Clinical Journal of Gastroenterology

, Volume 11, Issue 2, pp 97–102 | Cite as

The genetic backgrounds in nonalcoholic fatty liver disease

  • Yuya Seko
  • Kanji Yamaguchi
  • Yoshito Itoh
Clinical Review


Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease worldwide. Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, can lead to hepatocellular carcinoma (HCC) and hepatic failure. The development and progression of NAFLD are determined by environmental and genetic factors. The effect of genetic factors has been demonstrated by familial studies, twin studies and several cross-sectional studies. In the past 10 years, genome-wide association studies have revealed several single nucleotide polymorphisms (SNPs) associated with the pathology of NAFLD. Among them, the Patatin-like phospholipase domain-containing 3 (PNPLA3) gene variant I148M showed a strong relationship with the development and progression of NAFLD, NASH, and NAFLD-related HCC. The transmembrane 6 superfamily member 2 (TM6SF2) gene variant E167 K was also associated with NAFLD, and it has a relationship with cardiovascular disease. Furthermore, several genes have been proposed as candidate genes to be associated with NAFLD based on case–control studies. We conducted a comprehensive literature search and review on the genetic background of NAFLD.


Nonalcoholic fatty liver disease (NAFLD) Genome-wide association study (GWAS) PNPLA3 TM6SF2 Glucokinase regulator (GCKR


Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and results in serious public health problems. Globally, about 25% of the adult population is estimated to suffer from NAFLD [1]. NAFLD has a wide spectrum of liver pathology, ranging from nonalcoholic fatty liver (NAFL), which is usually benign, to nonalcoholic steatohepatitis (NASH), which is characterized by steatosis plus features of cellular injury, such as inflammation and hepatocyte ballooning, and may progress to liver cirrhosis (LC), hepatic failure and hepatocellular carcinoma (HCC) in the absence of significant alcohol consumption [2, 3]. NASH is now the second indication [4] and is predicted to become the main indication for liver transplantation in the United States by 2020 [5]. The most common cause of death in patients with NAFLD is cardiovascular disease, followed by non-liver malignancy and liver-related death [6, 7, 8]. It has become clear that patients with NASH, especially those with advanced fibrosis, are a high-risk group for HCC and death from liver-related causes. The risks for disease progression and development of NAFLD depend on environmental factors and multiple genetic factors.

NAFLD is strongly associated with metabolic syndrome, including type 2 diabetes mellitus (T2DM), dyslipidemia, and obesity. Because of a lifestyle of high-calorie food intake and lack of exercise, the prevalence of obesity and insulin resistance are increasing. Some dietary habits may influence the progression of NAFLD, such as monounsaturated fatty acid consumption [9], fructose consumption [10, 11], and coffee consumption [12, 13, 14]. Furthermore, some studies reported that the intestinal microbiome may influence NAFLD development [15, 16].

On the other hand, some familial and twin studies have supported a heritable effect of NAFLD [17, 18, 19]. Among monozygotic twins, the concordance of disease severity, including the degree of fibrosis and steatosis, was greater than that among dizygotic twins. The prevalence of NAFLD also differs among ethnic groups. NAFLD is most common in East Asian Indians, followed by Hispanics, Asians, Caucasians, and less frequently, African Americans [20, 21, 22]. These genetic backgrounds affect the pathology of NAFLD directly or via variability in metabolism and wound healing response. Understanding the contribution of genetic background may have relevance not only to surveillance and therapeutic strategies but also to preventative measures for developing NAFLD. In this review, we have tried to summarize the literature on the role of genetics in NAFLD.


Genome-wide association studies (GWAS) are used to identify the association between common variants in arrays and polymorphic diseases. Because the GWAS approach is called a “hypothesis-free method”, it can identify unreported genes or biologic pathways. On the other hand, we cannot always understand how identified loci contribute to disease progression. Furthermore, GWAS cannot check all of the genetic factors associated with a disease, and the results depend on the subjects in the study. However, GWAS are more likely to identify genetic risk than candidate gene studies.

