Genetics of non-alcoholic fatty liver disease: From susceptibility and nutrient interactions to management

World Journal of Hepatology

Volumn 8, Issue 20, 2016, Pages 827-837

  Ravi Kanth, Vishnubhotla Venkata ^a   Sasikala, Mitnala ^a   Sharma, Mithun ^a   Rao, Padaki Nagaraja ^a   Reddy, Duvvuru Nageshwar ^a  

^a ASIAN INSTITUTE OF GASTROENTEROLOGY   (India)

Author keywords

Genetic susceptibility; Genotyping; Non alcoholic fatty liver disease; Nutrient interactions; Patatin like phospholipase domain containing 3 gene; Transmembrane 6 superfamily member 2 gene

Indexed keywords

EID: 84988446519     PISSN: None     EISSN: 19485182     Source Type: Journal    
DOI: 10.4254/wjh.v8.i20.827     Document Type: Article

References (66)

1. Bellentani S, Scaglioni F, Marino M, Bedogni G. Epidemiology of non-alcoholic fatty liver disease. Dig Dis 2010; 28: 155-161 [PMID: 20460905 DOI: 10.1159/000282080]
2. 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 [PMID: 23419824 DOI: 10.1016/j.jhep.2012.12.005]
3. Kawaguchi T, Sumida Y, Umemura A, Matsuo K, Takahashi M, Takamura T, Yasui K, Saibara T, Hashimoto E, Kawanaka M, Watanabe S, Kawata S, Imai Y, Kokubo M, Shima T, Park H, Tanaka H, Tajima K, Yamada R, Matsuda F. Genetic polymorphisms of the human PNPLA3 gene are strongly associated with severity of non-alcoholic fatty liver disease in Japanese. PLoS One 2012; 7: e38322 [PMID: 22719876 DOI: 10.1371/journal.pone.0038322]
4. Amarapurkar D, Kamani P, Patel N, Gupte P, Kumar P, Agal S, Baijal R, Lala S, Chaudhary D, Deshpande A. Prevalence of nonalcoholic fatty liver disease: population based study. Ann Hepatol 2007; 6: 161-163 [PMID: 17786142]
5. Gerhard GS, Chu X, Wood GC, Gerhard GM, Benotti P, Petrick AT, Gabrielsen J, Strodel WE, Still CD, Argyropoulos G. Nextgeneration sequence analysis of genes associated with obesity and nonalcoholic fatty liver disease-related cirrhosis in extreme obesity. Hum Hered 2013; 75: 144-151 [PMID: 24081230 DOI: 10.1159/000351719]
6. 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 [PMID: 18820647 DOI: 10.1038/ng.257]
7. Akuta N, Kawamura Y, Arase Y, Suzuki F, Sezaki H, Hosaka T, Kobayashi M, Kobayashi M, Saitoh S, Suzuki Y, Ikeda K, Kumada H. Relationships between Genetic Variations of PNPLA3, TM6SF2 and Histological Features of Nonalcoholic Fatty Liver Disease in Japan. Gut Liver 2016; 10: 437-445 [PMID: 26610348 DOI: 10.5009/gnl15163]
8. Kanth VV, Sasikala M, Rao PN, Steffie Avanthi U, Rao KR, Nageshwar Reddy D. Pooled genetic analysis in ultrasound measured non-alcoholic fatty liver disease in Indian subjects: A pilot study. World J Hepatol 2014; 6: 435-442 [PMID: 25018854 DOI: 10.4254/wjh.v6.i6.435]
9. Bhatt SP, Nigam P, Misra A, Guleria R, Pandey RM, Pasha MA. Genetic variation in the patatin-like phospholipase domaincontaining protein-3 (PNPLA-3) gene in Asian Indians with nonalcoholic fatty liver disease. Metab Syndr Relat Disord 2013; 11: 329-335 [PMID: 23734760 DOI: 10.1089/met.2012.0064]
10. Zhang Y, Cai W, Song J, Miao L, Zhang B, Xu Q, Zhang L, Yao H. Association between the PNPLA3 I148M polymorphism and nonalcoholic fatty liver disease in the Uygur and Han ethnic groups of northwestern China. PLoS One 2014; 9: e108381 [PMID: 25290313 DOI: 10.1371/journal.pone.0108381]
