disease in Asian-Indian men. Proc. Natl. Acad. Sci. USA 2006, 103, 18273–18277. [Google Scholar] [CrossRef] [PubMed]
- Li, M.R.; Zhang, S.H.; Chao, K.; Liao, X.H.; Yao, J.Y.; Chen, M.H.; Zhong, B.H. Apolipoprotein C3 (-455T > C) polymorphism confers susceptibility to nonalcoholic fatty liver disease in the Southern Han Chinese population. World J. Gastroenterol. 2014, 20, 14010–14017. [Google Scholar] [CrossRef] [PubMed]
- Niu, T.H.; Jiang, M.; Xin, Y.N.; Jiang, X.J.; Lin, Z.H.; Xuan, S.Y. Lack of association between apolipoprotein C3 gene polymorphisms and risk of nonalcoholic fatty liver disease in a Chinese Han population. World J. Gastroenterol. 2014, 20, 3655–3662. [Google Scholar] [CrossRef] [PubMed]
- Hyysalo, J.; Stojkovic, I.; Kotronen, A.; Hakkarainen, A.; Sevastianova, K.; Makkonen, J.; Lundbom, N.; Rissanen, A.; Krauss, R.M.; Melander, O.; et al. Genetic variation in PNPLA3 but not APOC3 influences liver fat in non-alcoholic fatty liver disease. J. Gastroenterol. Hepatol. 2012, 27, 951–956. [Google Scholar] [CrossRef] [PubMed]
- Hussain, M.M.; Rava, P.; Walsh, M.; Rana, M.; Iqbal, J. Multiple functions of microsomal triglyceride transfer protein. Nutr. Metab. (Lond.) 2012, 9, 14. [Google Scholar] [CrossRef] [PubMed]
- Li, L.; Wang, S.J.; Shi, K.; Chen, D.; Jia, H.; Zhu, J. Correlation between MTP 493G > T polymorphism and non-alcoholic fatty liver disease risk: A meta-analysis. Genet. Mol. Res. 2014, 13, 10150–10161. [Google Scholar] [CrossRef] [PubMed]
- Namikawa, C.; Shu-Ping, Z.; Vyselaar, J.R.; Nozaki, Y.; Nemoto, Y.; Ono, M.; Akisawa, N.; Saibara, T.; Hiroi, M.; Enzan, H.; et al. Polymorphisms of microsomal triglyceride transfer protein gene and manganese superoxide dismutase gene in non-alcoholic steatohepatitis. J. Hepatol. 2004, 40, 781–786. [Google Scholar] [CrossRef] [PubMed]
- Gambino, R.; Cassader, M.; Pagano, G.; Durazzo, M.; Musso, G. Polymorphism in microsomal triglyceride transfer protein: A link between liver disease and atherogenic postprandial lipid profile in NASH? Hepatology 2007, 45, 1097–1107. [Google Scholar] [CrossRef] [PubMed]
- Oliveira, C.P.; Stefano, J.; Cavaleiro, A.M.; Zanella Fortes, M.A.; Vieira, S.M.; Rodrigues Lima, V.M.; Santos, T.E.; Santos, V.N.; de Azevedo Salgado, A.L.; Parise, E.R.; et al. Association of polymorphisms of glutamate-cystein ligase and microsomal triglyceride transfer protein genes in nonalcoholic fatty liver disease. J. Gastroenterol. Hepatol. 2010, 25, 357–361. [Google Scholar] [CrossRef] [PubMed]
- Hsiao, P.J.; Lee, M.Y.; Wang, Y.T.; Jiang, H.J.; Lin, P.C.; Yang, Y.H.; Kuo, K.K. MTTP-297H polymorphism reduced serum cholesterol but increased risk of non-alcoholic fatty liver disease-a cross-sectional study. BMC Med. Genet. 2015, 16, 93. [Google Scholar] [CrossRef] [PubMed]
- Song, J.; da Costa, K.A.; Fischer, L.M.; Kohlmeier, M.; Kwock, L.; Wang, S.; Zeisel, S.H. Polymorphism of the PEMT gene and susceptibility to nonalcoholic fatty liver disease (NAFLD). FASEB J. 2005, 19, 1266–1271. [Google Scholar] [CrossRef] [PubMed]
