A promoter variant of the APOA5 gene increases atherogenic LDL levels and arterial stiffness in hypertriglyceridemic patients
A promoter variant of the APOA5 gene increases atherogenic LDL levels and arterial stiffness in hypertriglyceridemic patients
Minjoo Kim 1 2
Minkyung Kim 1 2
Hye Jin Yoo 0 2
Eunji Lee 0 2
Jey Sook Chae 1 2
Sang- Hyun Lee 2 3
Jong Ho Lee 0 1 2
0 Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University , Seoul , Korea , 3 National Leading Research Laboratory of Clinical Nutrigenetics/Nutrigenomics, Department of Food and Nutrition, College of Human Ecology, Yonsei University , Seoul , Korea
1 Research Center for Silver Science, Institute of Symbiotic Life-TECH, Yonsei University , Seoul , Korea
2 Editor: Laura Calabresi, University of Milano , ITALY
3 Department of Family Practice, National Health Insurance Corporation, Ilsan Hospital , Goyang , Korea
Hypertriglyceridemia is recognized as an independent risk factor for coronary artery disease. The apolipoprotein A5 gene (APOA5) is a key regulator of triglyceride levels. We aimed to evaluate the associations of single nucleotide polymorphisms (SNPs) in APOA5, including -1131T>C and c.553G>T, with hypertriglyceridemia, apoA5 concentrations, atherogenic LDL cholesterol levels, and arterial stiffness in hypertriglyceridemic patients. The study population included 599 hypertriglyceridemic patients (case) and 1,549 untreated normotriglyceridemic subjects (control). We genotyped two APOA5 variants, -1131T>C (rs662799) and c.553G>T (rs2075291). The frequencies of the CC genotype of -1131T>C (0.165) and the T allele of c.553G>T (0.119) were significantly higher in hypertriglyceridemic patients than in normotriglyceridemic subjects (0.061 and 0.070, respectively; all p<0.001). In the control and case groups, both the -1131T>C and c.553G>T variants were associated with higher triglyceride and lower HDL cholesterol levels. Controls with the -1131CC variant had lower apoA5 concentrations than controls with the -1131TT variant. Similar effects of the -1131T>C variant on apoA5 were observed in the cases. In the hypertriglyceridemic group, the -1131T>C variant was associated with a smaller LDL particle size, higher levels of oxidized LDL and malondialdehyde, and higher brachial-ankle pulse wave velocity. The -1131T>C and c.553G>T polymorphisms were associated with hypertriglyceridemia in the study population, but only the -1131T>C polymorphism directly affected apoA5 concentrations. Hypertriglyceridemic patients carrying the APOA5 -1131T>C polymorphism exhibited increased atherogenic LDL levels and arterial stiffness, probably due to an effect of the -1131T>C polymorphism on apoA5 concentrations.
Data Availability Statement: The whole dataset
from Korean Chip cannot be shared with other
parties who did not sign in our research named
"Verification of metabolic disease related-new
biomarkers and development of efficacy prediction
of traditional natural substance based on clinical
nutritional genomic and metabolomic technology"
underlying Korean Chip Consortium in the Korean
Genome Organization. Data cannot be made
publicly available for ethical or legal reasons, e.g.,
public availability would compromise patient
confidentiality or participant privacy. Also, our data
include participants' privacy and written informed
Hypertriglyceridemia is recognized as an independent risk factor for coronary artery disease (CAD) [1,2]. Consistent with this notion, the 1131T>C single nucleotide polymorphism
consent was provided confined to above research
content. Authorship of this paper or study is
required for access to the data within the
consortium. However, if the other interested
researchers want to access the data from this
manuscript (part of the whole dataset), they can
request access to the data through the Korea
Genome Organization: . The
authors can also be contacted for assistance at
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Funding: This study was funded by the
BioSynergy Research Project
(NRF2012M3A9C4048762) and the Mid-career
Researcher Program (NRF-2016R1A2B4011662)
of the Ministry of Science and by ICT and Future
Planning through the National Research
Foundation of the Republic of Korea. The funders
had no role in study design, data collection and
analysis, decision to publish, or preparation of the
Competing interests: The authors have declared
that no competing interests exist.
(SNP) in the apolipoprotein A5 gene (APOA5) is associated with an increased risk of CAD in
several ethnic populations, probably due to its association with hypertriglyceridemia [3±5].