11. Peng XE, Wu YL, Lin SW, Lu QQ, Hu ZJ, Lin X. Genetic variants in PNPLA3 and risk of non-alcoholic fatty liver disease in a Han Chinese population. PLoS One 2012; 7: e50256 [PMID: 23226254 DOI: 10.1371/journal.pone.0050256]
12. Singal AG, Manjunath H, Yopp AC, Beg MS, Marrero JA, Gopal P, Waljee AK. The effect of PNPLA3 on fibrosis progression and development of hepatocellular carcinoma: a meta-analysis. Am J Gastroenterol 2014; 109: 325-334 [PMID: 24445574 DOI: 10.1038/ajg.2013.476]
13. 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 [PMID: 21381068 DOI: 10.1002/hep.24283]
14. Xu R, Tao A, Zhang S, Deng Y, Chen G. Association between patatin-like phospholipase domain containing 3 gene (PNPLA3) polymorphisms and nonalcoholic fatty liver disease: a HuGE review and meta-analysis. Sci Rep 2015; 5: 9284 [PMID: 25791171 DOI: 10.1038/srep09284]
15. Chalasani N, Guo X, Loomba R, Goodarzi MO, Haritunians T, Kwon S, Cui J, Taylor KD, Wilson L, Cummings OW, Chen YD, Rotter JI. Genome-wide association study identifies variants associated with histologic features of nonalcoholic Fatty liver disease. Gastroenterology 2010; 139: 1567-1576, 1576.e1-e6 [PMID: 20708005 DOI: 10.1053/j.gastro.2010.07.057]
16. Speliotes EK, Yerges-Armstrong LM, Wu J, Hernaez R, Kim LJ, Palmer CD, Gudnason V, Eiriksdottir G, Garcia ME, Launer LJ, Nalls MA, Clark JM, Mitchell BD, Shuldiner AR, Butler JL, Tomas M, Hoffmann U, Hwang SJ, Massaro JM, O'Donnell CJ, Sahani DV, Salomaa V, Schadt EE, Schwartz SM, Siscovick DS, Voight BF, Carr JJ, Feitosa MF, Harris TB, Fox CS, Smith AV, Kao WH, Hirschhorn JN, Borecki IB. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet 2011; 7: e1001324 [PMID: 21423719 DOI: 10.1371/journal.pgen.1001324]
17. Yuan X, Waterworth D, Perry JR, Lim N, Song K, Chambers JC, Zhang W, Vollenweider P, Stirnadel H, Johnson T, Bergmann S, Beckmann ND, Li Y, Ferrucci L, Melzer D, Hernandez D, Singleton A, Scott J, Elliott P, Waeber G, Cardon L, Frayling TM, Kooner JS, Mooser V. Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes. Am J Hum Genet 2008; 83: 520-528 [PMID: 18940312 DOI: 10.1016/j.ajhg.2008.09.012]
18. Chambers JC, Zhang W, Sehmi J, Li X, Wass MN, Van der Harst P, Holm H, Sanna S, Kavousi M, Baumeister SE, Coin LJ, Deng G, Gieger C, Heard-Costa NL, Hottenga JJ, Kühnel B, Kumar V, Lagou V, Liang L, Luan J, Vidal PM, Mateo Leach I, O'Reilly PF, Peden JF, Rahmioglu N, Soininen P, Speliotes EK, Yuan X, Thorleifsson G, Alizadeh BZ, Atwood LD, Borecki IB, Brown MJ, Charoen P, Cucca F, Das D, de Geus EJ, Dixon AL, Döring A, Ehret G, Eyjolfsson GI, Farrall M, Forouhi NG, Friedrich N, Goessling W, Gudbjartsson DF, Harris TB, Hartikainen AL, Heath S, Hirschfield GM, Hofman A, Homuth G, Hyppönen E, Janssen HL, Johnson T, Kangas AJ, Kema IP, Kühn JP, Lai S, Lathrop M, Lerch MM, Li Y, Liang TJ, Lin JP, Loos RJ, Martin NG, Moffatt MF, Montgomery GW, Munroe PB, Musunuru K, Nakamura Y, O'Donnell CJ, Olafsson I, Penninx BW, Pouta A, Prins BP, Prokopenko I, Puls R, Ruokonen A, Savolainen MJ, Schlessinger D, Schouten JN, Seedorf U, Sen-Chowdhry S, Siminovitch KA, Smit JH, Spector TD, Tan W, Teslovich TM, Tukiainen T, Uitterlinden AG, Van der Klauw MM, Vasan RS, Wallace C, Wallaschofski H, Wichmann HE, Willemsen G, Würtz P, Xu C, Yerges-Armstrong LM; Alcohol Genome-wide Association (AlcGen) Consortium; Diabetes Genetics Replication and Meta-analyses (DIAGRAM+) Study; Genetic Investigation of Anthropometric Traits (GIANT) Consortium; Global Lipids Genetics Consortium; Genetics of Liver Disease (GOLD) Consortium; International Consortium for Blood Pressure (ICBP-GWAS); Meta-analyses of Glucose and Insulin-Related Traits Consortium (MAGIC), Abecasis GR, Ahmadi KR, Boomsma DI, Caulfield M, Cookson WO, van Duijn CM, Froguel P, Matsuda K, McCarthy MI, Meisinger C, Mooser V, Pietiläinen KH, Schumann G, Snieder H, Sternberg MJ, Stolk RP, Thomas HC, Thorsteinsdottir U, Uda M, Waeber G, Wareham NJ, Waterworth DM, Watkins H, Whitfield JB, Witteman JC, Wolffenbuttel BH, Fox CS, Ala-Korpela M, Stefansson K, Vollenweider P, Völzke H, Schadt EE, Scott J, Järvelin MR, Elliott P, Kooner JS. Genomewide association study identifies loci influencing concentrations of liver enzymes in plasma. Nat Genet. 2011; 43: 1131-1138 [PMID: 22001757 doi: 10.1038/ng.970]
19. Kozlitina J, Smagris E, Stender S, Nordestgaard BG, Zhou HH, Tybjærg-Hansen A, Vogt TF, Hobbs HH, Cohen JC. Exomewide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2014; 46: 352-356 [PMID: 24531328 DOI: 10.1038/ng.2901]
20. Holmen OL, Zhang H, Fan Y, Hovelson DH, Schmidt EM, Zhou W, Guo Y, Zhang J, Langhammer A, Løchen ML, Ganesh SK, Vatten L, Skorpen F, Dalen H, Zhang J, Pennathur S, Chen J, Platou C, Mathiesen EB, Wilsgaard T, Njølstad I, Boehnke M, Chen YE, Abecasis GR, Hveem K, Willer CJ. Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk. Nat Genet 2014; 46: 345-351 [PMID: 24633158 DOI: 10.1038/ng.2926]
21. Mahdessian H, Taxiarchis A, Popov S, Silveira A, Franco-Cereceda A, Hamsten A, Eriksson P, van't Hooft F. TM6SF2 is a regulator of liver fat metabolism influencing triglyceride secretion and hepatic lipid droplet content. Proc Natl Acad Sci USA 2014; 111: 8913-8918 [PMID: 24927523 DOI: 10.1073/pnas.1323785111]
22. Day CP. From fat to inflammation. Gastroenterology 2006; 130: 207-210 [PMID: 16401483 DOI: 10.1053/j.gastro.2005.11.017]
23. Karathanasis SK, Oettgen P, Haddad IA, Antonarakis SE. Structure, evolution, and polymorphisms of the human apolipoprotein A4 gene (APOA4). Proc Natl Acad Sci USA 1986; 83: 8457-8461 [PMID: 3095836]
24. Petersen KF, Dufour S, Hariri A, Nelson-Williams C, Foo JN, Zhang XM, Dziura J, Lifton RP, Shulman GI. Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease. N Engl J Med 2010; 362: 1082-1089 [PMID: 20335584 DOI: 10.1056/NEJMoa0907295]
25. Kozlitina J, Boerwinkle E, Cohen JC, Hobbs HH. Dissociation between APOC3 variants, hepatic triglyceride content and insulin resistance. Hepatology 2011; 53: 467-474 [PMID: 21274868 DOI: 10.1002/hep.24072]
26. TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute, Crosby J, Peloso GM, Auer PL, Crosslin DR, Stitziel NO, Lange LA, Lu Y, Tang ZZ, Zhang H, Hindy G, Masca N, Stirrups K, Kanoni S, Do R, Jun G, Hu Y, Kang HM, Xue C, Goel A, Farrall M, Duga S, Merlini PA, Asselta R, Girelli D, Olivieri O, Martinelli N, Yin W, Reilly D, Speliotes E, Fox CS, Hveem K, Holmen OL, Nikpay M, Farlow DN, Assimes TL, Franceschini N, Robinson J, North KE, Martin LW, DePristo M, Gupta N, Escher SA, Jansson JH, Van Zuydam N, Palmer CN, Wareham N, Koch W, Meitinger T, Peters A, Lieb W, Erbel R, Konig IR, Kruppa J, Degenhardt F, Gottesman O, Bottinger EP, O'Donnell CJ, Psaty BM, Ballantyne CM, Abecasis G, Ordovas JM, Melander O, Watkins H, Orho-Melander M, Ardissino D, Loos RJ, McPherson R, Willer CJ, Erdmann J, Hall AS, Samani NJ, Deloukas P, Schunkert H, Wilson JG, Kooperberg C, Rich SS, Tracy RP, Lin DY, Altshuler D, Gabriel S, Nickerson DA, Jarvik GP, Cupples LA, Reiner AP, Boerwinkle E, Kathiresan S. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med 2014; 371: 22-31 [PMID: 24941081 DOI: 10.1056/NEJMoa1307095]
