COMMENTARIES
TM6SF2: Catch-22
in the Fight
Against
Nonalcoholic
Fatty Liver
Disease and
Cardiovascular
Disease?
N onalcoholic fatty liver disease
(NAFLD) is rapidly becoming
the most common cause of chronic
liver disease worldwide.1,2 NAFLD in-
cludes a spectrum of disease ranging
from the accumulation of fat in the
liver (steatosis) to histologic evidence
of necroinammation (nonalcoholic
steatohepatitis [NASH]), then brosis
and cirrhosis, in the absence of exces-
sive alcohol ingestion.2,3 Approxi-
mately one-third of the US population
has radiologic evidence of NAFLD.
Although the majority (70%90%) will
have relatively benign simple
steatosis,46 NAFLD may progress to
cirrhosis or hepatocellular carcinoma,
and can lead to liver failure in the
absence of lifestyle change or effective
pharmacological treatments.2,7
Although morbidity and mortality
from liver disease are increased
greatly in patients with NAFLD,
morbidity and mortality from cardio-
vascular disease is even more preva-
lent in this population.8 NAFLD, a
complex trait inuenced by inter-
patient genetic variations and envi-
ronmental inuences, is widely
considered to be the hepatic manifes-
tation of the metabolic syndrome.1,2 It
correlates epidemiologically with the
presence of features of the metabolic
syndrome, which consists of having
3
of the following: impaired fasting
glucose, central obesity, dyslipidemia
(low high-density lipoprotein choles-
terol, high low-density lipoprotein
[LDL], or both) and hypertension.8
There is substantial interpatient vari-
ation in which features of the meta-
bolic syndrome are exhibited, and
which clinical sequelae an individual
may develop. In some cases the meta-
bolic syndrome predisposes to NAFLD9
and in others to cardiovascular dis-
ease.10 Determining why this occurs is
critical to making clinical recommen-
dations based on personal rather than
population risk.
Although the exact cause of NAFLD
or NASH has not been elucidated, we
are now able to begin to understand
the genetic basis for the disease.
NAFLD clusters in families,11 and its
heritability is estimated to be 26%
27% for CT-measured hepatic stea-
tosis.12 Genome-wide association
studies (GWAS) and candidate gene
studies have provided important in-
sights into the genetic contribution to
NAFLD.13 The nonsynonymous single
nucleotide polymorphism (SNP),
rs738409 (c.444 C>G, I148M) in
patatin-like phospholipase domain-
containing 3 (PNPLA3) was associated
signicantly with 1H-magnetic reso-
nance spectroscopy measured hepatic
triglyceride (TG) content14 and has
subsequently been validated globally
as a major genetic determinant of not
only steatosis, but also severity of
NASH, stage of hepatic brosis/
cirrhosis, and occurrence of NAFLD-
associated HCC.12,15,16 The largest
GWAS meta-analysis for NAFLD to
date, using 2.4 million SNPs imputed to
HapMap in 7176 individuals of Euro-
pean ancestry, identied common
variants at 5 loci. These variants are in
or near the genes PNPLA3, GCKR,
LYPLAL1, and PPP1R3B, and a region
on chromosome 19 (19p13.11) that
contains multiple genes and has vari-
ously been called NCAN/TM6SF2/
CILP2/PBX4 in the literature.12 The
variants at most of these loci are
also associated with NASH/brosis
(all but those at PPP1R3B).12 Variants
at the PNPLA3 locus conferred the
strongest effect, predisposing to
advanced liver disease with an odds
ratio (OR) of 3.26 (95% CI, 2.117.21),
with the variants at the 19p13.11
locus being the second strongest at
1.65 (95% CI, 1.152.65) per mutant
allele.12 The PNPLA3 and chromosome
19p13.11 locus also associated with
histologic NASH/brosis in an inde-
pendent sample of bariatric surgery
patients.17 Interestingly, NAFLD-
associated variants did not result in
uniform abnormalities of serum lipids
or glycemic and anthropometric
traits.12 In particular, variants at the
chromosome 19p13.11 locus associ-
ated with increased hepatic steatosis/
NASH/brosis were also associated
with decreased serum LDL cholesterol
and lower serum TGs,12,18,19 which
was contrary to the usually observed
epidemiologic pattern of these traits.
Variants at 19p13.11 were not as-
sociated signicantly with serum
glucose or measures of insulin resis-
tance in the best powered analyses at
the time.12,18,19 Variants at PNPLA3
and LYPLAL1 did not affect serum
lipid or glycemic traits, whereas those
at GCKR and PPP1R3B were associated
with increased serum LDL cholesterol
and lower serum glucose levels.12
These results suggested a heteroge-
neous etiology to NAFLD and the
existence of multiple genetic meta-
bolic disease subtypes that may re-
quire more precision treatment in the
future.12
Work from several groups has now
extended these ndings. It has recently
been reported that a nonsynonymous
genetic variant within a gene of un-
known function called TM6SF2, trans-
membrane 6 superfamily member 2,
(rs58542926 c.449 C>T) at the
19p13.11 locus was associated with
hepatic steatosis in 2,736 individuals
genotyped using a human exome
chip.20 This variant is in strong linkage
disequilibrium (r2 0.798) with vari-
ants in the chromosome 19p13.11
locus previously reported to be NAFLD
risk factors,12 making it likely that the
new and old signals are the same.
Indeed, conditional analyses indicate
that TM6SF2 rs58542926 may be
the causal variant driving the associa-
tion at this locus.20,21 The TM6SF2
rs58542926 variant has subsequently
been associated with severity of
NAFLD-associated hepatic brosis/
cirrhosis (OR, 1.88 [95% CI, 1.412.5]
for advanced brosis per each copy of
the minor allele carried), independent
of confounding factors including age,
diabetes, obesity, or PNPLA3 genotype,
in a cohort of >1000 histologically
characterized patients,21 consistent
with previous associations at this
Gastroenterology 2015;148:679684
COMMENTARIES
locus.12 This association has itself been

