Digestive Diseases and Sciences

, Volume 61, Issue 8, pp 2284–2293 | Cite as

APOC3 rs2070666 Is Associated with the Hepatic Steatosis Independently of PNPLA3 rs738409 in Chinese Han Patients with Nonalcoholic Fatty Liver Diseases

  • Rui-Nan Zhang
  • Rui-Dan Zheng
  • Yu-Qiang Mi
  • Da Zhou
  • Feng Shen
  • Guang-Yu Chen
  • Chan-Yan Zhu
  • Qin PanEmail author
  • Jian-Gao FanEmail author
Original Article


Background and Aim

The association between nonalcoholic fatty liver disease (NAFLD) and apolipoprotein C3 gene (APOC3) promoter region single-nucleotide polymorphisms (SNPs) rs2854117 and rs2854116 is controversial. The aim of this study was to investigate the relationship between other polymorphisms of APOC3 and NAFLD in Chinese.


Fifty-nine liver biopsy-proven NAFLD patients and 72 healthy control subjects were recruited to a cohort representing Chinese Han population. The polymorphisms in the exons and flanking regions of APOC3 and patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 polymorphisms were genotyped.


Among the five SNPs (rs4225, rs4520, rs5128, rs2070666, and rs2070667) in APOC3, only rs2070666 (c.179 + 62 T/A) was significantly different in genotype and allele frequency (both p < 0.01) between groups of NAFLD and control. After adjusting for sex, age, serum triglycerides, total cholesterol, body mass index, and the PNPLA3 rs738409 polymorphism, the APOC3 rs2070666 A allele was an independent risk factor for NAFLD with an odds ratio (OR) of 3.683 and 95 % confidence interval (CI) of 1.037–13.084. The APOC3 rs2070666 A allele was linked to the fourth quartile of the controlled attenuation parameter values (OR 2.769, 95 % CI 1.002–7.651) in 131 subjects, and also linked to the significant histological steatosis (OR 4.986, 95 % CI 1.020–24.371), but neither to liver stiffness measurement values nor to hepatic histological activity and fibrosis in NAFLD patients.


The APOC3 rs2070666 A allele is a risk factor for NAFLD independent of obesity, dyslipidemia, and PNPLA3 rs738409, and it might contribute to increased liver fat content in Chinese Han population.


Nonalcoholic fatty liver disease Single-nucleotide polymorphisms Apolipoprotein C3 Liver biopsy FibroScan 



This work was supported by the State Key Development Program for Basic Research of China (2012CB517501), the National Natural Science Foundation of China (81270491 and 81470840), the 100 Talents Program of the Shanghai Board of Health (XBR2011007), the Program of the Shanghai Committee of Science and Technology (10411956300).