27. Ravikanth VV, Mitnala S, Avanthi US, Manjeera B, Aswini R, Mukherjee RM, Rao PN, Reddy DN. PNPLA3 gene polymorphism but not APOC3 enhances risk for nonalcoholic fatty liver disease in Indian subjects. J Clin Exp Hepatol 2013; 3: S24 [DOI: 10.1016/j.jceh.2013.03.049]
28. Narcisi TM, Shoulders CC, Chester SA, Read J, Brett DJ, Harrison GB, Grantham TT, Fox MF, Povey S, de Bruin TW. Mutations of the microsomal triglyceride-transfer-protein gene in abetalipoproteinemia. Am J Hum Genet 1995; 57: 1298-1310 [PMID: 8533758]
29. Li L, Wang SJ, 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 [PMID: 25501226 DOI: 10.4238/2014.December.4.9]
30. Braunersreuther V, Viviani GL, Mach F, Montecucco F. Role of cytokines and chemokines in non-alcoholic fatty liver disease. World J Gastroenterol 2012; 18: 727-735 [PMID: 22371632 DOI: 10.3748/wjg.v18.i8.727]
31. Lesmana CR, Hasan I, Budihusodo U, Gani RA, Krisnuhoni E, Akbar N, Lesmana LA. Diagnostic value of a group of biochemical markers of liver fibrosis in patients with non-alcoholic steatohepatitis. J Dig Dis 2009; 10: 201-206 [PMID: 19659788 DOI: 10.1111/j.1751-2980.2009.00386.x]
32. Hui JM, Hodge A, Farrell GC, Kench JG, Kriketos A, George J. Beyond insulin resistance in NASH: TNF-alpha or adiponectin? Hepatology 2004; 40: 46-54 [PMID: 15239085 DOI: 10.1002/hep.20280]
33. Crespo J, Cayón A, Fernández-Gil P, Hernández-Guerra M, Mayorga M, Domínguez-Díez A, Fernández-Escalante JC, Pons-Romero F. Gene expression of tumor necrosis factor alpha and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology 2001; 34: 1158-1163 [PMID: 11732005 DOI: 10.1053/jhep.2001.29628]
34. Manco M, Marcellini M, Giannone G, Nobili V. Correlation of serum TNF-alpha levels and histologic liver injury scores in pediatric nonalcoholic fatty liver disease. Am J Clin Pathol 2007; 127: 954-960 [PMID: 17509993 DOI: 10.1309/6VJ4 DWGYDU0XYJ8Q]
35. Hu ZW, Luo HB, Xu YM, Guo JW, Deng XL, Tong YW, Tang X. Tumor necrosis factor-alpha gene promoter polymorphisms in Chinese patients with nonalcoholic fatty liver diseases. Acta Gastroenterol Belg 2009; 72: 215-221 [PMID: 19637776]
36. Stärkel P, Sempoux C, Leclercq I, Herin M, Deby C, Desager JP, Horsmans Y. Oxidative stress, KLF6 and transforming growth factor-beta up-regulation differentiate non-alcoholic steatohepatitis progressing to fibrosis from uncomplicated steatosis in rats. J Hepatol 2003; 39: 538-546 [PMID: 12971963 DOI: 10.1016/S0168-8278(03)00360-X]
37. Nieto-Vazquez I, Fernández-Veledo S, de Alvaro C, Lorenzo M. Dual role of interleukin-6 in regulating insulin sensitivity in murine skeletal muscle. Diabetes 2008; 57: 3211-3221 [PMID: 18796617 DOI: 10.2337/db07-1062]
38. Wieckowska A, Papouchado BG, Li Z, Lopez R, Zein NN, Feldstein AE. Increased hepatic and circulating interleukin-6 levels in human nonalcoholic steatohepatitis. Am J Gastroenterol 2008; 103: 1372-1379 [PMID: 18510618 DOI: 10.1111/j.1572-0241. 2007.01774.x]
