Hepatology International

, Volume 12, Issue 5, pp 429–437 | Cite as

Single-nucleotide rs738409 polymorphisms in the PNPLA3 gene are strongly associated with alcoholic liver disease in Han Chinese males

  • Yanfang Zhang
  • Tongsheng Guo
  • Funing Yang
  • Yuanli Mao
  • Liubing Li
  • Chenxi Liu
  • Qiang Sun
  • Yongzhe LiEmail author
  • Jing HuangEmail author
Review Article



Alcoholic liver disease (ALD) is a chronic liver disorder caused by the consumption of large amounts of alcohol. Genome-wide association studies have recently confirmed that polymorphisms in PNPLA3 predispose individuals to ALD and have identified risk loci of MBOAT7 and TM6SF2 in persons of European descent. However, the association with alcoholic liver damage has not been evaluated thus far in a Han Chinese population.


We performed a large case-control multicenter study of 507 ALD patients and 645 ethnically matched healthy controls. Five SNPs were genotyped using matrix-assisted laser desorption/ionization time of flight mass spectrometry, and association analysis was performed using PLINK 1.07 software.


The rs738409 in the PNPLA3 gene was found to be significantly associated with ALD in allele and genotype frequencies (p = 6.25 × 10−14 and p = 9.05 × 10−13). The frequencies of the risk allele G in rs738409 were notably higher in ALD compared to controls (odds ratio = 1.93, 95% confidence interval = 1.63–2.28). The current study showed that the genotype frequencies of three genetic models were also statistically significant (p = 1.07 × 10−13, p = 9.3 × 10−8, and p = 1.57 × 10−12). Additionally, the G-allele of rs738409 was associated with a variety of clinical manifestations such as elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyl transpeptidase (GGT), and mean corpuscular volume (MCV) in the patients with ALD.


In a Han Chinese population, the present study confirmed that PNPLA3 polymorphism rs738409 was more likely to influence the susceptibility to ALD. However, no statistically significant differences for the allele and genotype frequencies of rs626283, rs641738 in MBOAT7, rs10401969 in SUGP1 and rs58542926 in TM6SF2 were found between ALD patients and healthy controls.


Alcoholic liver diseases Han Chinese Single-nucleotide polymorphism PNPLA3 MBOAT7 TM6SF2 SUGP1 



Alcoholic liver disease


Single-nucleotide polymorphism


Genome-wide association studies


Hardy–Weinberg equilibrium


Linkage disequilibrium


Odds ratio


Confidence interval




Alanine aminotransferase


Aspartate aminotransferase


γ-Glutamyl transpeptidase


Prothrombin time


Erythrocyte mean corpuscular volume


Total bilirubin



We are most grateful to all our colleagues who contributed to the ALD study. We thank Chunlei Cao of the Beijing Institute of Genomics for help and suggestions in genotyping and data analysis.

Author contributions

YFZ and FNY conceived the project, conducted the experiment, statistical analysis, and drafting of manuscript; TSG and YLM collected the samples and provided valuable discussion; YZL and JH supervised the experiment, revised the paper, and performed statistical analysis; LBL, CXL, and SQ collected the samples and extracted genomic DNA.

Compliance with ethical standards

Conflict of interest

Yanfang Zhang, Tongsheng Guo, Funing Yang, Yuanli Mao, Liubing Li, Chenxi Liu, Qiang Sun, Yongzhe Li, and Jing Huang declare no conflict of interest.

Ethical statements

The study followed the rules of the ethical committees of four participating centers.

Informed consent

All participants in this study gave informed consent prior to enrollment.