pressure; HOMA-IR, homeostatic model assessment for insulin resistance; LDL-C, low-density lipoprotein cholesterol; MAF, minor allele frequency in Europeans; NA, not
assessed in the study referenced; NASH, nonalcoholic steatohepatitis; SBP, systolic blood pressure; T2D, type 2 diabetes; TC, total cholesterol; TG, triglycerides; [,
ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate transaminase; CAD/MI, coronary artery disease/myocardial infarction; DBP, diastolic blood
NASH/Fibrosis
validated independently21,22 and other
studies have also associated the
TM6SF2 variant with decreased levels
of serum LDL cholesterol and TG20,23

NA

NA

NA
[

[
(consistent with the earlier reports12).
Studies have also described associa-

ALP/ALT/AST
tions of the minor allele at this locus

NA/NA/NA

NA/NA/NA

NA/NA/NA

NA/NA/NA
with increased serum alanine trans-

NA/[/NA
aminase, aspartate transaminase,20

Y/[/[
and increased risk of diabetes,24 with
decreased serum alkaline phosphatase

Fatty
and lower risk of myocardial infarc-

liver

NA

NA

NA
tion,23 atherosclerosis, and cardiovas-

[
cular disease22 (Table 1).

TC

NA

NA

NA
Because the association signal in

Association With Other Traits

Y
the chromosome 19p13.11 region

TG

NA
covers >20 genes and the SNPs across

Y
this region are in high LD with one

LDL-C
another (highly correlated) and

NA
include both known (in TM6SF2, NCAN,

Y
CILP2) and yet to be discovered non-
HOMA-IR
synonymous SNPs, it remains to be
Table1.Association of Variants at chr 19p13.11 Locus With Manifestations of the Metabolic Syndrome

proven whether all of these pheno-

types are owing to 1 or possibly mul-
NSa

NSa

NA

NA
NA

NA
tiple correlated functional variants/
genes in the region. Toward this end,
Glucose
Fasting