However, limited data are available regarding the association between the APOA5 locus and a
phenotypic manifestation of atherosclerosis in humans. Brachial-ankle pulse wave velocity
(ba-PWV) is correlated with aortic PWV [
], is a predictor for cardiovascular morbidity and
], and has been suggested to be a composite risk factor for the identification of
subjects with early atherosclerotic changes [
Both apolipoprotein A5 (apoA5) and APOA5 are key regulators of plasma triglyceride (TG)
levels [8±11]. In many human populations, APOA5 SNPs are associated with variations in
serum TG levels. Among the five commonly studied APOA5 SNPs (-1131T>C, -3A>G,
56C>G, IVS3+476G>A, and 1129T >C) [12±14], -1131T>C and 56C>G are considered
functional tag SNPs [15±17]; however, the minor 56G allele is not detected in the Korean
]. The c.553G>T (p.185Gly>Cys, rs2075291) SNP is associated with marked
hypertriglyceridemia among Asians in some studies; specifically, T allele carriers in Asian
populations have a 4-fold higher risk of high TG levels [19±21]. Therefore, we aimed to evaluate
the association of APOA5 SNPs, including -1131T>C and c.553G>T, with
hypertriglyceridemia and apoA5 concentrations in a Korean population. We also investigated the variations at
the APOA5 gene locus encoding apoA5, which correlates with a more atherogenic pattern of
low-density lipoprotein (LDL) cholesterol levels and arterial stiffness in hypertriglyceridemic
Materials and methods
Two thousand one hundred sixty-seven study participants with nondiabetic normotriglyc
eridemia (TG levels<150 mg/dL) and hypertriglyceridemia (TG levels 150 mg/dL) were
recruited for this study from the Health Service Center (HSC) during routine checkups at the
National Health Insurance Corporation Ilsan Hospital in Goyang, Korea (January 2010-March
2015). Based on data from the HSC, subjects who agreed to participate in the study were
referred to the Department of Family Medicine or Internal Medicine, and their health and
serum lipid profiles were rechecked. The exclusion criteria were a current diagnosis or history
of cardiovascular disease, liver disease, renal disease, pancreatitis, or cancer; and regular use of
any medication. The aim of the study was carefully explained to all participants, who then
provided written informed consent. The Institutional Review Board of Yonsei University and the
National Health Insurance Corporation Ilsan Hospital approved the study protocol, which complied with the Declaration of Helsinki.
General anthropometry, blood pressure (BP) measurements, and sample collection procedures
are described elsewhere [
]. Participants' body weights and heights were measured, and their
body mass indexes (BMIs) were calculated in units of kilograms per square meter. BP was
measured twice with an automatic BP monitor (FT-200S; Jawon Medical, Gyeongsan, Korea)
after a resting period of at least 20 min, and the average value was used. Blood samples were
collected following an overnight fast of at least 12 hours.
The levels of fasting TGs, total cholesterol, high-density lipoprotein (HDL) cholesterol, LDL
cholesterol, and glucose were analyzed using an autoanalyzer (Hitachi 7600 Autoanalyzer,
Hitachi Ltd., Tokyo, Japan). LDL particle size and oxidized (ox)-LDL and malondialdehyde (MDA)
levels were measured using previously described methods [
]. Plasma apoA5 concentrations
were measured using an enzyme immunoassay (Human apoA5 ELISA Kit; Cusabio, Zhejiang,
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China). The absorbance of the resulting color was measured at 450 nm using a VersaMax ELISA microplate reader (Molecular Devices, Sunnyvale, CA, USA). The ba-PWV was measured with an automatic waveform analyzer (model VP-1000; Nippon Colin Ltd., Komaki, Japan).
Affymetrix Axiom™ KORV1.0±96 array hybridization and SNP selection
Two thousand one hundred sixty-seven samples were genotyped using the Axiom1 2.0 Reagent
Kit (Affymetrix Axiom1 2.0 Assay User Guide; Affymetrix, Santa Clara, CA, USA) according
to the manufacturer's protocol. Approximately 200 ng of genomic DNA (gDNA) was amplified
and randomly fragmented into 25- to 125-base pair (bp) fragments. The gDNA was initially
amplified in a 40-μL reaction containing 20 μL of a 10 ng/μL genomic DNA stock and 20 μL of
a master mix. The initial amplification reaction conditions were a 10-min initial amplification
at room temperature, followed by amplification with 130 μL of Axiom 2.0 Neutral Solution,
225 μL of Axiom 2.0 Amp Solution and 5 μL of Axiom 2.0 Amp Enzyme. The amplification
reactions were performed for 23±1 hours at 37ÊC. The amplification products were analyzed in
an optimized reaction to amplify fragments between 200 and 1100 bp in length. A
fragmentation step reduced the amplified products into segments of approximately 25±50 bp in length,
which were end-labeled using biotinylated nucleotides. Following hybridization, the bound
target was washed under stringent conditions to remove non-specific background and to minimize
the background noise caused by random ligation events. Each polymorphic nucleotide was
queried in a multicolor ligation event conducted on the array surface. After ligation, the arrays were
stained and imaged on a GeneTitan MC Instrument (Affymetrix, Santa Clara, CA, USA). The
images were analyzed using the Genotyping Console™ Software (Affymetrix, Santa Clara, CA,
USA). The genotype data were produced using the Korean Chip (K-CHIP) available through
the K-CHIP consortium. The K-CHIP was designed by the Center for Genome Science at the
Korea National Institute of Health (4845±301, 3000±3031).