Romeo et al. first reported in 2008 that rs738409 C > G SNP in the Patatin-like phospholipase domain-containing 3 (PNPLA3) gene was significantly associated with liver steatosis [23]. After that study, several GWAS have been performed in different populations and have identified phenotypes [24, 25, 26, 27, 28, 29, 30, 31] (Table 1). The identified SNPs were different depending on the population studied and the phenotype. The PNPLA3 rs738409 SNP showed a strong relationship with the development of NAFLD or NASH, hepatic steatosis and hepatic fibrosis in almost all studies. There were 2 studies analyzed the association of genetic risk with liver histology in Japanese population [26, 27]. NAFLD was diagnosed by liver biopsy in both studies. Kawaguchi et al. recruited 529 histologically diagnosed NAFLD patients and 932 population controls. They found that PNPLA3 rs738409 showed strong association with Matteoni type4 subgroup (P = 1.7610216, OR = 2.18, 95% CI 1.81–2.63). Kitamoto et al. analyzed 392 biopsy-proven NAFLD subjects and 934 control individuals. PNPLA3 rs738409 was most strongly associated with NAFLD after adjusted by age, gender, and BMI (P = 6.8 9 10–14, OR = 2.05). Based on these GWAS, PNPLA3 rs738409 and Transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 are thought to be the main contributors to NAFLD pathogenesis and progression.
Table 1

Genome-wide association studies of non-alcohol fatty liver disease



Subjects (N)




Romeo S et al. [23]

Multi ethnic



Hepatic fat content

PNPLA3 rs738409

Chalasani et al. [24]

Non-Hispanic white women




hepatic fibrosis,

lobular inflammation,


FDFT1 rs2645424

PDGFA rs343062

COL13A1 rs1227756, LTBP3 rs6591182, EFCAB4B rs887304

rs2499604, PZP rs6487679, rs1421201, 2710833

Speliotes et al. [25]

Multi ethnic


592 (biopsy)

− 2.4million

Steatosis by CT

histological NAFLD

PNPLA3 rs738409, NCAN rs2228603, PPP1R3B rs4240624

PNPLA3 rs738409, NCAN rs2228603, GCKR rs780094, LYPLAL1 rs12137855

Kawaguchi et al. [26]




Matteoni type 4

PNPLA3 rs738409

Kitamoto et al. [27]




NAFLD, steatosis, fibrosis, NAS

PNPLA3 rs738409, SAMM50 rs3761472, PARVB rs6006611

Feitosa et al. [28]



− 2.5million

Steatosis by CT

PNPLA3 rs738409, PPP1R3B rs2126259, ERLIN-CHUK-CWF19L1 gene cluster

Kozlitina et al. [29]

Multi ethnic



Hepatic fat content by 1H-MRS

PNPLA3 rs738409, TM6SF2 rs58542926

DiStefano et al. [30]

Multi ethnic



Hepatic fat content

PNPLA3 rs738409, SUGP1 rs10401969

Adams et al. [31]