several groups have started to carry

NSa

NSa

NSa

out functional experiments with the

NA

NA
NA

genes under the GWAS signal and their

variants to narrow down the causal
SBP

NSa
NA

NA

NA
NA

NA

gene(s) and variant(s). TM6SF2

rs58542926 c.449 C>T heterozygous
DBP

NSa

variant is a nonsynonymous change

NA

NA
NA

NA

NA

producing a glutamate to lysine amino

acid substitution at residue 167
CAD/MI

(E167K), with the glutamate being

highly conserved across mammals.20 In
NA

NA
NA

NA
Y

mice, overexpression of human wild-

T2D

type TM6SF2 in liver resulted in

NA

NA

NA

NA
[

higher total cholesterol, LDL choles-

Based on P value after correcting for multiple tests.

terol, TGs and lower high-density li-

rs58542926

Same SNP

Same SNP
Same SNP

poprotein cholesterol, whereas

LD (r2)

0.798
With

0.97

0.98

knockdown of mouse Tm6sf2 in liver

signicant increase; Y, signicant decrease.

resulted in decreased serum total

cholesterol.23 Because the E167K allele
results in lower total cholesterol in
exonic:TM6SF2:E167K

exonic:TM6SF2:E167K

exonic:TM6SF2:E167K

humans, these data suggest that the

SNP Annotation

exonic: NCAN:P92S
Gene: Protein

E167K mutation in TM6SF2 was a loss

intronic: SUGP1

intronic: SUGP1
Change

of function allele.23 Kozlitina et al20

showed that expression of TM6SF2
(E167K) protein is lower than wild
type, consistent with this being a loss
of function allele, and showed that
knockdown of mouse Tm6sf2 resulted
rs1040196919

rs1040196924

rs5854292623

rs5854292620

rs5854292621
Allele, MAF)

rs222860312

in increased liver lipid accumulation

(Minor
SNP

(T, 0.084)
(C, 0.09)

(C, 0.08)

and decreased serum TG and LDL.

(T, 0.07)

(T, 0.07)

(T, 0.12)