Samples with the following characteristics were excluded: sex inconsistency, markers with a
high missing rate (>5%), individuals with a high missing rate (>10%), minor allele frequency
<0.01, and a significant deviation from Hardy-Weinberg equilibrium (HWE) (p<0.001).
SNPs in linkage disequilibrium with each other were excluded; therefore, the remaining 394,379 SNPs and 2,159 samples were used in subsequent association analyses.
Descriptive statistical analyses were performed using SPSS version 23.0 (IBM, Chicago, IL,
USA). The skewed variables were transformed to logarithmic form, and a two-tailed p-value
<0.05 was considered statistically significant. An independent t-test was performed on the
continuous variables to compare parameters between the controls and cases. HWE was
assessed using PLINK version 1.07 (http://pngu.mgh.harvard.edu/purcell/plink/). The
association between SNPs and TG levels was evaluated using a linear regression analysis. The
frequency was tested using the chi-square test. The association of hypertriglyceridemia with a
genotype was determined using the odds ratio (OR) [95% confidence intervals (CIs)] of a
logistic regression model after adjusting for confounding factors. One-way ANOVA
followed by Bonferroni post hoc test was performed to compare the differences among the
APOA5 -1131T>C genotypes in the normotriglyceridemic controls and hypertriglyceri
A total of 394,379 SNPs and 2,159 samples were used in the analyses. The associations between genotypes and TG levels were evaluated with a linear regression analysis after adjusting for age
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and sex. Among the ten SNPs with the strongest association with TG levels, APOA5 -1131T>C
and APOA5 c.553G>T exhibited the top two strongest associations (p = 4.83E-27 and p =
8.75E13, respectively). In addition, the coverage of APOA5 -1131T>C and APOA5 c.553G>T was
99.7% and 99.8%, respectively. Therefore, we performed an association analysis using these two
SNPs. Among 2,159 subjects, both APOA5 variants were genotyped in 2,148 subjects; therefore,
11 subjects were excluded from this study.
The clinical and biochemical characteristics of normotriglyceridemic controls (n = 1,549)
and hypertriglyceridemic cases (n = 599) are shown in Table 1. Case subjects were significantly
older, more often male, heavier, and more often smokers than the controls. After adjusting for
age, sex, BMI, smoking, and drinking, the hypertriglyceridemic subjects exhibited higher
systolic and diastolic BPs; higher levels of TG, total cholesterol and ox-LDL; lower levels of HDL
cholesterol, LDL cholesterol and apoA5; and smaller LDL particle sizes (Table 1).
Controls (n = 1,549)
564 (36.4)/985 (63.6)
Distribution of APOA5 -1131T>C and APOA5 c.553G>T polymorphisms
Genotypic distributions of the APOA5 -1131T>C and APOA5 c.553G>T polymorphisms in
the entire study population were in HWE. The genotypic distribution of the -1131T>C
polymorphism was significantly different between normotriglyceridemic controls and
hypertriglyceridemic patients (p<0.001). The minor C allele frequency was significantly increased in
hypertriglyceridemic participants (0.404) compared with that in controls (0.270; p<0.001;
Table 1). Similarly, the genotypic distribution of the c.553G>T polymorphism was
significantly different between normotriglyceridemic controls and hypertriglyceridemic patients
(p<0.001). The minor T allele frequency was significantly increased in hypertriglyceridemic
participants (0.119) compared with that in controls (0.070; p<0.001; Table 1). Regarding the
APOA5 c.553G>T polymorphism, we pooled heterozygotes (GT) and rare allele homozygotes
(TT) to increase the statistical power. Additionally, since the -1131T>C and c.553G>T
polymorphisms were not in strong linkage disequilibrium (r2 = 0.202), we separately analyzed the
effects of these genotypes on the biochemical parameters.
The presence of the CC genotype of the APOA5 -1131T>C polymorphism was associated
with a higher risk of hypertriglyceridemia [OR 3.322 (95% CI 2.421±4.559); p<0.001] after
adjusting for age, sex, BMI, smoking, and drinking. Similarly, the presence of the T allele of
the APOA5 c.553G>T polymorphism was associated with a higher risk of
hypertriglyceridemia [OR 1.956 (95% CI 1.522±2.515); p<0.001] after adjusting for age, sex, BMI, smoking, and
Effects of the APOA5 -1131T>C and APOA5 c.553G>T polymorphisms
on apoA5 levels and serum lipid profiles
No significant genotype-related differences in age and BMI were observed between controls
and hypertriglyceridemic patients with the -1131T>C or c.553G>T polymorphisms (data not
shown). Regarding the APOA5 -1131T>C polymorphism, a significant association was
observed between apoA5 concentrations and the -1131T>C polymorphism in controls (p =
0.043), with CC controls having lower values than TT controls (Table 2). Similarly, a
significant association between apoA5 concentrations and the -1131T>C polymorphism was
observed in hypertriglyceridemic patients (p = 0.027), with CC patients having lower values than
TT patients. A significant association was observed between serum TG levels and the -1131T>
C polymorphism. Additionally, an association of the APOA5 -1131T>C polymorphism with
HMeans ± SE.
