Skip to main content
SpringerLink
Log in

Genetics of nonalcoholic fatty liver disease in Asian populations

  • Review Article
  • Published:
Journal of Genetics Aims and scope Submit manuscript

Abstract

Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of fat in the liver without any history of chronic alcohol consumption. It encompasses a wide spectrum of diseases that range from simple steatosis to nonalcoholic steatohepatitis. NAFLD is strongly associated with obesity, insulin resistance / type-2 diabetes mellitus and the metabolic syndrome. NAFLD is a complex disorder; environmental and genetic factors interact with NAFLD manifestation and determine its progression. In this review, an attempt was made to provide current information on the genetic variants of NAFLD in Asian populations. Literature search was performed by using PubMed, Medline and Google Scholar database. Candidate gene, validation and genomewide association studies (GWASs) were included in this review. A total of 41 studies fulfilled inclusion criteria of which 12 candidate gene studies exclusively focussed on the PNPLA3 gene and 17 other studies on other important candidate genes such as NCAN-CILP2, PPARG, AGTR1, FABP1, APOC3 etc. reported significant association with NAFLD. Eight validation studies identified associations of variants on PNPLA3, LYPLAL1, TM6SF2, ADIPOR2, STAT3, GCKR, SAMM50 etc. with NAFLD. Thus, so far, four GWASs have been conducted in Asian population that reported PNPLA3, SAMM50, PARVB and GATAD2A genes which were significantly associated with NAFLD. Findings indicate that PNPLA3, APOC3, PPARG, NCAN and GCKR genes emerge out to be the important biological markers associated with NAFLD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Aly F. Z. and Kleiner D. E. 2011 Update on fatty liver disease and steatohepatitis. Adv. Anat. Pathol. 18, 294–300.

    Article  Google Scholar 

  • Amarapurkar D., Kamani P., Patel N., Gupte P., Kumar P., Agal S. et al. 2007 Prevalence of non-alcoholic fatty liver disease: population based study. Ann. Hepatol. 6, 161–163.

    PubMed  Google Scholar 

  • Angulo P. 2002 Treatment of nonalcoholic fatty liver disease. Ann. Hepatol. 1, 12–19.

    PubMed  Google Scholar 

  • Anstee Q. M., Targher G. and Day C. P. 2013 Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat. Rev. Gastroenterol. Hepatol. 10, 330–344.

    Article  CAS  Google Scholar 

  • Bellentani S. and Tiribelli C. 2001 The spectrum of liver disease in the general population: lesson from the Dionysos study. J. Hepatol. 35, 531–537.

    Article  CAS  Google Scholar 

  • Bhatt S. P., Nigam P., Misra A., Guleria R., Luthra K., Vaidya M. et al. 2011 SREBP-2 1784 G/C genotype is associated with non-alcoholic fatty liver disease in north Indians. Dis. Markers 31, 371–377.

    Article  CAS  Google Scholar 

  • Bhatt S. P., Nigam P., Misra A., Guleria R., Luthra K., Pandey R. M. et al. 2013 Association of peroxisome proliferator activated receptor-\(\upgamma \) gene with non-alcoholic fatty liver disease in Asian Indians residing in north India. Gene 512, 143–147.

    Article  CAS  Google Scholar 

  • Boonvisut S., Nakayama K., Makishima S., Watanabe K., Miyashita H., Lkhagvasuren M. et al. 2016 Replication analysis of genetic association of the NCAN-CILP2 region with plasma lipid levels and non-alcoholic fatty liver disease in Asian and Pacific ethnic groups. Lipids Health Dis. 15, 8.

    Article  Google Scholar 

  • Browning J. D., Szczepaniak L. S., Dobbins R., Nuremberg P., Horton J. D., Cohen J. C. et al. 2004 Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 40, 1387–1395.

    Article  Google Scholar 

  • Brunt E. M. and Tiniakos D. G. 2010 Histopathology of nonalcoholic fatty liver disease. World J. Gastroenterol. 16, 5286–5296.

    Article  Google Scholar 

  • Chan W. K., Tan A. T., Vethakkan S. R., Tah P. C., Vijayananthan A. and Goh K. L. 2013 Non-alcoholic fatty liver disease in diabetics–prevalence and predictive factors in a multiracial hospital clinic population in Malaysia. J. Gastroenterol. Hepatol. 28, 1375–1383.