They also found that knockdown of

mouse Tm6sf2 resulted in decreased
a

680

very low-density lipoprotein (VLDL)
cholesterol secretion.20 In other inde-
pendent work25 using confocal
microscopy, investigators observed
localization of green uorescent pro-
teintagged TM6SF2 to the endo-
plasmic reticulum in 2 human
hepatoma cell lines. Additionally,
knockdown of TM6SF2 in both cell
lines resulted in reduced secretion of
TG-rich lipoproteins, apolipoprotein B,
and increased cellular TG levels. At the
subcellular level, a marked increase in
lipid droplet area, which could be
attributed to increases in both the
number and average size of lipid
droplets, was reported. Conversely,
overexpression of TM6SF2 caused a
decrease in the number and average
size of lipid droplets.25 In parallel ex-
periments, Kozlitina et al20 also
observed an increase in the size and
number of lipid droplets in the livers of
mice after knockdown of Tm6sf2.
These results suggest a role for
TM6SF2 in regulating the supply of
lipids for the synthesis of TG-rich li-
poproteins. Finally, RNAi knockdown
of both TM6SF2 and NCAN in HeLa
cells resulted in increased free choles-
terol,26 suggesting that the product of
>1 gene in this region may be involved
in hepatic lipid handling.
Not all the studies have unequivo-
cal ndings. Neither Kozlitina et al20
nor Holmen et al23 observed changes
with serum alkaline phosphatase in the
mouse experiments described, con-
trary to the results observed in
humans. Kozlitina et al20 reported
increased accumulation of hepatic TGs
in Tm6sf2 knockdown mice, whereas
Holmen et al23 found no evidence of TG
accumulation in the livers of Tm6sf2
knockdown mice. Kozlitina et al used
adeno-associated virus knockdown,
whereas Holmen used adenovirus
knockdown of TM6SF2 in liver in
C57BL/6J mice. These differences in
hepatic steatosis may be owing to dif-
ferences between humans and mice, to
the short duration of gene-altering
studies in mouse livers, or to species-
or tissue-specic effects of TM6SF2.
Targeting just the liver for knock-
down/overexpression in mice, for
example, may result in phenotypes
related to just this organ, whereas
TM6SF2, which is expressed more
widely, may exert some of its effects
via its role in extrahepatic organs.
TM6SF2 has highest expression levels
in the intestine, where alkaline
phosphatase is also expressed (in
addition to the liver) and thus
TM6SF2 may inuence on serum
alkaline phosphatase via intestinal
effects. The association between
TM6SF2 rs58542926 and the NAFLD
phenotype spectrum from steatosis to
advanced brosis/cirrhosis has now
been robustly demonstrated in several
large independent cohorts12,2022,25;
however, 2 studies1 from China27
and 1 from South America28have
been unable to replicate these associ-
ations. This may, in part, be owing to
the generally low minor allele fre-
quency of NAFLD associating variants
in the 19p13.11 locus and interethnic
variations in their frequency of car-
riage. Specically, the minor allele at
rs58542926 (T), has a frequency of
0.07 in Europeans, 0.04 in Hispanics,
and 0.02 in African Americans.29 Thus,
the liver disease promoting allele at
TM6SF2 will affect more individuals of
European ancestry than Hispanic or
African ancestry. Inadequate statistical
power to detect an effect on histologic
markers of disease progression is a
particular issue in the South American
study,28 where only 226 NAFLD cases
with histologically mild disease were
included. Of these cases, only 130 had
anything more than bland steatosis,
but these cases exhibited a mean
brosis stage of only 1.4 out of 4,
further degrading the sensitivity of the
study. It is, therefore, not surprising
that the authors were unable to detect
an association with features of steato-
hepatitis or brosis, whereas groups
with larger cohorts have been
successful.12,21,22
The above functional studies
in vivo20,23 and in vitro20,23,25 suggest
that the TM6SF2 gene affects hepatic
lipid efux, with its deletion or mu-
tation resulting in a reduction of li-
poprotein secretion (VLDL, TG, and
apolipoprotein B) coincident with
increased hepatocellular lipid droplet
size and TG content. The 19p13.11
locus overall, and the TM6SF2
rs58542926 variant in particular,
COMMENTARIES
provide new insights into the mecha-
nistic basis of progressive NAFLD, and
the association between NAFLD and
cardiovascular disease. They suggest
that TM6SF2 is an important deter-
minant of clinical outcome across
metabolic syndrome related end-
organ damage. Indeed, current evi-
dence suggests that TM6SF2 may
act as a switch with TM6SF2
rs58542926 T-allele mediating hepat-
ic retention of TG and cholesterol
predisposing to NAFLD-brosis,
whereas C-allele carriage promotes
VLDL excretion, protecting the liver at
the expense of increased risk of
atherosclerosis and cardiovascular