Tested using logarithmic transformation.
p-values for each group were derived by one-way ANOVA. All letters indicate p<0.05, as derived using Bonferroni post hoc tests; the same letter indicates
no significant difference, whereas different letters indicate significant differences.
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HMeans ± SE.
Tested using logarithmic transformation.
p-values were derived from an independent t-test comparing the GG genotype and the T allele in each group.
lower HDL cholesterol levels was observed in controls (p = 0.011) and hypertriglyceridemic
patients (p<0.001). However, significant genotype-related differences in the LDL and total
cholesterol levels were not observed (Table 2).
Regarding the APOA5 c.553G>T polymorphism, a significant association between serum
TG levels and the c.553G>T polymorphism was observed in controls (p = 0.004) and
hypertriglyceridemic cases (p<0.001) (Table 3). Additionally, an association of the APOA5 c.553G>T
polymorphism with lower HDL cholesterol levels was identified in controls (p = 0.013) and
hypertriglyceridemic patients (p = 0.001). However, significant genotype-related differences in
the levels of apoA5, LDL and total cholesterol were not observed (Table 3).
Effects of the APOA5 -1131T>C and APOA5 c.553G>T polymorphisms
on LDL particle size, ox-LDL and MDA levels, and ba-PWV
Regarding the APOA5 -1131T>C polymorphism, a significant association was observed
between LDL particle size and the -1131T>C polymorphism in hypertriglyceridemic patients
(p = 0.006), with patients with the CC genotype having smaller LDL particle sizes than patients
with the TT or TC genotypes (Fig 1). Additionally, a significant association between ox-LDL
levels and the -1131T>C polymorphism was observed in hypertriglyceridemic patients (p =
0.033), with patients with the CC genotype displaying higher levels than patients with the TT
genotype. A significant association between MDA levels and the -1131T>C genotype was also
observed in hypertriglyceridemic patients (p<0.001), with patients with the CC genotype
displaying higher levels than patients with the TT or TC genotype. Furthermore, a significant
association was observed between ba-PWV and the -1131T>C polymorphism in
hypertriglyceridemic patients (p = 0.007), with patients with the CC genotype displaying higher levels
than patients with the TT or TC genotype (Fig 1). However, for the APOA5 c.553G>T
polymorphism, no significant genotype-related differences in LDL particle size, ox-LDL and MDA
levels, and ba-PWV were observed between controls and hypertriglyceridemic patients (data
Correlation between the apoA5 concentration and lipid profiles and
In the total study population, apoA5 concentrations were negatively correlated with TG (r =
-0.170, p<0.001) and MDA levels (r = -0.087, p = 0.001) and positively correlated with HDL
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Fig 1. Association of the APOA5 -1131T>C polymorphism with LDL particle size, oxidized LDL and malondialdehyde levels, anH d ba-PWV in
normotriglyceridemic controls (TG levels<150 mg/dL) and hypertriglyceridemic patients (TG levels 150 mg/dL). Means ± SE. Tested using
logarithmic transformation. p-values for each group were derived by one-way ANOVA. All letters represent p<0.05, as derived using Bonferroni post hoc
tests after adjusting for age, sex, BMI, smoking, and drinking; differences that are not significant are marked with the same letter, and significant differences
are marked with different letters.
cholesterol levels (r = 0.298, p<0.001) and LDL particle size (r = 0.193, p<0.001). Additionally,
ba-PWV was positively correlated with TG (r = 0.319, p<0.001) and MDA levels (r = 0.196,
p<0.001) and negatively correlated with LDL particle size (r = -0.125, p<0.001).
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The -1131T>C and c.553G>T polymorphisms were associated with hypertriglyceridemia in
this study population, but only the -1131T>C polymorphism directly affected apoA5
concentrations. Additionally, hypertriglyceridemic patients carrying the APOA5 -1131T>C
polymorphism displayed smaller LDL particle sizes and higher ox-LDL levels and ba-PWV, a marker
of arterial stiffness [
]. Thus, the APOA5 variants, particularly the CC genotype of the APOA5
-1131T>C polymorphism, predispose hypertriglyceridemic patients to increased atherogenic
LDL levels and arterial stiffness, probably due to the effects of the -1131T>C polymorphism on apoA5 concentrations.
