Page 1001 - Read Online

Page 4 of 10 Kim et al. Hepatoma Res 2020;6:85 I http://dx.doi.org/10.20517/2394-5079.2020.96

[OR: 2.03 (1.50-2.73), P < 0.001] and significant fibrosis [OR: 1.61 (1.19-2.17), P < 0.002], after adjustment
[31]
[32]
for confounding variables . Similar findings were reported in a Chinese cohort . These results indicate
that the rs58542926 variant in TM6SF2 is associated with NAFLD, even in East Asia, where the allele
frequency is low.

MEMBRANE-BOUND O-ACYLTRANSFERASE DOMAIN CONTAINING 7
Membrane-bound O-acyltransferase domain containing 7 (MBOAT7) is a protein involved in
phosphatidylinositol remodeling with arachidonic acid in the Lands cycle. MBOAT7 is mainly expressed
in the liver, including in hepatic sinusoidal cells, hepatic stellate cells, and hepatocytes. In several studies,
the T allele of rs641738 in MBOAT7 (chr19:54173068, rs641738 C>T) has been reported to increase the risk
of developing the whole spectrum of NAFLD. Each T allele was associated with an increased risk of the
development of hepatic steatosis [OR: 1.42 (1.07-1.91), P = 0.015], NASH [OR: 1.18 (1.00-1.40), P = 0.05],
significant fibrosis [OR: 1.30 (1.06-1.70), P = 0.012], and HCC without advanced fibrosis [OR: 2.10 (1.33-
3.31)] [33-35] .

GLUCOKINASE REGULATOR
Glucokinase regulator (GCKR) controls de novo lipogenesis by regulating the glucose influx into
hepatocytes, which boosts the lipogenic pathway by providing further substrate for liver biosynthesis.
Several variants in the GCKR gene are reportedly associated with NAFLD [8,36] . The rs1260326 variant
(chr2:27508073, C>T) encoding P446L has been considered as a causal variant for this association. In
NAFLD patients, the T allele of rs1260326 is significantly associated with the hepatic fibrosis stage as
compared to the F1 stage [OR: 2.06 (1.02-1.14), P = 0.0008] . The rs780094 variant in GCKR has also been
[37]
significantly associated with computed tomography-proven and biopsy-proven NAFLD in a genome-wide
-8 [8]
association study (OR: 1.45, P = 2.59 × 10 ) , and in a meta-analysis of five studies comprising of 2,091
[38]
NAFLD cases and 3,003 controls [OR: 1.25 (1.14-1.36), P < 0.00001] .

[39]
The T risk allele of rs1260326 is associated with higher GCKR expression . Unlike the wild-type GCKR
protein, the GCKR P446L protein is not sustained by fructose-6-phosphate, resulting in enhanced hepatic
[40]
[41]
uptake of glucose, glucokinase activity , and de novo lipogenesis . Interestingly, the risk allele of
rs1260326 is also associated with decreased serum glucose levels and reduced T2DM risk [42,43] .
17β-HYDROXYSTEROID DEHYDROGENASE TYPE 13
Several recent GWAS have identified a protective variant against NAFLD: rs72613567:TA in hydroxysteroid
17β dehydrogenase 13 (HSD17B13) [44,45] . This variant seems to be associated with decreased serum aspartate
-10
aminotransferase (AST, P = 6.2 × 10 ) and serum ALT (P = 4.2 × 10 ), and ameliorated progressive
-12
NASH among persons of European descent (n = 46,544). Furthermore, this splice variant (chr4:87310241,
rs72613567: TA) in HSD17B13 protects against chronic liver diseases, including both NAFLD and alcoholic
liver disease, and this finding has been replicated in two studies [45,46] .

The protective effect of HSD17B13 is mediated by reduced activity of the enzyme, which is involved in the
conversion of retinol to retinoic acid . Retinoic acid reportedly suppresses fibrosis in NAFLD. This means
[47]
that the protective effect of HSD17B13 is not due to changes in hepatic fat accumulation, but rather caused
by the enzymatic activity of lipid droplet-associated retinol dehydrogenase activity.

ASSOCIATION BETWEEN NAFLD-PREDISPOSING POLYMORPHISMS AND CARDIOVASCULAR
DISEASE
Several studies report that cardiovascular disease (CVD) is the most common cause of mortality among
NAFLD patients [48-50] . This can be explained by the fact that NAFLD and CVD share common pathological