- Dong, H.; Wang, J.; Li, C.; Hirose, A.; Nozaki, Y.; Takahashi, M.; Ono, M.; Akisawa, N.; Iwasaki, S.; Saibara, T.; et al. The phosphatidylethanolamine N-methyltransferase gene V175M single nucleotide polymorphism confers the susceptibility to NASH in Japanese population. J. Hepatol. 2007, 46, 915–920. [Google Scholar] [CrossRef] [PubMed]
- Romeo, S.; Cohen, J.C.; Hobbs, H.H. No association between polymorphism in PEMT (V175M) and hepatic triglyceride content in the Dallas Heart Study. FASEB J. 2006, 20, 2180. [Google Scholar] [CrossRef] [PubMed]
- Jun, D.W.; Han, J.H.; Jang, E.C.; Kim, S.H.; Kim, S.H.; Jo, Y.J.; Park, Y.S.; Chae, J.D. Polymorphisms of microsomal triglyceride transfer protein gene and phosphatidylethanolamine N-methyltransferase gene in alcoholic and nonalcoholic fatty liver disease in Koreans. Eur. J. Gastroenterol. Hepatol. 2009, 21, 667–672. [Google Scholar] [CrossRef] [PubMed]
- Valenti, L.; Motta, B.M.; Alisi, A.; Sartorelli, R.; Buonaiuto, G.; Dongiovanni, P.; Rametta, R.; Pelusi, S.; Fargion, S.; Nobili, V. LPIN1 rs13412852 polymorphism in pediatric nonalcoholic fatty liver disease. J. Pediatr. Gastroenterol. Nutr. 2012, 54, 588–593. [Google Scholar] [CrossRef] [PubMed]
- Auinger, A.; Valenti, L.; Pfeuffer, M.; Helwig, U.; Herrmann, J.; Fracanzani, A.L.; Dongiovanni, P.; Fargion, S.; Schrezenmeir, J.; Rubin, D. A promoter polymorphism in the liver-specific fatty acid transport protein 5 is associated with features of the metabolic syndrome and steatosis. Horm. Metab. Res. 2010, 42, 854–859. [Google Scholar] [CrossRef] [PubMed]
- Younossi, Z.M.; Baranova, A.; Ziegler, K.; del Giacco, L.; Schlauch, K.; Born, T.L.; Elariny, H.; Gorreta, F.; VanMeter, A.; Younoszai, A.; et al. A genomic and proteomic study of the spectrum of nonalcoholicfatty liver disease. Hepatology 2005, 42, 665–674. [Google Scholar] [CrossRef] [PubMed]
- Borradaile, N.M.; Han, X.; Harp, J.D.; Gale, S.E.; Ory, D.S.; Schaffer, J.E. Disruption of endoplasmic reticulum structure and integrity in lipotoxic cell death. J. Lipid Res. 2006, 47, 2726–2737. [Google Scholar] [CrossRef] [PubMed]
- Chalasani, N.; Guo, X.; Loomba, R.; Goodarzi, M.O.; Haritunians, T.; Kwon, S.; Cui, J.; Taylor, K.D.; Wilson, L.; Cummings, O.W.; et al. Genome-wide association study identifies variants associated with histologic features of nonalcoholic Fatty liver disease. Gastroenterology 2010, 139, 1567–1576. [Google Scholar] [CrossRef] [PubMed]
- Santoro, N.; Feldstein, A.E.; Enoksson, E.; Pierpont, B.; Kursawe, R.; Kim, G.; Caprio, S. The association between hepatic fat content and liver injury in obese children and adolescents: Effects of ethnicity, insulin resistance, and common gene variants. Diabetes Care 2013, 36, 1353–1360. [Google Scholar] [CrossRef] [PubMed]
- Krawczyk, M.; Rau, M.; Schattenberg, J.M.; Bantel, H.; Pathil, A.; Demir, M.; Kluwe, J.; Boettler, T.; Lammert, F.; Geier, A.; et al. Combined effects of the PNPLA3 rs738409, TM6SF2 rs58542926, and MBOAT7 rs641738 variants on NAFLD severity: A multicenter biopsy-based study. J. Lipid Res. 2017, 58, 247–255. [Google Scholar] [CrossRef] [PubMed]
- Viitasalo, A.; Eloranta, A.M.; Atalay, M.; Romeo, S.; Pihlajamäki, J.; Lakka, T.A. Association of MBOAT7 gene variant with plasma ALT levels in children: the PANIC study. Pediatr. Res. 2016, 80, 651–655. [Google Scholar] [CrossRef] [PubMed]