39. Carulli L, Canedi I, Rondinella S, Lombardini S, Ganazzi D, Fargion S, De Palma M, Lonardo A, Ricchi M, Bertolotti M, Carulli N, Loria P. 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 [PMID: 19403348 DOI: 10.1016/j.dld.2009.03.005]
40. Giannitrapani L, Soresi M, Balasus D, Licata A, Montalto G. Genetic association of interleukin-6 polymorphism (-174 G/C) with chronic liver diseases and hepatocellular carcinoma. World J Gastroenterol 2013; 19: 2449-2455 [PMID: 23674845 DOI: 10.3748/wjg.v19.i16.2449]
41. Eskdale J, Kube D, Tesch H, Gallagher G. Mapping of the human IL10 gene and further characterization of the 5' flanking sequence. Immunogenetics 1997; 46: 120-128 [PMID: 9162098 DOI: 10.1007/s002510050250]
42. Couper KN, Blount DG, Riley EM. IL-10: the master regulator of immunity to infection. J Immunol 2008; 180: 5771-5777 [PMID: 18424693 DOI: 10.4049/jimmunol.180.9.5771]
43. den Boer MA, Voshol PJ, Schröder-van der Elst JP, Korsheninnikova E, Ouwens DM, Kuipers F, Havekes LM, Romijn JA. Endogenous interleukin-10 protects against hepatic steatosis but does not improve insulin sensitivity during high-fat feeding in mice. Endocrinology 2006; 147: 4553-4558 [PMID: 16709607 DOI: 10.1210/en.2006-0417]
44. Cintra DE, Pauli JR, Araújo EP, Moraes JC, de Souza CT, Milanski M, Morari J, Gambero A, Saad MJ, Velloso LA. Interleukin-10 is a protective factor against diet-induced insulin resistance in liver. J Hepatol 2008; 48: 628-637 [PMID: 18267346 DOI: 10.1016/j.jhep.2007.12.017]
45. Pedersen O. Genetics of insulin resistance. Exp Clin Endocrinol Diabetes 1999; 107: 113-118 [PMID: 10320051 DOI: 10.1055/s-0029-1212085]
46. Dongiovanni P, Valenti L, Rametta R, Daly AK, Nobili V, Mozzi E, Leathart JB, Pietrobattista A, Burt AD, Maggioni M, Fracanzani AL, Lattuada E, Zappa MA, Roviaro G, Marchesini G, Day CP, Fargion S. 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 [PMID: 20176643 DOI: 10.1136/gut.2009.190801]
47. Sanyal AJ, Campbell-Sargent C, Mirshahi F, Rizzo WB, Contos MJ, Sterling RK, Luketic VA, Shiffman ML, Clore JN. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 2001; 120: 1183-1192 [PMID: 11266382 DOI: 10.1053/gast.2001.23256]
48. Day CP. Pathogenesis of steatohepatitis. Best Pract Res Clin Gastroenterol 2002; 16: 663-678 [PMID: 12406438 DOI: 10.1053/bega.2002.0333]
49. Wang K. Molecular mechanisms of hepatic apoptosis. Cell Death Dis 2014; 5: e996 [PMID: 24434519 doi: 10.1038/cddis. 2013.499]
50. Namikawa C, Shu-Ping Z, Vyselaar JR, Nozaki Y, Nemoto Y, Ono M, Akisawa N, Saibara T, Hiroi M, Enzan H, Onishi S. Polymorphisms of microsomal triglyceride transfer protein gene and manganese superoxide dismutase gene in non-alcoholic steatohepatitis. J Hepatol 2004; 40: 781-786 [PMID: 15094225 DOI: 10.1016/j.jhep.2004.01.028]
51. Ghobadloo SM, Yaghmaei B, Bakayev V, Goudarzi H, Noorinayer B, Rad FH, Samiy S, Aghabozorghi S, Zali MR. GSTP1, GSTM1, and GSTT1 genetic polymorphisms in patients with cryptogenic liver cirrhosis. J Gastrointest Surg 2004; 8: 423-427 [PMID: 15120366 DOI: 10.1016/j.gassur.2004.02.005]
52. Assy N. Nutritional recommendations for patients with nonalcoholic fatty liver diseases. World J Gastroenterol 2011; 17: 3375-3376 [PMID: 21876629 DOI: 10.3748/wjg.v17.i29.3375]
53. Eslamparast T, Eghtesad S, Poustchi H, Hekmatdoost A. Recent advances in dietary supplementation, in treating non-alcoholic fatty liver disease. World J Hepatol 2015; 7: 204-212 [PMID: 25729475 DOI: 10.4254/wjh.v7.i2.204]