disease (Figure 1). Thus, although in
the general population, NAFLD is
associated with an increased risk of
cardiovascular disease, these can
become dissociated: individuals car-
rying the minor (T) allele of TM6SF2
rs58542926 (167K) may be prone to
experience liver-related rather than
cardiovascular morbidity and mortal-
ity.2,30,31 Corroborating this nding,
even though only about 0.5% of in-
dividuals of European ancestry in the
population are homozygous for the
minor allele of TM6SF2, 1.5% of in-
dividuals selected for having histo-
logic NASH/brosis have this
genotype, suggesting that carrying 2
copies of the T allele predisposes to
developing advanced liver disease.21
In contrast, carriage of the C-allele is
associated with multiple classic char-
acteristics of the metabolic syndrome,
including dyslipidemia and cardiovas-
cular disease.23 Thus, carrying the T
allele protects against development of
dyslipidemia and cardiovascular dis-
ease.23 Whether the effects of variants
at the 167 position will be strong
enough to overshadow the effects of
many other environmental or genetic
variants on the risk of liver and car-
diovascular disease at an individual
level, and so merit distinct medical
recommendations for patients car-
rying this allele, remains to be deter-
mined. Nevertheless, studying the
effects of NAFLD-associated human
genetic variants on related metabolic
traits promises to teach us much
about how these traits interrelate to
one another pathophysiologically.
681
COMMENTARIES
Although we have learned many
things already from these discoveries,
some interesting questions remain.
The T allele of TM6SF2 rs58542926
has been associated with decreased
alkaline phosphatase levels, but how
the E167K change in TM6SF2 actually
results in this biochemical effect re-
mains to be determined. Interestingly,
knocking down hepatic TM6SF2
expression did not result in changes in
serum alkaline phosphatase.20 Because
TM6SF2 is expressed not only in liver
but also in intestine where alkaline
phosphatase is also present at high
levels, the authors suggest that intes-
tine may be where the E167K change
may exert its effect to cause lower
levels of alkaline phosphatase.20 This
theory remains to be tested. Another
unresolved question relates to the role
of TM6SF2 in the development of type
2 diabetes mellitus. Although one large
meta-analysis suggests that TM6SF2
T-allele carriage is associated with an
increased risk of type 2 diabetes,24 its
effect on serum glucose and on insulin
resistance is not signicant24 and
direct evidence of an effect on insulin
sensitivity is currently lacking, with
clamp studies nding no reduction in
682
whole body, hepatic, or adipose tissue
insulin sensitivity.31 Further research,
perhaps utilizing stable global and
tissue-specic knockouts of TM6SF2 in
mice, may help to clarify these ques-
tions. Even though there is evidence
that the E167K mutation of TM6SF2
results in less VLDL in serum, the
exact mechanism by which this occurs
is not known. Because VLDL forma-
tion requires a multistep process
where TGs are combined with apoli-
poproteins that are then secreted,
altered, and eventually taken up again
by the liver as VLDL remnants, how if
at all this cycle is disrupted by the
E167K variant at TM6SF2 remains
to be tested. Because chylomicron
assembly and circulation in intestine
parallels VLDL assembly and circula-
tion in liver and because TM6SF2 is
also expressed in intestine, it remains
to be determined whether chylomi-
cron biology is also affected by the
E167K TM6SF2 change in humans
and mice. Through further study of
TM6SF2 and other NAFLD-related
loci, we will be able to better under-
stand the mechanisms by which
metabolic disease develops so that we
can hopefully better tailor clinical
Figure 1.Effects of TM6SF2. TM6SF2
plays a role in VLDL export from liver to
serum which results in increased serum
lipids and myocardial infarction, and
decreased risk of liver steatosis. chol,
cholesterol; LDL, low-density lipoprotein
cholesterol; IHTG, intrahepatic triglycer-
ide; NASH, nonalcoholic steatohepatitis;
TG, triglyceride; VLDL, very low-density
lipoprotein.
recommendations for disease treat-
ment in the future. Indeed, although
genetic testing for common diseases is
currently limited, this may change
with a better understanding of how
this information can be used to inform
patient care.
BRATATI KAHALI
University of Michigan
Ann Arbor, Michigan
YANG-LIN LIU
ANN K. DALY
CHRISTOPHER P. DAY
QUENTIN M. ANSTEE
Newcastle University
Newcastle-upon-Tyne, UK
ELIZABETH K. SPELIOTES
University of Michigan
Ann Arbor, Michigan
References
1. Dietrich P, Hellerbrand C. Non-
alcoholic fatty liver disease, obesity
and the metabolic syndrome. Best
Pract Res Clin Gastroenterol 2014;
28:637653.
2. Anstee QM, Targher G, Day CP.
Progression of NAFLD to diabetes