Australian adolescent




LPPR4 rs12743824, GC rs222054, LCP1 rs7324845, SLC38A8 rs11864146


PNPLA3, also called adiponutrin is the most robust genetic variant associated with NAFLD. The first GWAS revealed the association of a PNPLA3 variant with hepatic fat content [23]. The result was validated by other GWAS independently, and many candidate studies in various ethnic groups clarified the association with histological severity, including hepatic fibrosis [32, 33, 34]. This relationship has been reported in pediatric patients as well, such as Hispanic, Taiwanese, and Caucasian children and adolescents [35, 36, 37]. The PNPLA3 variant also confers an increased risk of NAFLD-related HCC in European and Japanese populations [38, 39]. This hepatocarcinogenetic effect has been reported not only in patients with NAFLD, but also in patients with alcohol-related disease and chronic viral hepatitis in a meta-analysis [40]. These effects of the I148M substitution were independent from obesity, T2DM, and insulin resistance [41, 42]. In an animal model and in human hepatocytes, PNPLA3 activity is regulated by glucose and insulin via pathways involving the sterol regulatory element binding protein 1-c [43]. The I148M substitution leads to loss of enzymatic activity of hydrolyzed triglycerides and retinyl esters, resulting in the accumulation of triglycerides and esters in lipid droplets of hepatocytes and hepatic stellate cells up to twofold greater than with wild type [44, 45, 46]. It also induces hepatic inflammation and fibrosis. Moreover, carriers of the I148M variant have lower levels of adiponectin, which has an anti-inflammatory effect [47] and inhibits the activation of pro-fibrotic hepatic stellate cells [48, 49]. In contrast, no study has reported an association of PNPLA3 with other fibrogenic factors, such as TNF, α-smooth muscle actin, and type 1 collagen. In an animal model, the PNPLA3 deletion produced no change in phenotype; however, overexpression and knock-in mutations led to increased hepatic fat concentrations [50]. These findings suggest the hypothesis that the accumulation of the I148M mutation on droplets escapes degradation by the proteasome and inhibits the activity of PNPLA3 in hepatocytes [50]. Other studies also revealed that the I148M variant was associated with the response to lifestyle change [51, 52]. In that study, researchers found that liver fat content decreased significantly more in the PNPLA3 genotype GG group than in the PNPLA3 genotype CC group after a short course of a low carbohydrate diet, although patients of both genotypes lost similar amounts of body weight [51]. A recent study proposed that the downregulation of the I148M mutation could be a therapeutic target for NAFLD [53]. Additional studies are warranted to determine the utility of PNPLA3 rs738409 in risk classification of NASH and NAFLD-related HCC.


The TM6SF2 variant was shown to associate with hepatic fat content by Kozlitina et al. [29]. A validation study revealed the association of TM6SF2 with hepatic fibrosis [54]. In that study, carriers of the TM6SF2 E167K mutation had 1.9-fold increased risk of advanced fibrosis independent of the PNPLA3 genotype. However, a relationship between TM6SF2 E167K and NAFLD was not reported in the Japanese population. Though a plausible reason for this was not clear, the discrepancy may be based on the difference in minor allele frequency and inter-ethnic variation or an underpowered cohort. TM6SF2 is involved in the secretion of very low-density lipoprotein from the hepatocyte. It concerns the triglyceride to apolipoprotein B100 pathway. The E167K mutation leads to loss of this function and results in increasing liver triglyceride content and decreasing circulating lipoproteins. It is well known that carriers of the E167K mutation tend to have greater risk of fatty liver, but a lower risk of cardiovascular disease [29, 54, 55, 56]. Kozlitina et al. [29] identified the association of the TM6SF2 variant with increased hepatic triglyceride content, a reduced serum triglyceride level, and low-density lipoprotein cholesterol. They hypothesized that TM6SF2 regulated not only hepatic lipoprotein secretion, but also hepatic synthesis of triglycerides. Carriers of the E167K form had an approximately 50% lower risk of developing atherosclerotic carotid plaques, and a 40% reduction in the risk of cardiovascular events in Western countries [56]. At present, no study has determined whether the TM6SF2 variant affects the risk of NAFLD-related HCC. Further study regarding the association between TM6SF2 and the risk of HCC in the pathogenesis of NAFLD is needed.


Glucokinase regulator (GCKR) regulates the flow of glucose in hepatocytes and de novo lipogenesis. The missense mutation (P446L) of GCKR rs1260326 was associated with liver fat content in NAFLD [57]. The P446L mutation leads to a reduction in the ability of glucokinase in response to fructose-6-phosphate, and results in hepatic glucose intake [58]. This mutation also leads to a decrease in the serum level of glucose and insulin, but an increase in malonyl Co-A, which is used as substrate for hepatic lipogenesis and blocks fatty acid β-oxidation. This pathway increases hepatic fat accumulation. Recently, several studies reported that mutation of GCKR affects not only lipogenesis and liver fat content, but also hepatic fibrosis in patients with NAFLD [59, 60]. This result was confirmed by a recent meta-analysis [61] that revealed the association of GCKR with NAFLD-related fibrosis in both the Asian and non-Asian populations.

