Genetic factors that affect nonalcoholic fatty liver disease: A systematic clinical review

Table 1 Genes and variants emphasized in this review

Gene name	Genetic variant	Coding DNA change	Amino acid change	Putative effect of variant
PNPLA3	rs738409	444C>G	I148M	Increased hepatocyte triglyceride content
	rs6006460	1531G>T	S453I	Lower-than-average hepatic triglyceride accumulation
TM6SF2	rs58542926	499A>G	E167K	Elevated AST/ALT, increased hepatic triglyceride levels, decreased serum cholesterol
	rs10401969	613+80A>G	Intron	Lower hepatic TM6SF2 mRNA levels correlate with larger hepatocellular lipid droplets
LIPA	rs116928232	894G>A	E8SJM	Cholesterol ester storage disease often resulting in fibrosis→cirrhosis
IFNλ4	rs12979860	151-152G>A	Intron	Increased degree of hepatic inflammation and fibrosis
HFE	rs1800562	845G>A	C282Y	Increased hepatic iron uptake, associated with greater NAFLD risk/severity
	rs1799945	187C>G	H63D	Increased hepatic iron uptake, associated with greater NAFLD risk/severity
HMOX1	rs2071746	-413A>T	Affects promoter	Higher HMOX1 activity correlated with less frequent and less severe NAFLD
FTO	rs1421085	46-43098T>C	Affects repressor	Adipocytic phenotype shift from beige (energy-dissipating) to white (energy-storing)
GNPAT	rs11558492	1556A>G	D519G	Worsened iron overload in patients with HFE

Table 2 Variation in frequency of the common PNPLA3 polymorphism in different regions and among different ethnic groups

Descent/ethnicity	Alleles C1	Alleles G2	Genotypes C|C	Genotypes C|G	Genotypes G|G	Allele count		Genotype count
						C allele	G allele	C|C	C|G	G|G
All (n = 2504)	73.8%	26.2%	56.9%	33.8%	9.3%	3695	1313	1424	847	233
African (n = 661)	88.2%	11.8%	78.8%	18.8%	2.4%	1166	156	521	124	16
Latin American (n = 347)	51.6%	48.4%	27.7%	47.8%	24.5%	358	336	96	166	85
Asian (n = 504)	65.0%	35.0%	44.0%	41.9%	14.1%	655	353	222	211	71
European (n = 503)	77.4%	22.6%	60.2%	34.4%	5.4%	779	227	303	173	27
Southern Asian (n = 489)	75.4%	24.6%	57.7%	35.4%	7.0%	737	241	282	173	34

¹Allele C: Wild type;

²Allele G: Variant rs738409, codes I148M protein.