- Rotman, Y.; Koh, C.; Zmuda, J.M.; Kleiner, D.E.; Liang, T.J. The association of genetic variability in patatin-like phospholipase domain-containing protein 3 (PNPLA3) with histological severity of nonalcoholic fatty liver disease. Hepatology 2010, 52, 894–903. [Google Scholar] [CrossRef] [PubMed]
- Sookoian, S.; Pirola, C.J. 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. [Google Scholar] [CrossRef] [PubMed]
- 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. [Google Scholar] [CrossRef] [PubMed]
- Speliotes, E.K.; Butler, J.L.; Palmer, C.D.; Voight, B.F.; Hirschhorn, J.N. PNPLA3 variants specifically confer increased risk for histologic nonalcoholic fatty liver disease but not metabolic disease. Hepatology 2010, 52, 904–912. [Google Scholar] [CrossRef] [PubMed]
- Valenti, L.; Alisi, A.; Galmozzi, E.; Bartuli, A.; Del Menico, B.; Alterio, A.; Dongiovanni, P.; Fargion, S.; Nobili, V. I148M patatinlike phospholipase domain-containing 3 gene variant and severity of pediatric nonalcoholic fatty liver disease. Hepatology 2010, 52, 1274–1280. [Google Scholar] [CrossRef] [PubMed]
- Valenti, L.; Al-Serri, A.; Daly, A.K.; Galmozzi, E.; Rametta, R.; Dongiovanni, P.; Nobili, V.; Mozzi, E.; Roviaro, G.; Vanni, E.; et al. Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease. Hepatology 2010, 51, 1209–1217. [Google Scholar] [CrossRef] [PubMed]
- Santoro, N.; Caprio, S.; Giannini, C.; Kim, G.; Kursawe, R.; Pierpont, B.; Shaw, M.M.; Feldstein, A.E. Oxidized fatty acids: A potential pathogenic link between fatty liver and type 2 diabetes in obese adolescents? Antioxid. Redox Signal. 2014, 20, 383–389. [Google Scholar] [CrossRef] [PubMed]
- Chen, L.Z.; Xin, Y.N.; Geng, N.; Jiang, M.; Zhang, D.D.; Xuan, S.Y. PNPLA3 I148M variant in nonalcoholic fatty liver disease: demographic and ethnic characteristics and the role of the variant in nonalcoholic fatty liver fibrosis. World J. Gastroenterol. 2015, 21, 794–802. [Google Scholar] [CrossRef] [PubMed]
- Dongiovanni, P.; Donati, B.; Fares, R.; Lombardi, R.; Mancina, R.M.; Romeo, S.; Valenti, L. PNPLA3 I148M polymorphism and progressive liver disease. World J. Gastroenterol. 2013, 19, 6969–6978. [Google Scholar] [CrossRef] [PubMed]
- Petta, S.; Miele, L.; Bugianesi, E.; Cammà, C.; Rosso, C.; Boccia, S.; Cabibi, D.; Di Marco, V.; Grimaudo, S.; Grieco, A.; et al. Glucokinase regulatory protein gene polymorphism affects liver fibrosis in non-alcoholic fatty liver disease. PLoS ONE 2014, 9, e87523. [Google Scholar] [CrossRef] [PubMed]
- Kitamoto, T.; Kitamoto, A.; Yoneda, M.; Hyogo, H.; Ochi, H.; Nakamura, T.; Teranishi, H.; Mizusawa, S.; Ueno, T.; Chayama, K.; et al. Genomewide scan revealed that polymorphisms in the PNPLA3, SAMM50, and PARVB genes are associated with development and progression of nonalcoholic fatty liver disease in Japanese population. Hum. Genet. 2013, 132, 783–792. [Google Scholar] [CrossRef] [PubMed]
- Frosst, P.; Blom, H.J.; Milos, R.; Goyette, P.; Sheppard, C.A.; Matthews, R.G.; Boers, G.J.; den Heijer, M.; Kluijtmans, L.A.; van den Heuvel, L.P.; et al. A candidate genetic risk factor for vascular disease: A common mutation in methylenetetrahydrofolate reductase. Nat. Genet. 1995, 10, 111–113. [Google Scholar] [CrossRef] [PubMed]