    Article  CAS  Google Scholar 

  • Chatterjee A., Basu A., Chowdhury A., Das K., Sarkar-Roy N., Majumder P. P. et al. 2015 Comparative analyses of genetic risk prediction methods reveal extreme diversity of genetic predisposition to nonalcoholic fatty liver disease (NAFLD) among ethnic populations of India. J. Genet. 94, 105–113.

    Article  CAS  Google Scholar 

  • Chen L., Lin Z., Jiang M., Lu L., Zhang H., Xin Y. et al. 2015 Genetic variants in the SAMM50 gene create susceptibility to nonalcoholic fatty liver disease in a Chinese Han population. Hepat. Mon. 15, e31076.

    PubMed  PubMed Central  Google Scholar 

  • Dassanayake A. S., Kasturiratne A., Rajindrajith S., Kalubowila U., Chakrawarthi S., De Silva A. P. et al. 2009 Prevalence and risk factors for non-alcoholic fatty liver disease among adults in an urban Sri Lankan population. J. Gastroenterol. Hepatol. 24, 1284–1288.

    Article  Google Scholar 

  • Fan J. G., Zhu J., Li X. J., Chen L., Lu Y. S., Li L. et al. 2005 Fatty liver and the metabolic syndrome among Shanghai adults. J. Gastroenterol. Hepatol. 20, 1825–1832.

    Article  Google Scholar 

  • He S., McPhaul C., Li J. Z., Garuti R., Kinch L., Grishin N. V. et al. 2010 A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis. J. Biol. Chem. 285, 6706–6715.

    Article  CAS  Google Scholar 

  • Hernaez R., Lazo M., Bonekamp S., Kamel I., Brancati F. L., Guallar E. et al. 2011 Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: a meta-analysis. Hepatology 54, 1082–1090.

    Article  Google Scholar 

  • Hotta K., Yoneda M., Hyogo H., Ochi H., Mizusawa S., Ueno T. et al. 2010 Association of the rs738409 polymorphism in PNPLA3 with liver damage and the development of nonalcoholic fatty liver disease. BMC Med. Genet. 11, 172.

    Article  CAS  Google Scholar 

  • Jiang S., Zhang R., Li H., Fang Q., Jiang F., Hou X. et al. 2014 The single nucleotide polymorphism rs499765 is associated with fibroblast growth factor 21 and nonalcoholic fatty liver disease in a Chinese population with normal glucose tolerance. J. Nutrigenet. Nutrigenomics 7, 121–129.

    Article  CAS  Google Scholar 

  • Kasturiratne A., Akiyama K., Niriella M. A., Takeuchi F., Isono M., Dassanayake A. S. et al. 2015 Association of genetic variants with non-alcoholic fatty liver disease in an urban Sri Lankan community. Liver Int. 35, 676–679.

    Article  Google Scholar 

  • Kawaguchi T., Sumida Y., Umemura A., Matsuo K., Takahashi M., Takamura T. et al. 2012 Genetic polymorphisms of the human PNPLA3 gene are strongly associated with severity of non-alcoholic fatty liver disease in Japanese. PLoS One 7, e38322.

    Article  CAS  Google Scholar 

  • Kawaguchi T, Shima T, Mizuno M, Mitsumoto Y, Umemura A, Kanbara Y. et al. 2018 Risk estimation model for non-alcoholic fatty liver disease in the Japanese using multiple genetic markers. PLoS One 13, e0185490.

    Article  Google Scholar 

  • Kemmer N., Neff G. W., Franco E., Osman-Mohammed H., Leone J., Parkinson E. et al. 2013 Nonalcoholic fatty liver disease epidemic and its implications for liver transplantation. Transplantation 96, 860–862.

    CAS  PubMed  Google Scholar 

  • Kitamoto T., Kitamoto A., Yoneda M., Hyogo H., Ochi H., Nakamura T. et al. 2013 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. 132, 783–792.

    Article  CAS  Google Scholar 

  • Kitamoto A., Kitamoto T., Nakamura T., Ogawa Y., Yoneda M., Hyogo H. et al. 2014 Association of polymorphisms in GCKR and TRIB1 with nonalcoholic fatty liver disease and metabolic syndrome traits. Endocr. J. 61, 683–689.

    Article  CAS  Google Scholar 

  • Lee S. S., Byoun Y. S., Jeong S. H., Woo B. H., Jang E. S., Kim J. W. et al. 2014 Role of the PNPLA3 I148M polymorphism in nonalcoholic fatty liver disease and fibrosis in Korea. Dig. Dis. Sci. 59, 2967–2974.