Table 3 Summary of genetic modifiers of nonalcoholic fatty liver disease

Gene	Protein	Study details and comments
Glucose metabolism and insulin resistance
ENPP1; IRS1	Ectonucleotide pyrophosphatase/phosphodiesterase family member 1; insulin receptor substrate 1	Functional variants promote insulin resistance by impairing insulin receptor signaling[114,115]. Carriage of nonsynonymous SNPs in ENPP1 (rs1044498, encoding Lys121Gln) and IRS1 (rs1801278, encoding Gln972Arg) reduced AKT activation, promoted insulin resistance, and showed independent association with greater fibrosis[116]
GCKR	Glucokinase regulatory protein	GCKR SNP rs780094 has been associated with hepatic TG accumulation[117] and greater NAFLD fibrosis[118]
PPARG	Peroxisome proliferator-activated receptor γ	A loss-of-function SNP (rs1805192, encoding Pro12Ala) impairs transcriptional activation and affects insulin sensitivity[119]
SLC2A1	Solute carrier family 2, facilitated glucose transporter member 1	Variants in SCLA1 are associated with NAFLD independent of insulin resistance or T2DM[120]
		Downregulation of SLC2A1 in vitro promoted lipid accumulation and increased oxidative stress, potentially linking the key pathogenic features of NAFLD: oxidative injury and increased lipid storage
Steatosis: Hepatic lipid import or synthesis
FTO	Fat mass and obesity-associated protein	SNP rs1421085 (c.46-43098T>C) disrupts a conserved motif, which leads to de-repression of a potent preadipocyte enhancer and to a shift in phenotype from energy-dissipating beige adipocytes to energy-storing white adipocytes, with reduction in mitochondrial thermogenesis[70]
LPIN1	Phosphatidate phosphatase LPIN1	Required for adipogenesis and the normal metabolic flux between adipose tissue and liver; also acts to regulate fatty acid metabolism[121,122]
		Variants have been associated with multiple components of the metabolic syndrome[121,123]
SLC27A5	Very long chain acyl-CoA synthetase	Silencing Slc27a5 reverses diet-induced NAFLD and improves hyperglycemia in mice[124]
		Carriage of the SLC27A5 rs56225452 polymorphism has been associated with higher ALT and greater postprandial insulin and triglyceride levels[124]
		In patients with histologically proven NAFLD, the effect of BMI on degree of steatosis differed with SLC27A5 genotype[125]
Steatosis: Hepatic lipid export or oxidation in steatosis
APOE	Apolipoprotein E	Plasma protein involved in lipid transport and metabolism[126]. Three alleles (ε2, ε3, and ε4) determine three isoforms (ApoE2, ApoE3, and ApoE4) resulting in six ApoE genotypes (E2/2, E3/3, E4/4, E2/3, E2/4, E3/4). Overall homozygosity for the ε2 allele in one study was associated with dyslipidemia, but not NAFLD[127]
		In a subgroup of non-obese individuals, the ε2 allele and the E2/3 genotype were more prevalent in controls, suggesting it might be protective[127]. Consistent with this result, the E3/3 genotype was associated with NASH in a Turkish cohort, whereas E3/4 was protective[128]
LEPR	Human leptin receptor	SNP rs1805096 (c.3057G>A) may contribute to the onset of NAFLD via regulation of lipid metabolism[129]. Combination of either of LEPR SNPs rs1137100 or rs1137101 with PNPLA3 rs738409 exacerbates risk of developing NAFLD more than either of the variants on its own[130]
NR1I2	Nuclear receptor subfamily 1 group I member 2 (also known as pregnane X receptor)	NR1I2 encodes a transcription factor that regulates hepatic detoxification and acts through CD36 (fatty-acid translocase) and various lipogenic enzymes to control lipid metabolism[131]
		Nr1i2-deficient mice develop steatosis[131]
		Two SNPs (rs7643645 and rs2461823) were associated with NAFLD and were also a predictor of disease severity[132]
PNPLA3	Patatin-like phospholipase domain-containing 3	The nonsynonymous c.444C>G nucleotide transversion mutation SNP (rs738409, encoding p.I148M) has been consistently associated with steatosis, steatohepatitis, and hepatic fibrosis. Function remains incompletely understood[39,42]
PPARα	Peroxisome proliferator-activated receptor α	PPAR-α is a molecular sensor for long chain fatty acids, eicosanoids, and fibrates[133]; activated by increased hepatocyte fatty-acid load, it limits TAG accumulation by increasing fatty acid oxidation
		Carriage of a non-synonymous SNP (rs1800234, encoding p. V227A) increases activity, and was associated with NAFLD despite reduced BMI[134,135]
		A loss-of-function polymorphism (rs1800206, encoding p. L162V) was not associated with NAFLD[136]
TM6SF2	Transmembrane 6 super family 2	The TM6SF2 rs58542926 minor allele is associated with greater steatosis, steatohepatitis, and NAFLD fibrosis. The major allele is associated with dyslipidemia and greater CVD risk[61,66,68,69]
Steatohepatitis: Oxidative stress
ABCC2	ATP-binding cassette, subfamily C (CFTR/MRP), member 2	Association studies support a role for ABCC2 (also known as MRP2), which facilitates terminal excretion and detoxification of endogenous and xenobiotic organic anions, including lipid peroxidation products[137]
GCLC; GCLM	Glutamate-cysteine ligase catalytic unit; glutamate-cysteine ligase regulatory unit	Glutamate-cysteine ligase is the rate-controlling step in glutathione synthesis; absence of the Gclc gene causes steatosis and liver failure in mice[138]
		A study of 131 patients with NFLD reported the GCLC promoter region polymorphism (c. c-129t, rs17883901) was associated with steatohepatitis compared with simple steatosis[139]
HFE	Hereditary hemochromatosis protein	Hepatic iron accumulation promotes oxidative stress. Two studies, examining 177 patients, reported carriage of an HFE polymorphism (rs1800562) that was associated with more severe steatohepatitis and advanced fibrosis[95,140]
		However, three other studies have not shown increased carriage of either the C282Y or H63D (rs1799945) mutations[105-107]. Meta-analysis have also provided conflicting results[108,109]
SOD2	Superoxide dismutase [Mn], mitochondrial	Carriage of the nonsynonymous SNP rs4880 has been associated with advanced hepatic fibrosis in NAFLD in both Japanese[141] and European[142] cohorts
Endotoxin response
CD14	Monocyte differentiation antigen CD14	A lipopolysaccharide receptor expressed on monocytes, macrophages, and neutrophils that enhances TLR4 endotoxin signaling. An association with promoter-region polymorphism rs2569190 increasing CD14 expression has been reported[143]
TLR4	Toll-like receptor 4	Study of a spontaneous Tlr4 null mutation in C3H/J mice has established the contribution of TLR4/endotoxin to NAFLD pathogenesis in the laboratory[144]
		TLR4 polymorphisms rs4986791 and rs4986790 influence hepatitis-C-related fibrosis[145,146], but no association with NAFLD and TLR4 variants has been found
Cytokines
IFNλ4	Interferon lambda 4	The intronic rs12979860 SNP in IFNλ4 is a strong predictor of fibrosis in an etiology-independent manner, including a cohort of 488 NAFLD cases. Those with rs12979860 cc had greater hepatic inflammation and fibrosis[85]
TNF	Tumor necrosis factor	A promoter polymorphism (c.238G>A) has been associated with NASH[147,148] suggesting a primary role in the transition from steatosis to steatohepatitis. A separate study found that two other promoter region polymorphisms (rs1799964 and rs1800630) were more common in NAFLD than a control population[148]
Fibrosis
AGTR1	Type-1 angiotensin II receptor	Studies link SNP rs3772622 with grade of steatohepatitis and stage of fibrosis; the most recent study also suggests an interaction with PNPLA3 genotype[149,150]
KLF6	Kruppel-like factor 6	SNP rs3750861 has been associated with milder NAFLD-related hepatic fibrosis in three separate European cohorts[151]
MERTK	Myeloid epithelial reproductive tyrosine kinase	Homozygosity for common non-coding rs4374383 G>A polymorphism associated with less fibrosis in hepatitis C and NAFLD. Mechanism suggested is modulation of HSC activation[152]

Adapted from Anstee and Day[153] with permission of copyright holder.