mellitus, cardiovascular disease or
cirrhosis. Nat Rev Gastroenterol
Hepatol 2013;10:330344.
3. Clark JM. The epidemiology of
nonalcoholic fatty liver disease in
adults. J Clin Gastroenterol 2006;
40(Suppl 1):S5S10.
4. Hernaez R, McLean J, Lazo M,
et al. Association between variants
in or near PNPLA3, GCKR, and
PPP1R3B with ultrasound-dened
steatosis based on data from
the third National Health and
Nutrition Examination Survey. Clin
Gastroenterol Hepatol 2013;11:
11831190 e2.
5. Speliotes EK, Massaro JM,
Hoffmann U, et al. Fatty liver
is associated with dyslipidemia
and dysglycemia independent
of visceral fat: the Framingham
Heart Study. Hepatology 2010;51:
19791987.
6. Browning JD, Szczepaniak LS,
Dobbins R, et al. Prevalence of
hepatic steatosis in an urban pop-
ulation in the United States: impact
of ethnicity. Hepatology 2004;40:
13871395.
7. Harrison SA, Neuschwander-
Tetri BA. Nonalcoholic fatty liver
disease and nonalcoholic steato-
hepatitis. Clin Liver Dis 2004;8:
861879.
8. Review T, LaBrecque DR, Abbas Z,
et al. World Gastroenterology
Organisation global guidelines:
Nonalcoholic fatty liver disease and
nonalcoholic steatohepatitis. J Clin
Gastroenterol 2014;48:467473.
9. Hamaguchi M, Kojima T, Takeda N,
et al. The metabolic syndrome as a
predictor of nonalcoholic fatty liver
disease. Ann Intern Med 2005;
143:722728.
10. Wang J, Ruotsalainen S,
Moilanen L, et al. The metabolic
syndrome predicts cardiovascular
mortality: a 13-year follow-up study
in elderly non-diabetic Finns. Eur
Heart J 2007;28:857864.
11. Schwimmer JB, Celedon MA,
Lavine JE, et al. Heritability of nonal-
coholic fatty liver disease. Gastroen-
terology 2009;136:15851592.
12. Speliotes EK, Yerges-
Armstrong LM, Wu J, et al.
Genome-wide association analysis
identies variants associated
with nonalcoholic fatty liver disease
that have distinct effects on meta-
bolic traits. PLoS Genet 2011;
7:e1001324.
13. Anstee QM, Day CP. The genetics
of NAFLD. Nat Rev Gastroenterol
Hepatol 2013;10:645655.
14. Romeo S, Kozlitina J, Xing C, et al.
Genetic variation in PNPLA3 con-
fers susceptibility to nonalcoholic
fatty liver disease. Nat Genet 2008;
40:14611465.
15. Liu YL, Patman GL, Leathart JB,
et al. Carriage of the PNPLA3
rs738409 C >G polymorphism
confers an increased risk of non-
alcoholic fatty liver disease asso-
ciated hepatocellular carcinoma.
J Hepatol 2014;61:7581.
16. Valenti L, Al-Serri A, Daly AK, et al.
Homozygosity for the patatin-like
phospholipase-3/adiponutrin I148M
polymorphism inuences liver -
brosis in patients with nonalcoholic
fatty liver disease. Hepatology 2010;
51:12091217.
17. Gorden A, Yang R, Yerges-
Armstrong LM, et al. Genetic vari-
ation at NCAN locus is associated
with inammation and brosis in
non-alcoholic fatty liver disease in
morbid obesity. Hum Hered 2013;
75:3443.
18. Teslovich TM, Musunuru K,
Smith AV, et al. Biological, clinical
and population relevance of 95 loci
for blood lipids. Nature 2010;
466:707713.
19. Global Lipids Genetics Consortium;
Willer CJ, Schmidt EM, Sengupta S,
et al. Discovery and renement of
loci associated with lipid levels. Nat
Genet 2013;45:12741283.
20. Kozlitina J, Smagris E, Stender S,
et al. Exome-wide association
study identies a TM6SF2 variant
that confers susceptibility to