54. Dongiovanni P, Lanti C, Riso P, Valenti L. Nutritional therapy for nonalcoholic fatty liver disease. J Nutr Biochem 2016; 29: 1-11 [PMID: 26895659 DOI: 10.1016/j.jnutbio.2015.08.024]
55. Phillips CM, Tierney AC, Roche HM. Gene-nutrient interactions in the metabolic syndrome. J Nutrigenet Nutrigenomics 2008; 1: 136-151 [PMID: 19776623 DOI: 10.1159/000112461]
56. Wise C, Kaput J. A strategy for analyzing gene-nutrient interactions in type 2 diabetes. J Diabetes Sci Technol 2009; 3: 710-721 [PMID: 20144318 DOI: 10.1177/193229680900300416]
57. Kim CH, Younossi ZM. Nonalcoholic fatty liver disease: a manifestation of the metabolic syndrome. Cleve Clin J Med 2008; 75: 721-728 [PMID: 18939388 DOI: 10.3949/ccjm.75.10.721]
58. Prentice AM, Hennig BJ, Fulford AJ. Evolutionary origins of the obesity epidemic: natural selection of thrifty genes or genetic drift following predation release? Int J Obes (Lond) 2008; 32: 1607-1610 [PMID: 18852700 DOI: 10.1038/ijo.2008.147]
59. Bos G, Snijder MB, Nijpels G, Dekker JM, Stehouwer CD, Bouter LM, Heine RJ, Jansen H. Opposite contributions of trunk and leg fat mass with plasma lipase activities: the Hoorn study. Obes Res 2005; 13: 1817-1823 [PMID: 16286530 DOI: 10.1038/oby.2005.221]
60. Santos JL, Boutin P, Verdich C, Holst C, Larsen LH, Toubro S, Dina C, Saris WH, Blaak EE, Hoffstedt J, Taylor MA, Polak J, Clement K, Langin D, Astrup A, Froguel P, Pedersen O, Sorensen TI, Martinez JA. Genotype-by-nutrient interactions assessed in European obese women. A case-only study. Eur J Nutr 2006; 45: 454-462 [PMID: 17080261 DOI: 10.1007/s00394-006-0619-6]
61. Ordovas JM, Corella D, Demissie S, Cupples LA, Couture P, Coltell O, Wilson PW, Schaefer EJ, Tucker KL. Dietary fat intake determines the effect of a common polymorphism in the hepatic lipase gene promoter on high-density lipoprotein metabolism: evidence of a strong dose effect in this gene-nutrient interaction in the Framingham Study. Circulation 2002; 106: 2315-2321 [PMID: 12403660 DOI: 10.1161/01.CIR.0000036597.52291.C9]
62. Nilsson SK, Christensen S, Raarup MK, Ryan RO, Nielsen MS, Olivecrona G. "Endocytosis of apolipoprotein A-V by members of the low density lipoprotein receptor and the VPS10p domain receptor families". The Journal of Biological Chemistry 2008; 283: 25920-25927 [PMID: 18603531 doi: 10.1074/jbc.M802721200]
63. Lai CQ, Corella D, Demissie S, Cupples LA, Adiconis X, Zhu Y, Parnell LD, Tucker KL, Ordovas JM. Dietary intake of n-6 fatty acids modulates effect of apolipoprotein A5 gene on plasma fasting triglycerides, remnant lipoprotein concentrations, and lipoprotein particle size: the Framingham Heart Study. Circulation 2006; 113: 2062-2070 [PMID: 16636175 DOI: 10.1161/CIRCULATIONAHA.105.577296]
64. 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 [PMID: 21525193 DOI: 10.3945/ajcn.111.012369]
65. 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: e37827 [PMID: 22629460 DOI: 10.1371/journal.pone.0037827]
66. Kitamoto T, Kitamoto A, Yoneda M, Hyogo H, Ochi H, Nakamura T, Teranishi H, Mizusawa S, Ueno T, Chayama K, Nakajima A, Nakao K, Sekine A, Hotta K. Genome-wide scan revealed that polymorphisms in the PNPLA3, SAMM50, and PARVB genes are associated with development and progression of nonalcoholic fatty liver disease in Japan. Hum Genet 2013; 132: 783-792 [PMID: 23535911 DOI: 10.1007/s00439-013-1294-3]