- Ventura, P.; Rosa, M.C.; Abbati, G.; Marchini, S.; Grandone, E.; Vergura, P.; Tremosini, S.; Zeneroli, M.L. Hyperhomocysteinaemia in chronic liver diseases: Role of disease stage, vitamin status and methylenetetrahydrofolate reductase genetics. Liver Int. 2005, 25, 49–56. [Google Scholar] [CrossRef] [PubMed]
- Ji, C.; Kaplowitz, N. Hyperhomocysteinemia, endoplasmic reticulum stress, and alcoholic liver injury. World J. Gastroenterol. 2004, 10, 1699–1708. [Google Scholar] [CrossRef] [PubMed]
- Sazci, A.; Ergul, E.; Aygun, C.; Akpinar, G.; Senturk, O.; Hulagu, S. Methylenetetrahydrofolate reductase gene polymorphisms in patients with nonalcoholic steatohepatitis (NASH). Cell Biochem. Funct. 2008, 26, 291–296. [Google Scholar] [CrossRef] [PubMed]
- Serin, E.; Güçlü, M.; Ataç, F.B.; Verdi, H.; Kayaselçuk, F.; Ozer, B.; Bilezikçi, B.; Yilmaz, U. Methylenetetrahydrofolate reductase C677T mutation and nonalcoholic fatty liver disease. Dig. Dis. Sci. 2007, 52, 1183–1186. [Google Scholar] [CrossRef] [PubMed]
- Franco Brochado, M.J.; Domenici, F.A.; Candolo Martinelli Ade, L.; Zucoloto, S.; de Carvalho da Cunha, S.F.; Vannucchi, H. Methylenetetrahydrofolate reductase gene polymorphism and serum homocysteine levels in nonalcoholic fatty liver disease. Ann. Nutr. Metab. 2013, 63, 193–199. [Google Scholar] [CrossRef] [PubMed]
- Hotamisligil, G.S.; Peraldi, P.; Budavari, A.; Ellis, R.; White, M.F.; Spiegelman, B.M. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-a2 and obesity-induced insulin resistance. Science 1996, 271, 665–668. [Google Scholar] [CrossRef] [PubMed]
- Valenti, L.; Fracanzani, A.L.; Dongiovanni, P.; Santorelli, G.; Branchi, A.; Taioli, E.; Fiorelli, G.; Fargion, S. Tumor necrosis factor alpha promoter polymorphisms and insulin resistance in nonalcoholic fatty liver disease. Gastroenterology 2002, 122, 274–280. [Google Scholar] [CrossRef] [PubMed]
- Huang, J.; Li, Y.Y.; Zhou, Y.J. Association between tumor necrosis factor-alpha gene polymorphism and insulin resistance in nonalcoholic fatty liver disease. Zhonghua Ganzangbing Zazhi 2006, 14, 613–615. [Google Scholar] [PubMed]
- Tokushige, K.; Takakura, M.; Tsuchiya-Matsushita, N.; Taniai, M.; Hashimoto, E.; Shiratori, K. Influence of TNF gene polymorphisms in Japanese patients with NASH and simple steatosis. J. Hepatol. 2007, 46, 1104–1110. [Google Scholar] [CrossRef] [PubMed]
- Wong, V.W.; Wong, G.L.; Tsang, S.W.; Hui, A.Y.; Chan, A.W.; Choi, P.C.; So, W.Y.; Tse, A.M.; Chan, F.K.; Sung, J.J.; et al. Genetic polymorphisms of adiponectin and tumor necrosis factor-alpha and nonalcoholic fatty liver disease in Chinese people. J. Gastroenterol. Hepatol. 2008, 23, 914–921. [Google Scholar] [CrossRef] [PubMed]
- Wang, J.K.; Feng, Z.W.; Li, Y.C.; Li, Q.Y.; Tao, X.Y. Association of tumor necrosis factor-α gene promoter polymorphism at sites -308 and -238 with non-alcoholic fatty liver disease: A meta-analysis. J. Gastroenterol. Hepatol. 2012, 27, 670–676. [Google Scholar] [CrossRef] [PubMed]
- Tilg, H.; Moschen, A.R. Insulin resistance, inflammation, and non-alcoholic fatty liver disease. Trends Endocrinol. Metab. 2008, 19, 371–379. [Google Scholar] [CrossRef] [PubMed]