Compliance with ethical standards

Conflict of interest



  1. 1.
    Chitturi S, Wong VW, Farrell G. Nonalcoholic fatty liver in Asia: firmly entrenched and rapidly gaining ground. J Gastroenterol Hepatol. 2011;26:163–172.CrossRefPubMedGoogle Scholar
  2. 2.
    Adams LA, Waters OR, Knuiman MW, et al. NAFLD as a risk factor for the development of diabetes and the metabolic syndrome: an eleven-year follow-up study. Am J Gastroenterol. 2009;104:861–867.CrossRefPubMedGoogle Scholar
  3. 3.
    Rinella ME. Nonalcoholic fatty liver disease: a systematic review. JAMA. 2015;313:2263–2273.CrossRefPubMedGoogle Scholar
  4. 4.
    Browning JD, Szczepaniak LS, Dobbins R, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology. 2004;40:1387–1395.CrossRefPubMedGoogle Scholar
  5. 5.
    Li YY. Genetic and epigenetic variants influencing the development of nonalcoholic fatty liver disease. World J Gastroenterol. 2012;18:6546–6551.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Duseja A, Aggarwal R. APOC3 and PNPLA3 in non-alcoholic fatty liver disease: need to clear the air. J Gastroenterol Hepatol. 2012;27:848–851.CrossRefPubMedGoogle Scholar
  7. 7.
    Li Y, Xing C, Cohen JC, et al. Genetic variant in PNPLA3 is associated with nonalcoholic fatty liver disease in China. Hepatology. 2012;55:327–328.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Peng XE, Wu YL, Lin SW, et al. Genetic variants in PNPLA3 and risk of non-alcoholic fatty liver disease in a Han Chinese population. PLoS One. 2012;7:e50256.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Li X, Zhao Q, Wu K, et al. I148 M variant of PNPLA3 confer increased risk for nonalcoholic fatty liver disease not only in European population, but also in Chinese population. Hepatology. 2011;54:2275.CrossRefPubMedGoogle Scholar
  10. 10.
    Pan Q, Zhang RN, Wang YQ, et al. Linked PNPLA3 polymorphisms confer susceptibility to nonalcoholic steatohepatitis and decreased viral load in chronic hepatitis B. World J Gastroenterol. 2015;21:8605–8614.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Karathanasis SK. Apolipoprotein multigene family: tandem organization of human apolipoprotein AI, CIII, and AIV genes. Proc Natl Acad Sci USA. 1985;82:6374–6378.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Petersen KF, Dufour S, Hariri A, et al. Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease. N Engl J Med. 2010;362:1082–1089.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Olivieri O, Bassi A, Stranieri C, et al. Apolipoprotein C-III, metabolic syndrome, and risk of coronary artery disease. J Lipid Res. 2003;44:2374–2381.CrossRefPubMedGoogle Scholar
  14. 14.
    van Hoek M, van Herpt TW, Dehghan A, et al. Association of an APOC3 promoter variant with type 2 diabetes risk and need for insulin treatment in lean persons. Diabetologia. 2011;54:1360–1367.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Shanker J, Perumal G, Rao VS, et al. Genetic studies on the APOA1-C3-A5 gene cluster in Asian Indians with premature coronary artery disease. Lipids Health Dis. 2008;7:33.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Miller M, Rhyne J, Chen H, et al. APOC3 promoter polymorphisms C-482T and T-455C are associated with the metabolic syndrome. Arch Med Res. 2007;38:444–451.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Herron KL, Lofgren IE, Adiconis X, et al. Associations between plasma lipid parameters and APOC3 and APOA4 genotypes in a healthy population are independent of dietary cholesterol intake. Atherosclerosis. 2006;184:113–120.CrossRefPubMedGoogle Scholar
  18. 18.
    Li MR, Zhang SH, Chao K, et al. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Verrijken A, Beckers S, Francque S, et al. A gene variant of PNPLA3, but not of APOC3, is associated with histological parameters of NAFLD in an obese population. Obesity (Silver Spring). 2013;21:2138–2145.CrossRefGoogle Scholar
  20. 20.
    Hyysalo J, Stojkovic I, Kotronen A, 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.CrossRefPubMedGoogle Scholar
  21. 21.
    Valenti L, Nobili V, Al-Serri A, et al. The APOC3 T-455C and C-482T promoter region polymorphisms are not associated with the severity of liver damage independently of PNPLA3 I148M genotype in patients with nonalcoholic fatty liver. J Hepatol. 2011;55:1409–1414.CrossRefPubMedGoogle Scholar
  22. 22.
