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Kim et al. Hepatoma Res 2020;6:85 I http://dx.doi.org/10.20517/2394-5079.2020.96 Page 3 of 10
[18]
[17]
studies . The PNPLA3 protein hydrolyzes triglycerides and retinyl esters . The variant rs738409 C>G
causes an isoleucine-to-methionine substitution at amino acid position 148 in PNPLA3, which results in
impaired retinyl ester release and reduced hydrolase activity, causing fat accumulation within hepatocytes,
[19]
including hepatic stellate cells .
Studies of PNPLA3 have transformed our knowledge of hepatic steatosis, revealing that lipid remodeling
in intracellular lipid droplets is a common pathway underlying NAFLD progression, regardless of the
environmental triggers. While the wild-type PNPLA3 protein is rapidly degraded, the variant protein
has no lipase activity, thereby leading to triglyceride accumulation in the liver [19,20] . This can induce liver
damage and inflammation, and can block the release of several extracellular proteins that protect against
[21]
liver fibrosis, including matrix metalloproteinases and tissue inhibitor of metalloproteinases . The G
allele of rs738409 is significantly associated with NAFLD activity score (NAS, P = 0.004), steatosis (P =
-6 [22]
-4
0.03), lobular inflammation (P = 0.005), portal inflammation (P = 2.5 × 10 ), and fibrosis (P = 7.7 × 10 ) .
Moreover, homozygosity of this variant is reportedly linked to a 10-fold increased risk of developing
[23]
NAFLD-associated HCC in the European population . Overall, these findings indicate that the G allele
of rs738409 increases susceptibility to the whole spectrum of NAFLD - from steatosis to NASH (an
inflammation-associated form of NAFLD), fibrosis, and HCC.

The PNPLA3 gene could also be responsible for the different prevalence rates of NAFLD between ethnic
groups. Different populations showed diverse odds ratios (ORs) for the variant rs738409 C>G, ranging from
2.08 to 18.23 [combined OR: 3.41 (2.57-4.52), P < 0.00001] [7,8,11,12] . According to the genome aggregation
database browser (gnomAD, https://gnomad.broadinstitute.org/), the G allele of rs738409 has a frequency
of 27.1% in the general population, but occurs at a lower frequency in persons of African ethnicity (26.1%),
and at a higher frequency in persons of Latino ethnicity (54.9%), which may have an impact on NAFLD
risk in Latino populations [7,12] . Accordingly, compared to other ethnic groups, persons of Latino ethnicity
are reportedly more likely to progress to more severe forms of NAFLD . The effect of PNPLA3 on NAFLD
[24]
has also been described in East Asian cohorts. In two Japanese cohorts, the G risk allele of the rs738409
variant is significantly associated with NAFLD [OR: 1.66 (1.43-1.94), P = 1.4 × 10 and OR: 2.05, P = 6.8 ×
-10
-14 [11,25]
10 ] . Similarly, among Korean NAFLD patients, rs738409 in PNPLA3 is significantly associated with
NAFLD [OR: 1.537 (1.383-1.709), P = 1.74 × 10 ] . Therefore, the rs738409 variant C>G in PNPLA3 is
-15 [26]
strongly related to NAFLD progression in both Latino and East Asian cohorts.

TRANSMEMBRANE 6 SUPERFAMILY 2
Transmembrane 6 superfamily member 2 (TM6SF2) is a protein that localizes to the endoplasmic
reticulum-Golgi apparatus of hepatocytes, and is involved in the increased hepatocytic secretion of
triglyceride-rich lipoproteins via the pathway of very-low-density lipoprotein secretion. The TM6SF2
polymorphism rs58542926 C>T (chr19:19268740, C>T) involves a C-to-T substitution at nucleotide 499,
encoding a glutamate-to-lysine change at codon 167 (E167K). The variant rs58542926 leads to reduced
TM6SF2 expression, and is thus associated with increased hepatic lipid content. In a multi-ancestry study,
the rs58542926 polymorphism was related to increased serum liver enzyme [alanine transaminase (ALT)]
[27]
levels and a decreased serum lipid profile (total cholesterol and triglycerides) . Interestingly, rs58542926
has also been linked to a decreased risk of cardiovascular events based on the decreased circulating
lipoprotein levels [28,29] . The relationship between TM6SF2 and serum liver enzyme (ALT) has also been
[27]
identified in other large cohorts (n > 80,000) . Moreover, the variant rs58542926 has been associated with
increased liver fibrosis (P = 5.57 × 10 ), independently of PNPLA3 I148M .
[30]
-5
The G risk allele of rs58542926 occurs with a lower frequency (0.06969, gnomAD) in East Asia; thus, we
explored the association of rs58542925 with NAFLD in East Asian studies. A Korean study reported that
the co-existence of the risk alleles rs738409 and rs58542926 was associated with an increased risk of NASH