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Page 4 of 12 Liu et al. Hepatoma Res 2020;6:42 I http://dx.doi.org/10.20517/2394-5079.2020.25

technology, small sample size, inappropriate study population and not accounting for underlying ethnic
variability. The most widely known genetic mutations altering the risk of ALD and ALD-HCC are in the
alcohol-metabolizing enzymes. These mutations alter the enzyme kinetics of alcohol dehydrogenase (ADH)
and acetaldehyde dehydrogenase (ALDH) [35,36] . ADH1B rs1229984 induces ADH activity and acetaldehyde
formation, whereas ALDH2*2 rs671 reduces ALDH activity, impairing its ability to clear acetaldehyde [35,37] .
Carriage of both mutations results in the accumulation of toxic acetaldehyde levels with intense rise in
arterial blood flow to the face, causing the well-known flushing and nausea. In East Asian populations with
high prevalence of these mutations, this may result in reduced alcohol intake conferring protection against
[38]
alcoholism . Conversely, the risk of developing ALD and ALD-HCC increases in drinkers who carry one
[36]
or both mutations .
Recent technological advances such as genome-wide association studies (GWAS) and next-generation
sequencing have added to the growing field of genetic and epigenetic factors that modulate the risk
for ALD/AC-related HCC. In recent years, a few single nucleotide polymorphisms (SNPs) have been
discovered that are associated with risk of AC [39-41] . The single most commonly reproduced association with
liver cirrhosis is the rs738409 SNP (p. I148M) in patatin-like phospholipase domain protein 3 (PNPLA3),
[42]
which is also associated with increased HCC risk . This C>G mutation is accompanied by a change from
isoleucine to methionine at a conserved amino acid residue (I148M). Association of rs738409 (C>G) with
increased risk of liver diseases has been confirmed in AC [40,41] and alcohol-related HCC [43,44] . Dose effect
of the G-allele has been shown with ancestry-adjusted odds ratio (OR) increasing by 1.79 per G allele
-7
[46]
-5
[45]
(P = 1.9 × 10 ) for ALD risk and 1.77 (95%CI: 1.42-2.19, P = 2.78 × 10 ) per G allele for HCC .
The influence of this variant on HCC risk prediction revealed that the rs738409 (GG) genotype was an
[46]
independent risk factor specifically for alcohol- (but not HCV-) related HCC . Moreover, OR among
the AC patients with HCC increased from 2.87 (95%CI: 1.61-5.10) in carriers of the CG genotype to 12.41
[43]
(95%CI: 6.99-22.03) in GG patients .
A study in a Chinese population showed that rs17401966 (A>G) in kinesin-like factor 1 B (KIF1B), a
tumor suppressor gene, was associated with risk of HCC. The risk of HCC was higher in carriers of the
AA genotype, compared to GG or AG, but only in the presence of alcohol (OR 2.36, 95%CI: 1.49-3.74),
suggesting an additive gene-environment interaction between rs17401966 and alcohol consumption . But
[47]
this association has not been confirmed. Similarly, rs641738 (C>T) in membrane-bound O-acyltransferase 7
[40]
(MBOAT7), was identified as a risk locus for AC , but has yet to be replicated in other studies as a risk for
AC/ALD or HCC.

Another SNP, rs58542926 (*/T) in transmembrane 6 superfamily 2 (TM6SF2), is strongly associated with
the risk for HCC, particularly in patients with AC- and not HCV-related cirrhosis [44,48] . This variant was
independently confirmed to be associated with HCC using a multivariate model adjusted for age, sex, BMI
[48]
and diabetes (OR 2.5, 95%CI: 1.4-4.3) .
SNPs in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) are associated with decreased liver
[49]
transaminases and liver injury . In particular, recently identified splice variant SNP rs72613567 (T>A),
resulting in loss of function and reduced enzyme activity, also showed (1) interactions with PNPLA3
rs738409 risk allele, with each rs72613567:TA allele lowering the increase in transaminase levels conferred
by each PNPLA3 risk allele (I148M); and (2) allele dose-dependent association of rs72613567:TA with
[39]
decrease in PNPLA3 mRNA expression . Importantly, this rs72613566 (T>A) was associated with lower
odds of alcohol- and non-alcohol-related liver diseases/cirrhosis as well as lower risk for HCC. The lower
risk conferred by rs72613567 variant was PNPLA3 allele-dependent for AC and was confirmed in both men
and women . However, the rs72613567-associated lower risk for HCC was PNPLA3-dependent only in
[50]
[50]
men .