nonalcoholic fatty liver disease. Nat
Genet 2014;46:352356.
21. Liu YL, Reeves HL, Burt AD, et al.
TM6SF2 rs58542926 inuences
hepatic brosis progression in pa-
tients with non-alcoholic fatty liver
disease. Nat Commun 2014;
5:4309.
22. Dongiovanni P, Petta S, Maglio C,
et al. Transmembrane 6 super-
family member 2 gene
variant disentangles nonalcoholic
COMMENTARIES
steatohepatitis from cardiovascu-
lar disease. Hepatology 2015;
61:506514.
23. Holmen OL, Zhang H, Fan Y, et al.
Systematic evaluation of coding
variation identies a candidate
causal variant in TM6SF2 inu-
encing total cholesterol and
myocardial infarction risk. Nat
Genet 2014;46:345351.
24. Morris AP, Voight BF, Teslovich TM,
et al. Large-scale association anal-
ysis provides insights into the ge-
netic architecture and
pathophysiology of type 2 diabetes.
Nat Genet 2012;44:981990.
25. Mahdessian H, Taxiarchis A,
Popov S, et al. TM6SF2 is a regu-
lator of liver fat metabolism inu-
encing triglyceride secretion and
hepatic lipid droplet content. Proc
Natl Acad Sci U S A 2014;
111:89138918.
26. Blattmann P, Schuberth C,
Pepperkok R, et al. RNAi-based
functional proling of loci from
blood lipid genome-wide associa-
tion studies identies genes with
cholesterol-regulatory function.
PLoS Genet 2013;9:e1003338.
27. Wong VW, Wong GL, Tse CH, et al.
Prevalence of the TM6SF2 variant
and non-alcoholic fatty liver dis-
ease in Chinese. J Hepatol 2014;
61:708709.
28. Sookoian S, Castano GO, Scian R,
et al. Genetic variation in TM6SF2
and the risk of nonalcoholic fatty
liver disease and histological dis-
ease severity. Hepatology 2015;
61:515525.
29. Palmer ND, Musani SK, Yerges-
Armstrong LM, et al. Characteriza-
tion of European ancestry
nonalcoholic fatty liver disease-
associated variants in individuals
of African and Hispanic descent.
Hepatology 2013;58:966975.
30. Ekstedt M, Franzen LE,
Mathiesen UL, et al. Long-term
follow-up of patients with NAFLD
and elevated liver enzymes. Hep-
atology 2006;44:865873.
31. Zhou Y, Llaurad G, Oresic M, et al.
Circulating triacylglycerol signa-
tures and insulin sensitivity in
NAFLD associated with the E167K
variant in TM6SF2. J Hepatol 2015;
62:657663.
683
COMMENTARIES
Reprint requests
Address requests for reprints to: Elizabeth K.
Speliotes, MD, PhD, MPH, Division of
Gastroenterology and Hepatology, University of
Michigan Health System, 3912 Taubman Center,
1500 E. Medical Center Drive, SPC 5362, Ann
Arbor, MI 48109-5362. e-mail: espeliot@med.
umich.edu; Quentin M. Anstee, BSc, MBBS, PhD,
MRCP(UK), Institute of Cellular Medicine, The
Medical School, Newcastle University, 4th Floor,
684
William Leech Building, Framlington Place,
Newcastle-upon-Tyne, NE2 4HH, UK. e-mail:
quentin.anstee@newcastle.ac.uk
Conicts of interest
The authors disclose no conicts.
Funding
Bratati Kahali and Elizabeth K. Speliotes were
supported by the Doris Duke Medical Foundation,
and the University of Michigan Internal Medicine
Department, Division of Gastroenterology, and
Biological Sciences Scholars Program. Quentin
M. Anstee was supported by a Clinical Senior
Lectureship Award from the Higher Education
Funding Council for England (HEFCE).
2015 by the AGA Institute
0016-5085/$36.00
http://dx.doi.org/10.1053/j.gastro.2015.01.038