    Article  CAS  Google Scholar 

  • Li Y., Xing C., Tian Z. and Ku H. C. 2012 Genetic variant I148M in PNPLA3 is associated with the ultrasonography-determined steatosis degree in a Chinese population. BMC Med. Genet. 13, 113.

    Article  CAS  Google Scholar 

  • Lin Y. C., Chang P. F., Hu F. C., Yang W. S., Chang M. H. and Ni Y. H. 2011 A common variant in the PNPLA3 gene is a risk factor for non-alcoholic fatty liver disease in obese Taiwanese children. J. Pediatr. 158, 740–744.

    Article  CAS  Google Scholar 

  • Lin Y. C., Chang P. F., Chang M. H. and Ni Y. H. 2013 A common variant in the peroxisome proliferator-activated receptor-\(\gamma \) coactivator-1\(\alpha \) gene is associated with nonalcoholic fatty liver disease in obese children. Am. J. Clin. Nutr. 97, 326–331.

    Article  CAS  Google Scholar 

  • Lin Y. C., Chang P. F., Chang M. H. and Ni Y. H. 2014 Genetic variants in GCKR and PNPLA3 confer susceptibility to nonalcoholic fatty liver disease in obese individuals. Am. J. Clin. Nutr. 99, 869–874.

    Article  CAS  Google Scholar 

  • Machado M., Marques-Vidal P. and Cortez-Pinto H. 2006 Hepatic histology in obese patients undergoing bariatric surgery. J. Hepatol. 45, 600–606.

    Article  Google Scholar 

  • Nishioji K., Mochizuki N., Kobayashi M., Kamaguchi M., Sumida Y., Nishimura T. et al. 2015 The impact of PNPLA3 rs738409 genetic polymorphism and weight gain \({\ge }\)10 kg after age 20 on non-alcoholic fatty liver disease in non-obese Japanese individuals. PLoS One 20, e0140427.

  • Niu T. H., Jiang M., Xin Y. N., Jiang X. J., Lin Z. H. and Xuan S. Y. 2014 Lack of association between apolipoprotein C3 gene polymorphisms and risk of nonalcoholic fatty liver disease in a Chinese Han population. World J. Gastroenterol. 20, 3655–3662.

    Article  Google Scholar 

  • Oniki K., Saruwatari J., Izuka T., Kajiwara A., Morita K., Sakata M. et al. 2015 Influence of the PNPLA3 rs738409 polymorphism on non-alcoholic fatty liver disease and renal function among normal weight subjects. PLoS One 10, e0132640.

    Article  Google Scholar 

  • Pan Q., Zhang R. N., Wang Y. Q., Zheng R. D., Mi Y. Q., Liu W. B. et al. 2015 Linked PNPLA3 polymorphisms confer susceptibility to nonalcoholic steatohepatitis and decreased viral load in chronic hepatitis B. World J. Gastroenterol. 21, 8605–8614.

    Article  CAS  Google Scholar 

  • Palmer N. D., Musani S. K., Yerges-Armstrong L. M., Feitosa M. F., Bielak L. F., Hernaez R. et al. 2013 Characterization of European ancestry nonalcoholic fatty liver disease-associated variants in individuals of African and Hispanic descent. Hepatology 58, 966–975.

    Article  CAS  Google Scholar 

  • Peng X. E., Wu Y. L., Lu Q. Q., Hu Z. J. and Lin X. 2012 Two genetic variants in FABP1 and susceptibility to non-alcohol fatty liver disease in a Chinese population. Gene 500, 54–58.

    Article  CAS  Google Scholar 

  • Peng X. E., Wu Y. L., Lu Q. Q., Hu Z. J. and Lin X. 2014 MTTP polymorphisms and susceptibility to non-alcoholic fatty liver disease in a Han Chinese population. Liver Int. 34, 118–128.

    Article  CAS  Google Scholar 

  • Romeo S., Kozlitina J., Xing C., Pertsemlidis A., Cox D., Pennacchio L. A. et al. 2008 Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 40, 1461–1465.

    Article  CAS  Google Scholar 

  • Rotman Y., Koh C., Zmuda J. M., Kleiner D. E., Liang T. J. and NASH CRN. 2010 The association of genetic variability in patatin-like phospholipase domain containing protein 3 (PNPLA3) with histological severity of nonalcoholic fatty liver disease. Hepatology 52, 894–903.