    Niu TH, Jiang M, Xin YN, et al. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Fan JG, Jia JD, Li YM, et al. Guidelines for the diagnosis and management of nonalcoholic fatty liver disease: update 2010. J Dig Dis. 2011;12:38–44. (published in Chinese on Chinese Journal of Hepatology 2010; 18:163–166).CrossRefPubMedGoogle Scholar
  24. 24.
    Wong VW, Vergniol J, Wong GL, et al. Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease. Hepatology. 2010;51:454–462.CrossRefPubMedGoogle Scholar
  25. 25.
    Gaia S, Carenzi S, Barilli AL, et al. Reliability of transient elastography for the detection of fibrosis in non-alcoholic fatty liver disease and chronic viral hepatitis. J Hepatol. 2011;54:64–71.CrossRefPubMedGoogle Scholar
  26. 26.
    Sasso M, Tengher-Barna I, Ziol M, et al. Novel controlled attenuation parameter for noninvasive assessment of steatosis using Fibroscan((R)): validation in chronic hepatitis C. J Viral Hepat. 2012;19:244–253.CrossRefPubMedGoogle Scholar
  27. 27.
    Bedossa P. Utility and appropriateness of the fatty liver inhibition of progression (FLIP) algorithm and steatosis, activity, and fibrosis (SAF) score in the evaluation of biopsies of nonalcoholic fatty liver disease. Hepatology. 2014;60:565–575.CrossRefPubMedGoogle Scholar
  28. 28.
    Dorfmeister B, Cooper JA, Stephens JW, et al. The effect of APOA5 and APOC3 variants on lipid parameters in European Whites, Indian Asians and Afro-Caribbeans with type 2 diabetes. Biochim Biophys Acta. 2007;1772:355–363.CrossRefPubMedGoogle Scholar
  29. 29.
    Fiegenbaum M, de Andrade FM, Hutz MH. Association between plasma lipid parameters and APOC3 genotypes in Brazilian subjects: effect of gender, smoking and APOE genotypes. Clin Chim Acta. 2007;380:175–181.CrossRefPubMedGoogle Scholar
  30. 30.
    Sun Y, Shi J, Zhang S, et al. The APOC3 SstI polymorphism is weakly associated with sporadic Alzheimer’s disease in a Chinese population. Neurosci Lett. 2005;380:219–222.CrossRefPubMedGoogle Scholar
  31. 31.
    Sookoian S, Castano G, Gianotti TF, et al. Genetic variants in STAT3 are associated with nonalcoholic fatty liver disease. Cytokine. 2008;44:201–206.CrossRefPubMedGoogle Scholar
  32. 32.
    Sano M, Kuroi N, Nakayama T, et al. Association study of calcitonin-receptor-like receptor gene in essential hypertension. Am J Hypertens. 2005;18:403–408.CrossRefPubMedGoogle Scholar
  33. 33.
    Lehman DM, Fu DJ, Freeman AB, et al. A single nucleotide polymorphism in MGEA5 encoding O-GlcNAc-selective N-acetyl-beta-d glucosaminidase is associated with type 2 diabetes in Mexican Americans. Diabetes. 2005;54:1214–1221.CrossRefPubMedGoogle Scholar
  34. 34.
    Euskirchen G, Royce TE, Bertone P, et al. CREB binds to multiple loci on human chromosome 22. Mol Cell Biol. 2004;24:3804–3814.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Santoro N, Kursawe R, D’Adamo E, 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.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Valenti L, Alisi A, Nobili V. Unraveling the genetics of fatty liver in obese children: additive effect of P446L GCKR and I148M PNPLA3 polymorphisms. Hepatology. 2012;55:661–663.CrossRefPubMedGoogle Scholar
  37. 37.
    Bedossa P, Poitou C, Veyrie N, et al. Histopathological algorithm and scoring system for evaluation of liver lesions in morbidly obese patients. Hepatology. 2012;56:1751–1759.CrossRefPubMedGoogle Scholar
  38. 38.
    Kim BK, Fung J, Yuen MF, et al. Clinical application of liver stiffness measurement using transient elastography in chronic liver disease from longitudinal perspectives. World J Gastroenterol. 2013;19:1890–1900.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Sentinelli F, Romeo S, Maglio C, et al. Lack of effect of apolipoprotein C3 polymorphisms on indices of liver steatosis, lipid profile and insulin resistance in obese Southern Europeans. Lipids Health Dis. 2011;10:93.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Rui-Nan Zhang
    • 1
  • Rui-Dan Zheng
    • 2
  • Yu-Qiang Mi
    • 3
  • Da Zhou
    • 1
  • Feng Shen
    • 1
  • Guang-Yu Chen
    • 1
  • Chan-Yan Zhu
    • 1
  • Qin Pan
    • 1
    Email author
  • Jian-Gao Fan
    • 1
    Email author
  1. 1.Department of Gastroenterology and Center for Fatty Liver, Xinhua HospitalShanghai Jiaotong University School of MedicineShanghaiChina
  2. 2.Department of HepatologyZhengxing HospitalZhangzhouChina
  3. 3.Department of Infective DiseaseTianjin Infectious Disease HospitalTianjinChina

Personalised recommendations