The present findings of associations of the APOA5 -1131T>C and c.553G>T
polymorphisms with higher TG levels and lower HDL cholesterol levels are highly consistent with the
results of meta-analyses reported by Zhao et al. [
] and He et al. [
], respectively. The apoA5
protein encoded by the APOA5 gene is a well-known apolipoprotein and an important
determinant of plasma TG levels, which are a major risk factor for CAD [
]. Two theories broadly
describe the mechanism by which apoA5 modulates TG levels: (i) apoA5 inhibits the rate of
very low-density lipoprotein (VLDL) production, the major carrier of TG, and (ii) apoA5
enhances the catabolism of TG-rich lipoproteins [
]. Merkel et al. [
] reported that apoA5
accelerates plasma hydrolysis of TG-rich lipoproteins by facilitating interaction with
lipoprotein lipase (LPL), and apoA5 acts as an allosteric LPL activator in the lipolytic system. With
respect to the c.553G>T mutation, the Gly185 amino acid residue is relatively conserved,
suggesting that this residue might play a crucial role in the function of LPL. Furthermore, all
c.553G>T carriers were found to have partial LPL activity, indicating that the c.553G>T
mutation likely affects the LPL, thereby reducing LPL activity [
]. Huang et al. [
investigated the effect of different amino acid substitution mutations at position 185 in apoA5 on its
LPL activation properties and found that Gly at this position is important for LPL activation in
vitro. The protein encoded by c.553G>T apoA5 consist of dimers and multimers in vitro,
although the most of the protein is monomeric [
]. The studies with members of the LDL
receptor family have indicated that c.553G>T apoA5 is functional, suggesting that defective
LPL activation is the underlying mechanism . Therefore, we speculate that even though
the apoA5 levels were not significantly different between the GG genotype and T allele in
APOA5 c.553G>T, the T allele of apoA5 results in less LPL activation than the GG genotype.
As shown in the study by Grosskopf et al. [
], apoA5-deficient mice exhibit decreased
lipoprotein lipase activity and the accumulation of larger VLDL particles, which are precursors of
small dense LDLs. According to the recent study by Guardiola et al. [
], carriers of a rare allele
of the APOA5 -1131T>C polymorphism have large VLDLs and small LDLs.
Hypertriglyceridemic patients with the CC genotype had significantly smaller LDL particle sizes than cases
with the TT or TC genotype in the present study, despite a lack of significant differences in
their LDL cholesterol concentrations. Additionally, LDL particle size was positively correlated
with apoA5 concentrations.
Small dense LDLs are more susceptible to in vitro oxidation . Moreover, changes in
the LDL profile towards smaller species and decreases in serum total antioxidant levels are
closely associated with increased ox-LDL levels in humans [
]. In this study,
hypertriglyceridemic patients with the CC genotype of the APOA5 -1131T>C polymorphism had smaller
LDL particle sizes and higher MDA and ox-LDL levels than those with the TT genotype. MDA
is an end product of lipid peroxidation. In addition to its high reactivity and toxicity, MDA is
one of the most popular and reliable clinical markers of oxidative stress [
], emphasizing the
relevance of this molecule to the biomedical research field. Additionally, MDA levels were
positively correlated with ba-PWV, consistent with the findings reported by Kim et al. [
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Serum MDA-LDL, which produces ox-LDL, has been reported to exert direct cytotoxicity on
endothelial cells, promote the secretion of adhesion molecules, facilitate platelet aggregation
and monocyte adhesion, and enhance foam cell formation in atherosclerotic lesions, all of
which lead to remodeling of vessel walls and have influence on ba-PWV [
serum levels of MDA are elevated in hypertension  indicating that oxidative stress is
associated with BP in which has been known to be related to ba-PWV [
The ba-PWV has been shown to be a suitable preventative measure to screen for vascular
dysfunction and the development of atherosclerosis [
]. In this study, hypertriglyceridemic
patients with the CC genotype of the APOA5 -1131T>C polymorphism had higher ba-PWV
than cases with the TT or TC genotype. Additionally, LDL particle size was negatively
correlated with ba-PWV. Recently, the atherogenic subclass distribution of lipoproteins has been
reported to be associated with increased carotid intima-media thickness (IMT), a surrogate
measure of the atherosclerotic burden [
]. Additionally, in the study by Elousa et al. [
-1131T>C polymorphism was significantly associated with increased common carotid IMT in
obese participants in the Framingham Offspring Study.
A few limitations should be considered when interpreting the findings from the present
study. Our results share the limitations of cross-sectional observational studies because we
identified only associations rather than prospective predictors. Additionally, in the present
study, we specifically focused on a representative group of Korean subjects. Therefore, our
results cannot be generalized to other ethnic, age or geographical groups. Moreover, further
studies with larger sample sizes are needed to verify the mechanism and associations of the
APOA5 c.553G>T polymorphism with apoA5 concentrations and cardiovascular disease risk
Despite these limitations, APOA5 variants, particularly the CC genotype of the APOA5
-1131T>C polymorphism, might predispose hypertriglyceridemic patients to increased
atherogenic LDL levels, smaller LDL particle sizes, higher ox-LDL levels, greater arterial stiffness,
and higher ba-PWV, probably due to the effects of the -1131T>C polymorphism on apoA5
concentrations. These changes have clinical importance because hypertriglyceridemic patients
with the CC genotype might exhibit subclinical atherosclerosis.