    Article  CAS  Google Scholar 

  • Sanyal A. J. 2011 NASH: a global health problem. Hepatol. Res. 41, 670–674.

    Article  Google Scholar 

  • Schwimmer J. B., Celedon M. A., Lavine J. E., Salem R., Campbell N., Schork N. J. et al. 2009 Heritability of nonalcoholic fatty liver disease. Gastroenterology 136, 1585–1592.

    Article  Google Scholar 

  • Shang X. R., Song J. Y., Liu F. H., Ma J. and Wang H. J. 2015 GWAS-identified common variants with nonalcoholic fatty liver disease in Chinese children. J. Pediatr. Gastroenterol. Nutr. 60, 669–674.

    Article  CAS  Google Scholar 

  • Song G., Xiao C., Wang K., Wang Y., Chen J., Yu Y. et al. 2016 Association of patatin-like phospholipase domain-containing protein 3 gene polymorphisms with susceptibility of nonalcoholic fatty liver disease in a Han Chinese population. Medicine (Baltimore) 95, e4569.

    Article  CAS  Google Scholar 

  • Speliotes E. K., Yerges-Armstrong L. M., Wu J., Hernaez R., Kim L. J., Palmer C. D. et al. 2011 Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet. 7, e1001324.

    Article  CAS  Google Scholar 

  • Wagenknecht L. E., Scherzinger A. L., Stamm E. R., Hanley A. J., Norris J. M., Chen Y. D. et al. 2009 Correlates and heritability of nonalcoholic fatty liver disease in a minority cohort. Obesity (Silver Spring) 17, 1240–1246.

    CAS  Google Scholar 

  • Wang C. W., Lin H. Y., Shin S. J., Yu M. L., Lin Z. Y., Dai C. Y. et al. 2011 The PNPLA3 I148M polymorphism is associated with insulin resistance and nonalcoholic fatty liver disease in a normoglycaemic population. Liver Int. 31, 1326–1331.

  • Wang Y., Tong J., Chang B., Wang B. F., Zhang D. and Wang B. Y. 2014 Relationship of SREBP-2 rs2228314 G\({>}\)C polymorphism with nonalcoholic fatty liver disease in a Han Chinese population. Genet. Test Mol. Biomarkers 18, 653–657.

  • Wang X., Liu Z., Peng Z. and Liu W. 2015a The TM6SF2 rs58542926 T allele is significantly associated with non-alcoholic fatty liver disease in Chinese. J. Hepatol. 62, 1438–1439.

    Article  CAS  Google Scholar 

  • Wang B., Wang B., Wang Y., Wen B., Liu S., Sang L. et al. 2015b Association of APPL1 gene polymorphism with non-alcoholic fatty liver disease susceptibility in a Chinese Han population. Clin. Lab. 61, 1659–1666.

    CAS  PubMed  Google Scholar 

  • Wang X., Liu Z., Wang K., Wang Z., Sun X., Zhong L. et al. 2016 Additive effects of the risk alleles of PNPLA3 and TM6SF2 on non-alcoholic fatty liver disease (NAFLD) in a Chinese population. Front Genet. 7, 140.

    PubMed  PubMed Central  Google Scholar 

  • Wei J. L., Leung J. C., Loong T. C., Wong G. L., Yeung D. K., Chan R. S. et al. 2015 Prevalence and severity of non-alcoholic fatty liver disease in non-obese patients: a population study using proton-magnetic resonance spectroscopy. Am. J. Gastroenterol. 110, 1306–1314.

    Article  CAS  Google Scholar 

  • Wong V. W. 2013 Nonalcoholic fatty liver disease in Asia: a story of growth. J. Gastroenterol. Hepatol. 28, 18–23.

    Article  Google Scholar 

  • Wong V. W., Wong G. L., Choi P. C., Chan A. W., Li M. K., Chan H. Y. et al. 2010 Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years. Gut 59, 969–974.

    Article  Google Scholar 

  • Wong V. W., Wong G. L., Tse C. H. and Chan H. L. 2014 Prevalence of the TM6SF2 variant and non-alcoholic fatty liver disease in Chinese. J. Hepatol. 61, 708–709.

    Article  CAS  Google Scholar 

  • Wu G., Wang K., Xue Y., Song G., Wang Y., Sun X. et al. 2016 Association of rs5764455 and rs6006473 polymorphisms in PARVB with liver damage of nonalcoholic fatty liver disease in Han Chinese population. Gene 575, 270–275.