- Nozaki, Y.; Saibara, T.; Nemoto, Y.; Ono, M.; Akisawa, N.; Iwasaki, S.; Hayashi, Y.; Hiroi, M.; Enzan, H.; Onishi, S. Polymorphisms of interleukin-1 beta and beta 3-adrenergic receptor in Japanese patients with nonalcoholic steatohepatitis. Alcohol. Clin. Exp. Res. 2004, 28, 106S–110S. [Google Scholar] [PubMed]
- Carulli, L.; Canedi, I.; Rondinella, S.; Lombardini, S.; Ganazzi, D.; Fargion, S.; De Palma, M.; Lonardo, A.; Ricchi, M.; Bertolotti, M.; et al. Genetic polymorphisms in non-alcoholic fatty liver disease: Interleukin-6-174G/C polymorphism is associated with non-alcoholic steatohepatitis. Dig. Liver Dis. 2009, 41, 823–828. [Google Scholar] [CrossRef] [PubMed]
- Nelson, J.E.; Handa, P.; Aouizerat, B.; Wilson, L.; Vemulakonda, L.A.; Yeh, M.M.; Kowdley, K.V. NASH Clinical Research Network. Increased parenchymal damage and steatohepatitis in Caucasian non-alcoholic fatty liver disease patients with common IL1B and IL6 polymorphisms. Aliment. Pharmacol. Ther. 2016, 44, 1253–1264. [Google Scholar] [CrossRef] [PubMed]
Gene | SNP | Function | Hepatic Fat | Circulating Lipids |
---|---|---|---|---|
PNPLA3 | rs738409 | Remodeling of lipid droplets | ||
>GCKR | >rs1260360 | >Modulation of hepatic lipogenesis | > | > |
TM6SF2 | rs58542926 | Modulation lipoprotein secretion |
Gene | Association |
---|---|
FDFT1 | rs2645424 could affect the progression toward fibrosis. |
MBOAT7 | rs626283 and rs641738 are two SNPs associated with fibrosis severity. |
PNPLA3 | The rs738409 variant is associated with an increased pro-apoptotic gene expression, NASH and fibrosis. |
GCKR | rs1260326 SNP has an independent association with NAFLD, biopsy proven NASH and fibrosis. |
TM6SF2 | rs58542926 SNP is associated with NAFLD, NASH, and fibrosis. |
NNPP1/PC-1 IRS-1 | The Lys121Gln variant in the NNPP1/PC-1 gene and the Gly972Arg in the IRS-1 gene are associated with fibrosis. |
ADIPOQ | 45G > T, 276G > T and 11377C > G are associated with lower adiponectin plasma levels, severity of steatosis, NASH, and fibrosis. |
SAMM50 | Sam50 polymorphisms might expose hepatic cells to higher oxidative stress. |
MTHFR | C677T and A1298C variants are associated with NASH. |
MTTP | −493G/T, E98D, I128T, N166S, and Q297H variants have been linked to an increased post prandial lipogenesisthat enhances the oxidative stress leading to Kupffer and stellate cells activation and then to inflammation. |
TNF-α | −1301C and -863A promoter polymorphisms are more prevalent in NASH. |
IL 1-β and IL-6 | IL 1-β rs16944, IL 1-β rs1143634 and IL-6 rs1049956 has been investigated in patients with biopsy proven NASH. |
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Umano, G.R.; Martino, M.; Santoro, N. The Association between Pediatric NAFLD and Common Genetic Variants. Children 2017, 4, 49. https://doi.org/10.3390/children4060049
Umano GR, Martino M, Santoro N. The Association between Pediatric NAFLD and Common Genetic Variants. Children. 2017; 4(6):49. https://doi.org/10.3390/children4060049
Chicago/Turabian StyleUmano, Giuseppina Rosaria, Mariangela Martino, and Nicola Santoro. 2017. "The Association between Pediatric NAFLD and Common Genetic Variants" Children 4, no. 6: 49. https://doi.org/10.3390/children4060049