The genotype data were generated using Korean Chip (K-CHIP), which is available through
the K-CHIP consortium. K-CHIP was designed by the Center for Genome Science at the
Korea National Institute of Health, Korea (4845±301, 3000±3031).
Conceptualization: Minjoo Kim, Sang-Hyun Lee, Jong Ho Lee.
Data curation: Minjoo Kim, Minkyung Kim, Hye Jin Yoo, Jong Ho Lee.
Formal analysis: Minkyung Kim, Hye Jin Yoo, Eunji Lee.
Funding acquisition: Jong Ho Lee.
Investigation: Minjoo Kim, Minkyung Kim, Hye Jin Yoo, Eunji Lee, Jey Sook Chae, Jong Ho Lee.
Methodology: Minjoo Kim, Minkyung Kim, Hye Jin Yoo, Jey Sook Chae, Sang-Hyun Lee.
Project administration: Jong Ho Lee.
Resources: Sang-Hyun Lee, Jong Ho Lee.
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Supervision: Jong Ho Lee.
Visualization: Hye Jin Yoo.
Writing ± original draft: Minjoo Kim, Jong Ho Lee.
Writing ± review & editing: Minjoo Kim.
10 / 12
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1. Cullen P . Evidence that triglycerides are an independent coronary heart disease risk factor . Am J Cardiol . 2000 ; 86 : 943 ± 949 . PMID: 11053704
2. Talmud PJ , Hawe E , Miller GJ , Humphries SE . Nonfasting apolipoprotein B and triglyceride levels as a useful predictor of coronary heart disease risk in middle-aged UK men . Arterioscler Thromb Vasc Biol . 2002 ; 22 : 1918 ± 1923 . PMID: 12426225
3. Jang Y , Paik JK , Hyun YJ , Chae JS , Kim JY , Choi JR , et al. The apolipoprotein A5 -1131T>C promoter polymorphism in Koreans: association with plasma APOA5 and serum triglyceride concentrations, LDL particle size and coronary artery disease . Clin Chim Acta . 2009 ; 402 : 83 ± 87 . https://doi.org/10.1016/j. cca. 2008 . 12 .024 PMID: 19159622
4. Szalai C , Keszei M , Duba J , ProhaÂszka Z , Kozma GT , CsaÂszaÂr A , et al. Polymorphism in the promoter region of the apolipoprotein A5 gene is associated with an increased susceptibility for coronary artery disease . Atherosclerosis . 2004 ; 173 : 109 ± 114 . https://doi.org/10.1016/j.atherosclerosis. 2003 . 12 .003 PMID: 15177130
5. Hsu LA , Ko YL , Chang CJ , Hu CF , Wu S , Teng MS , et al. Genetic variations of apolipoprotein A5 gene is associated with the risk of coronary artery disease among Chinese in Taiwan . Atherosclerosis. 2006 ; 185 : 143 ± 149 . https://doi.org/10.1016/j.atherosclerosis. 2005 . 05 .031 PMID: 16054149
6. Hung CS , Lin JW , Hsu CN , Chen HM , Tsai RY , Chien YF , et al. Using brachial-ankle pulse wave velocity to associate arterial stiffness with cardiovascular risks . Nutr Metab Cardiovasc Dis . 2009 ; 19 : 241 ± 246 . https://doi.org/10.1016/j.numecd. 2008 . 07 .006 PMID: 18815016
7. Yamashina A , Tomiyama H , Takeda K , Tsuda H , Arai T , Hirose K , et al. Validity, reproducibility, and clinical significance of noninvasive brachial-ankle pulse wave velocity measurement . Hypertens Res . 2002 ; 25 : 359 ± 364 . PMID: 12135313
8. Guardiola M , CofaÂn M , de Castro-Oros I , Cenarro A , Plana N , Talmud PJ , et al. APOA5 variants predispose hyperlipidemic patients to atherogenic dyslipidemia and subclinical atherosclerosis . Atherosclerosis . 2015 ; 240 : 98 ± 104 . https://doi.org/10.1016/j.atherosclerosis. 2015 . 03 .008 PMID: 25770687
9. Matsunaga A , Arishima H , Niimura H , Zhang B , Uehara Y , Ohwaki K , et al. Strong linkage disequilibrium and association of -1131T>C and c .553G> T polymorphisms of the apolipoprotein A5 gene with hypertriglyceridemia in a Japanese population . Circ J . 2007 ; 71 : 746 ± 752 . PMID: 17457003
10. Garelnabi M , Lor K , Jin J , Chai F , Santanam N. The paradox of ApoA5 modulation of triglycerides: evidence from clinical and basic research . Clin Biochem . 2013 ; 46 : 12 ± 19 . https://doi.org/10.1016/j. clinbiochem. 2012 . 09 .007 PMID: 23000317
11. He H , Lei L , Chen E , Dong J , Zhang K , Yang J . The c .553G> T Genetic Variant of the APOA5 Gene and Altered Triglyceride Levels in the Asian Population: A Meta-Analysis of Case-Control Studies . Genet Test Mol Biomarkers . 2016 ; 20 : 758 ± 765 . https://doi.org/10.1089/gtmb. 2016 .0047 PMID: 27813673
12. Nabika T , Nasreen S , Kobayashi S , Masuda J. The genetic effect of the apoprotein AV gene on the serum triglyceride level in Japanese . Atherosclerosis. 2002 ; 165 : 201 ± 204 . PMID: 12417270
13. Lai CQ , Tai ES , Tan CE , Cutter J , Chew SK , Zhu YP , et al. The APOA5 locus is a strong determinant of plasma triglyceride concentrations across ethnic groups in Singapore . J Lipid Res . 2003 ; 44 : 2365 ± 2373 . https://doi.org/10.1194/jlr.M300251-JLR200 PMID: 12951359
14. Corella D , Lai CQ , Demissie S , Cupples LA , Manning AK , Tucker KL , et al. APOA5 gene variation modulates the effects of dietary fat intake on body mass index and obesity risk in the Framingham Heart Study . J Mol Med (Berl). 2007 ; 85 : 119 ± 128 .