  1. 1.
    Rehm J, Samokhvalov AV, Shield KD. Global burden of alcoholic liver diseases. J Hepatol 2013;59:160–168Google Scholar
  2. 2.
    Tang YL, Xiang XJ, Wang XY, Cubells JF, Babor TF, Hao W. Alcohol and alcohol-related harm in China: policy changes needed. Bull World Health Organ 2013;91:270–276Google Scholar
  3. 3.
    Hao W, Chen H, Su Z. China: alcohol today. Addiction 2005;100:737–741Google Scholar
  4. 4.
    Lombardi R, Buzzetti E, Roccarina D, Tsochatzis EA. Non-invasive assessment of liver fibrosis in patients with alcoholic liver disease. World J Gastroenterol 2015;21:11044–11052Google Scholar
  5. 5.
    Tsukamoto H. Conceptual importance of identifying alcoholic liver disease as a lifestyle disease. J Gastroenterol 2007;42:603–609Google Scholar
  6. 6.
    Reed T, Page WF, Viken RJ, Christian JC. Genetic predisposition to organ-specific endpoints of alcoholism. Alcohol Clin Exp Res 1996;20:1528–1533Google Scholar
  7. 7.
    Stickel F, Osterreicher CH. The role of genetic polymorphisms in alcoholic liver disease. Alcohol Alcohol 2006;41:209–224Google Scholar
  8. 8.
    Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008;40:1461–1465Google Scholar
  9. 9.
    Hirschfield GM, Chapman RW, Karlsen TH, Lammert F, Lazaridis KN, Mason AL. The genetics of complex cholestatic disorders. Gastroenterology 2013;144:1357–1374Google Scholar
  10. 10.
    de Boer YS, van Gerven NM, Zwiers A, Verwer BJ, van Hoek B, van Erpecum KJ, et al. Genome-wide association study identifies variants associated with autoimmune hepatitis type 1. Gastroenterology 2014;147:443–452 e445Google Scholar
  11. 11.
    Lucena MI, Molokhia M, Shen YF, Urban TJ, Aithal GP, Andrade RJ, et al. Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles. Gastroenterology 2011;141:338–347Google Scholar
  12. 12.
    de Tayrac M, Roth MP, Jouanolle AM, Coppin H, le Gac G, Piperno A, et al. Genome-wide association study identifies TF as a significant modifier gene of iron metabolism in HFE hemochromatosis. J Hepatol 2015;62:664–672Google Scholar
  13. 13.
    Dongiovanni P, Donati B, Fares R, Lombardi R, Mancina RM, Romeo S, et al. PNPLA3 I148M polymorphism and progressive liver disease. World J Gastroenterol 2013;19:6969–6978Google Scholar
  14. 14.
    Valenti L, Fracanzani AL, Fargion S. The immunopathogenesis of alcoholic and nonalcoholic steatohepatitis: two triggers for one disease? Semin Immunopathol 2009;31:359–369Google Scholar
  15. 15.
    Chamorro AJ, Torres JL, Miron-Canelo JA, Gonzalez-Sarmiento R, Laso FJ, Marcos M. Systematic review with meta-analysis: the I148M variant of patatin-like phospholipase domain-containing 3 gene (PNPLA3) is significantly associated with alcoholic liver cirrhosis. Aliment Pharm Ther 2014;40:571–581Google Scholar
  16. 16.
    Buch S, Stickel F, Trepo E, Way M, Herrmann A, Nischalke HD, et al. A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis. Nat Genet 2015;47:1443Google Scholar
  17. 17.
    Trepo E, Gustot T, Degre D, Lemmers A, Verset L, Demetter P, et al. Common polymorphism in the PNPLA3/adiponutrin gene confers higher risk of cirrhosis and liver damage in alcoholic liver disease. J Hepatol 2011;55:906–912Google Scholar
  18. 18.
    Burza MA, Molinaro A, Attilia ML, Rotondo C, Attilia F, Ceccanti M, et al. PNPLA3 I148M (rs738409) genetic variant and age at onset of at-risk alcohol consumption are independent risk factors for alcoholic cirrhosis. Liver Int 2014;34:514–520Google Scholar
  19. 19.
    Stickel F, Buch S, Lau K, Schwabedissen HMZ, Berg T, Ridinger M, et al. Genetic variation in the PNPLA3 gene is associated with alcoholic liver injury in caucasians. Hepatology 2011;53:86–95Google Scholar