    Article  CAS  Google Scholar 

  • Xu Y. P., Liang L., Wang C. L., Fu J. F., Liu P. N., Lv L. Q. et al. 2013 Association between UCP3 gene polymorphisms and nonalcoholic fatty liver disease in Chinese children. World J. Gastroenterol. 19, 5897–5903.

    Article  CAS  Google Scholar 

  • Xie Y., Wang M., Zhang Y., Zhang S., Tan A., Gao Y. et al. 2013 Serum uric acid and non-alcoholic fatty liver disease in non-diabetic Chinese men. PLoS One 8, e67152.

    Article  CAS  Google Scholar 

  • Yang Z., Wen J., Tao X., Lu B., Du Y., Wang M. et al. 2011 Genetic variation in the GCKR gene is associated with non-alcoholic fatty liver disease in Chinese people. Mol. Biol. Rep. 38, 1145–1150.

    Article  Google Scholar 

  • Yang Z., Wen J., Li Q., Tao X., Ye Z., He M. et al. 2012 PPARG gene Pro12Ala variant contributes to the development of non-alcoholic fatty liver in middle-aged and older Chinese population. Mol. Cell. Endocrinol. 348, 255–259.

    Article  Google Scholar 

  • Yoneda M., Hotta K., Nozaki Y., Endo H., Uchiyama T., Mawatari H. et al. 2009 Association between angiotensin II type 1 receptor polymorphisms and the occurrence of nonalcoholic fatty liver disease. Liver Int. 29, 1078–1085.

    Article  CAS  Google Scholar 

  • Zain S. M., Mohamed Z., Mahadeva S., Rampal S., Basu R. C., Cheah P. L. et al. 2013 Susceptibility and gene interaction study of the angiotensin II type 1 receptor (AGTR1) gene polymorphisms with non-alcoholic fatty liver disease in a multi-ethnic population. PLoS One 8, e58538.

    Article  CAS  Google Scholar 

  • Zhang Y., Cai W., Song J., Miao L., Zhang B., Xu Q. et al. 2014 Association between the PNPLA3 I148M polymorphism and non-alcoholic fatty liver disease in the Uygur and Han ethnic groups of northwestern China. PLoS One 9, e108381.

    Article  Google Scholar 

  • Zhang Y., Cai W., Song J., Miao L., Zhang B., Xu Q. et al. 2015 The impact of PNPLA3 rs738409 genetic polymorphism and weight gain \(\ge \)10 kg after age 20 on non-alcoholic fatty liver disease in non-obese Japanese individuals. PLoS One 10, e0140427.

    Article  Google Scholar 

  • Zhang R. N., Zheng R. D., Mi Y. Q., Zhou D., Shen F., Chen G. Y. et al. 2016 APOC3 rs2070666 is associated with the Hepatic Steatosis independently of PNPLA3 rs738409 in Chinese Han patients with nonalcoholic fatty liver diseases. Dig. Dis. Sci. 61, 2284–2293.

    Article  CAS  Google Scholar 

  • Zhou Y. J., Li Y. Y., Nie Y. Q., Yang H., Zhan Q., Huang J. et al. 2010 Influence of polygenetic polymorphisms on the susceptibility to non-alcoholic fatty liver disease of Chinese people. J. Gastroenterol. Hepatol. 25, 772–777.

    Article  CAS  Google Scholar 

Download references

Acknowledgement

The authors would like to acknowledge the University of Delhi’s Research and Development Grant for funding this research work.

Author information

Authors and Affiliations

  1. Department of Anthropology, University of Delhi, New Delhi, 110 007, India

    Arun Kumar, Vipin Gupta & M. P. Sachdeva

  2. Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, 110 029, India

    Shalimar

  3. Public Health Foundation of India, Gurugram , 122 002, India

    Gagandeep Kaur Walia

Authors
  1. Arun Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shalimar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gagandeep Kaur Walia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vipin Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. P. Sachdeva
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Vipin Gupta or M. P. Sachdeva.

Additional information

Communicated by H. A. Ranganath

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kumar, A., Shalimar, Walia, G.K. et al. Genetics of nonalcoholic fatty liver disease in Asian populations. J Genet 98, 29 (2019). https://doi.org/10.1007/s12041-019-1071-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12041-019-1071-8

Keywords

Search

Navigation