15. Pennacchio LA , Olivier M , Hubacek JA , Cohen JC , Cox DR , Fruchart JC , et al. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing . Science . 2001 ; 294 : 169 ± 173 . https://doi.org/10.1126/science.1064852 PMID: 11588264
16. Talmud PJ , Martin S , Taskinen MR , Frick MH , Nieminen MS , KesaÈniemi YA , et al. APOA5 gene variants, lipoprotein particle distribution, and progression of coronary heart disease: results from the LOCAT study . J Lipid Res . 2004 ; 45 : 750 ± 756 . https://doi.org/10.1194/jlr.M300458-JLR200 PMID: 14729863
17. Pennacchio LA , Olivier M , Hubacek JA , Krauss RM , Rubin EM , Cohen JC . Two independent apolipoprotein A5 haplotypes influence human plasma triglyceride levels . Hum Mol Genet . 2002 ; 11 : 3031 ± 3038 . PMID: 12417524
18. Lee KH , Kim OY , Lim HH , Lee YJ , Jang Y , Lee JH . Contribution of APOA5-1131C allele to the increased susceptibility of diabetes mellitus in association with higher triglyceride in Korean women . Metabolism . 2010 ; 59 : 1583 ± 1590 . https://doi.org/10.1016/j.metabol. 2010 . 02 .008 PMID: 20303129
19. Pullinger CR , Aouizerat BE , Movsesyan I , Durlach V , Sijbrands EJ , Nakajima K , et al. An apolipoprotein A-V gene SNP is associated with marked hypertriglyceridemia among Asian-American patients . J Lipid Res . 2008 ; 49 : 1846 ± 1854 . https://doi.org/10.1194/jlr.P800011-JLR200 PMID: 18441017
20. Kao JT , Wen HC , Chien KL , Hsu HC , Lin SW . A novel genetic variant in the apolipoprotein A5 gene is associated with hypertriglyceridemia . Hum Mol Genet . 2003 ; 12 : 2533 ± 2539 . https://doi.org/10.1093/ hmg/ddg255 PMID: 12915450
21. Tang Y , Sun P , Guo D , Ferro A , Ji Y , Chen Q , et al. A genetic variant c.553G > T in the apolipoprotein A5 gene is associated with an increased risk of coronary artery disease and altered triglyceride levels in a Chinese population . Atherosclerosis . 2006 ; 185 : 433 ± 437 . https://doi.org/10.1016/j.atherosclerosis. 2005 . 06 .026 PMID: 16046221
22. Kim M , Song G , Kang M , Yoo HJ , Jeong TS , Lee SH , et al. Replacing carbohydrate with protein and fat in prediabetes or type-2 diabetes: greater effect on metabolites in PBMC than plasma . Nutr Metab (Lond) . 2016 ; 13 : 3 .