Other genetic variants associated with metabolism

Several genes were identified in cross-sectional or case–control studies as potential candidate genes associated with NAFLD. Table 2 shows the function and phenotype of these candidate genes. There are several candidate genes reported besides those in Table 2. In this review, we chose to discuss four genes associated with insulin signaling and lipid metabolism.
Table 2

Function and phenotype of candidate genes associated with non-alcohol fatty liver disease




PNPLA3 rs738409

Lipid droplet content in hepatocyte

Steatosis, fibrosis, NASH, HCC

TM6SF2 rs58542926

VLDL secretion

Fibrosis, NAFLD, NASH

LYPLAL1 rs12137855

TG catabolism


GCKR rs780094

de novo lipogenesis

Fibrosis, NAFLD, NASH

LPIN1 rs13412852

Lipid metabolism

Fibrosis, NASH

ENPP1 rs1044498

Insulin signaling inhibitor


IRS1 rs1801278

Insulin signaling


PPARα rs1800206

Lipid metabolism

Steatosis, inflammation, fibrosis

Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1)

Insulin receptor substrate 1 (IRS1)

Insulin resistance plays a key role in the pathology of NAFLD. That is a common feature of NAFLD, T2DM, and metabolic syndrome. The genes involved in hepatic insulin signaling have been reported to be associated with NAFLD. The ENPP1 rs1044498 K121Q mutation leads to an interaction between ENPP1 and the insulin receptor, inhibiting signaling. It was also reported that the IRS1 rs1801278 G972R variant was associated with decreased activity of IRS-1, thereby reducing insulin signaling in the liver. A large study that included 702 biopsy-proven NAFLD patients found that both ENPP1 and IRS-1 SNPs were associated with a reduction in insulin signaling activity and severe fibrosis [62]. These ENPP1 and IRS1 variants promoted insulin resistance by reducing AKT activation [62].

Peroxisome proliferative activated receptor (PPAR)


Peroxisome proliferator-activated nuclear receptors (PPAR) play a role in hepatic lipid metabolism. PPAR-α acts as a molecular sensor for long-chain fatty acids, eicosanoids, and fibrates by upregulation of mitochondrial uptake and β-oxidation. PPAR-α activation improves steatosis, inflammation, and fibrosis in NAFLD [63]. Chen et al. [64] reported the association of the PPAR-α V227A variant with NAFLD. They described that the V227 isoform has lower activity than the A227isoform, resulting in reduced lipid catabolism and an increased risk of NAFLD. PPARγ improves insulin resistance and has been reported to restore adipose tissue insulin sensitivity and decrease free fatty acid flux to the liver [65]. PPAR-γ rs1805192 P12A leads to loss of function of the gene product, impairing its ability to bind DNA and activate transcription. This variant decreases sensitivity to insulin and anti-inflammatory effects. However, the association of PPARs with the pathology of NAFLD remains controversial [66, 67].

LPIN1 is expressed mainly in liver and adipose tissue. LPIN1 plays a role in the synthesis of phospholipids and triglycerides, and regulates fatty acid metabolism [68]. A previous study reported that carriers of the LPIN1 rs13412852 TT genotype showed increased expression of LPIN1 and had a smaller risk of NAFLD [69]. Variants of LIPIN1 influence the phenotype not only of NAFLD, but also of other metabolic traits [70].


In this review, we found that several genes affect the development, histological changes, progression, and carcinogenesis of NAFLD in various manners. At present, the PNPLA3 gene variant is the most powerful and validated genetic factor for steatosis, fibrosis, disease progression, and HCC in multiple ethnic groups. These result support the hypothesis that PNPLA3 acts as a main player of disease progression in combination with a high-calorie diet or alcohol consumption. However, we cannot understand the pathology of NAFLD by only one gene. We must classify the risk of NAFLD by combining the potential effects of the risk genes in each patient. Further studies about how these risk genes influence the pathology of NAFLD are needed. Such information will help us define surveillance approaches and therapeutic strategies, including lifestyle interventions and pharmacological therapies.


Compliance with ethical standards

Conflict of interest

Yuya Seko, Kanji Yamaguchi, and Yoshito Itoh declare that they have no conflict of interest.

Human rights

This study does not involve any data about human subjects.

Informed consent

This study does not involve human subjects.


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Copyright information

© Japanese Society of Gastroenterology 2018

Authors and Affiliations

  1. 1.Molecular Gastroenterology and HepatologyKyoto Prefectural University of MedicineKyotoJapan

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