  20. 20.
    Tian C, Stokowski RP, Kershenobich D, Ballinger DG, Hinds DA. Variant in PNPLA3 is associated with alcoholic liver disease. Nat Genet 2010;42:21–23Google Scholar
  21. 21.
    Dutta AK. Genetic factors affecting susceptibility to alcoholic liver disease in an Indian population. Ann Hepatol 2013;12:901–907Google Scholar
  22. 22.
    Baulande S, Lasnier F, Lucas M, Pairault J. Adiponutrin, a transmembrane protein corresponding to a novel dietary- and obesity-linked mRNA specifically expressed in the adipose lineage. J Biol Chem 2001;276:33336–33344Google Scholar
  23. 23.
    He S, McPhaul C, Li JZ, Garuti R, Kinch L, Grishin NV, et al. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis. J Biol Chem 2010;285:6706–6715Google Scholar
  24. 24.
    Kotronen A, Johansson LE, Johansson LM, Roos C, Westerbacka J, Hamsten A, et al. A common variant in PNPLA3, which encodes adiponutrin, is associated with liver fat content in humans. Diabetologia 2009;52:1056–1060Google Scholar
  25. 25.
    Trepo E, Guyot E, Ganne-Carrie N, Degre D, Gustot T, Franchimont D, et al. PNPLA3 (rs738409 C > G) is a common risk variant associated with hepatocellular carcinoma in alcoholic cirrhosis. Hepatology 2012;55:1307–1308Google Scholar
  26. 26.
    Chambers JC, Zhang WH, Sehmi J, Li XZ, Wass MN, Van der Harst P, et al. Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma. Nat Genet 2011;43:1131–1138.Google Scholar
  27. 27.
    Hietala J, Koivisto H, Anttila P, Niemela O. Comparison of the combined marker GGT-CDT and the conventional laboratory markers of alcohol abuse in heavy drinkers, moderate drinkers and abstainers. Alcohol Alcohol 2006;41:528–533Google Scholar
  28. 28.
    Gorden A, Yang RZ, Yerges-Armstrong LM, Ryan KA, Speliotes E, Borecki IB, et al. Genetic variation at NCAN locus is associated with inflammation and fibrosis in non-alcoholic fatty liver disease in morbid obesity. Hum Hered 2013;75:34–43Google Scholar
  29. 29.
    Kim MJ, Yu CY, Theusch E, Naidoo D, Stevens K, Kuang YL, et al. SUGP1 is a novel regulator of cholesterol metabolism. Hum Mol Genet 2016;25:3106–3116Google Scholar
  30. 30.
    Holmen OL, Zhang H, Fan Y, Hovelson DH, Schmidt EM, Zhou W, et al. Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk. Nat Genet 2014;46:345–351Google Scholar
  31. 31.
    Gijon MA, Riekhof WR, Zarini S, Murphy RC, Voelker DR. Lysophospholipid acyltransferases and arachidonate recycling in human neutrophils. J Biol Chem 2008;283:30235–30245Google Scholar
  32. 32.
    Mancina RM, Dongiovanni P, Petta S, Pingitore P, Meroni M, Rametta R, et al. The MBOAT7-TMC4 variant rs641738 increases risk of nonalcoholic fatty liver disease in individuals of european descent. Gastroenterology 2016;150:1219–1230 e1216Google Scholar

Copyright information

© Asian Pacific Association for the Study of the Liver 2018

Authors and Affiliations

  • Yanfang Zhang
    • 1
    • 2
  • Tongsheng Guo
    • 3
  • Funing Yang
    • 1
    • 2
  • Yuanli Mao
    • 3
  • Liubing Li
    • 2
  • Chenxi Liu
    • 2
  • Qiang Sun
    • 1
  • Yongzhe Li
    • 2
    Email author
  • Jing Huang
    • 1
    Email author
  1. 1.Department of Clinical LaboratoryThe First Hospital of Jilin UniversityJilinChina
  2. 2.Department of Rheumatology and Clinical Immunology, Peking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of EducationBeijingChina
  3. 3.Department of Center of Clinical Laboratory Medicine302 Military Hospital of ChinaBeijingChina

Personalised recommendations