23. Zhao T , Zhao J . Association of the apolipoprotein A5 gene -1131 T>C polymorphism with fasting blood lipids: a meta-analysis in 37859 subjects . BMC Med Genet . 2010 ; 11 : 120 . https://doi.org/10.1186/ 1471 -2350-11-120 PMID: 20696075
24. Merkel M , Loeffler B , Kluger M , Fabig N , Geppert G , Pennacchio LA , et al. Apolipoprotein AV accelerates plasma hydrolysis of triglyceride-rich lipoproteins by interaction with proteoglycan-bound lipoprotein lipase . J Biol Chem . 2005 ; 280 : 21553 ± 21560 . https://doi.org/10.1074/jbc.M411412200 PMID: 15774484
25. Xie SL , Chen TZ , Huang XL , Chen C , Jin R , Huang ZM , et al. Genetic Variants Associated with Gestational Hypertriglyceridemia and Pancreatitis . PLoS One . 2015 ; 10 : e0129488. https://doi.org/10.1371/ journal.pone. 0129488 PMID: 26079787
26. Huang YJ , Lin YL , Chiang CI , Yen CT , Lin SW , Kao JT . Functional importance of apolipoprotein A5 185G in the activation of lipoprotein lipase . Clin Chim Acta . 2012 ; 413 : 246 ± 250 . https://doi.org/10. 1016/j.cca. 2011 . 09 .045 PMID: 22008704
27. Dorfmeister B , Zeng WW , Dichlberger A , Nilsson SK , Schaap FG , Hubacek JA , et al. Effects of six APOA5 variants, identified in patients with severe hypertriglyceridemia, on in vitro lipoprotein lipase activity and receptor binding . Arterioscler Thromb Vasc Biol . 2008 ; 28 : 1866 ± 1871 . https://doi.org/10. 1161/ATVBAHA.108.172866 PMID: 18635818
28. Sharma V , Witkowski A , Witkowska HE , Dykstra A , Simonsen JB , Nelbach L , et al. Hypertriglyceridemia associated with the c .553G> T APOA5 SNP results from aberrant hetero-disulfide bond formation . Arterioscler Thromb Vasc Biol . 2014 ; 34 : 2254 ± 2260 . https://doi.org/10.1161/ATVBAHA.114.304027 PMID: 25127531
29. Grosskopf I , Baroukh N , Lee SJ , Kamari Y , Harats D , Rubin EM , et al. Apolipoprotein A-V deficiency results in marked hypertriglyceridemia attributable to decreased lipolysis of triglyceride-rich lipoproteins and removal of their remnants . Arterioscler Thromb Vasc Biol . 2005 ; 25 : 2573 ± 2579 . https://doi.org/10. 1161/01.ATV. 0000186189 .26141.12 PMID: 16166565
30. de Graaf J , Hak-Lemmers HL , Hectors MP , Demacker PN , Hendriks JC , Stalenhoef AF . Enhanced susceptibility to in vitro oxidation of the dense low density lipoprotein subfraction in healthy subjects . Arterioscler Thromb . 1991 ; 11 : 298 ± 306 . PMID: 1998647
31. Belo L , Caslake M , Santos-Silva A , Castro EM , Pereira-Leite L , Quintanilha A , et al. LDL size, total antioxidant status and oxidised LDL in normal human pregnancy: a longitudinal study . Atherosclerosis . 2004 ; 177 : 391 ± 399 . https://doi.org/10.1016/j.atherosclerosis. 2004 . 07 .023 PMID: 15530915
32. Giera M , Lingeman H , Niessen WM . Recent Advancements in the LC- and GC-Based Analysis of Malondialdehyde (MDA): A Brief Overview . Chromatographia. 2012 ; 75 : 433 ± 440 . https://doi.org/10.1007/ s10337-012 -2237-1 PMID: 22593603
33. Kim OY , Paik JK , Lee JY , Lee SH , Lee JH . Follow-ups of metabolic, inflammatory and oxidative stress markers, and brachial-ankle pulse wave velocity in middle-aged subjects without metabolic syndrome . Clin Exp Hypertens . 2013 ; 35 : 382 ± 388 . https://doi.org/10.3109/10641963. 2012 .739232 PMID: 23148723
34. Berliner JA , Heinecke JW . The role of oxidized lipoproteins in atherogenesis . Free Radic Biol Med . 1996 ; 20 : 707 ± 727 . PMID: 8721615
35. Steinberg D . Low density lipoprotein oxidation and its pathobiological significance . J Biol Chem . 1997 ; 272 : 20963 ± 20966 . PMID: 9261091
36. Armas-Padilla MC , Armas-HernaÂndez MJ , Sosa-Canache B , Cammarata R , Pacheco B , Guerrero J , et al. Nitric oxide and malondialdehyde in human hypertension . Am J Ther . 2007 ; 14 : 172 ± 176 . https:// doi.org/10.1097/01.pap. 0000249914 .75895.48 PMID: 17414586
37. Kim EJ , Park CG , Park JS , Suh SY , Choi CU , Kim JW , et al. Relationship between blood pressure parameters and pulse wave velocity in normotensive and hypertensive subjects: invasive study . J Hum Hypertens . 2007 ; 21 : 141 ± 148 . https://doi.org/10.1038/sj.jhh. 1002120 PMID: 17136108
38. Shin JY , Lee HR , Lee DC . Increased arterial stiffness in healthy subjects with high-normal glucose levels and in subjects with pre-diabetes . Cardiovasc Diabetol . 2011 ; 10 : 30 . https://doi.org/10.1186/ 1475 - 2840-10-30 PMID: 21492487
39. Elosua R , Ordovas JM , Cupples LA , Lai CQ , Demissie S , Fox CS , et al. Variants at the APOA5 locus, association with carotid atherosclerosis, and modification by obesity: the Framingham Study . J Lipid Res . 2006 ; 47 : 990 ± 996 . https://doi.org/10.1194/jlr.M500446-JLR200 PMID: 16474174