Influences of APOA5 Variants on Plasma Triglyceride Levels in Uyghur Population
Citation: Li S, Hu B, Wang Y, Wu D, Jin L, et al. (
Influences of APOA5 Variants on Plasma Triglyceride Levels in Uyghur Population
Shuyuan Li 0
Bin Hu 0
Yi Wang 0
Di Wu 0
Li Jin 0
Xiaofeng Wang 0
Ge Zhang, Cincinnati Children's Hospital Medical Center, United States of America
0 1 Ministry of Education Key Laboratory of Contemporary Anthropology and State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University , Shanghai , China , 2 Fudan-Taizhou Institute of Health Sciences , Taizhou, Jiangsu , China
Objective: Single nucleotide polymorphisms (SNPs) in apolipoprotein A5 (APOA5) gene are associated with triglyceride (TG) levels. However, the minor allele frequencies and linkage disequilibriums (LDs) of the SNPs in addition to their effects on TG levels vary greatly between Caucasians and East Asians. The distributions of the SNPs/haplotypes and their associations with TG levels in Uyghur population, an admixture population of Caucasians and East Asians, have not been reported to date. Here, we performed a cross-sectional study to address these. Methods: Genotyping of four SNPs in APOA5 (rs662799, rs3135506, rs2075291, and rs2266788) was performed in 1174 unrelated Uyghur subjects. SNP/haplotype and TG association analyses were conducted. Results: The frequencies of the SNPs in Uyghurs were in between those in Caucasians and East Asians. The LD between rs662799 and rs2266788 in Uyghurs was stronger than that in East Asians but weaker than that in Caucasians, and the four SNPs resulted in four haplotypes (TGGT, CGGC, TCGT, and CGTT arranged in the order of rs662799, rs3135506, rs2075291, and rs2266788) representing 99.2% of the population. All the four SNPs were significantly associated with TG levels. Compared with non-carriers, carriers of rs662799-C, rs3135506-C, rs2075291-T, and rs2266788-C alleles had 16.0%, 15.1%, 17.1%, and 12.4% higher TG levels, respectively. When haplotype TGGT was defined as the reference, the haplotypes CGGC, TCGT, and CGTT resulted in 16.1%, 19.0%, and 19.8% higher TG levels, respectively. The proportions of variance in TG explained by APOA5 locus were 2.5%, 0.3%, 0.4%, and 1.9% for single SNP rs662799, rs3135506, rs2075291, and rs2266788, respectively, and 3.0% for the haplotypes constructed by them. Conclusions: The association profiles between the SNPs and haplotypes at APOA5 locus and TG levels in this admixture population differed from those in Caucasians and East Asians. The functions of these SNPs and haplotypes need to be elucidated comprehensively.
Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. Data are available from DRYAD using the
Funding: This work was supported by grants-in-aids from National Science and Technology Supporting Program (2011BAI09B02), National Natural Science
Foundation (311712160 and 30890034), and grants from and National Basic Research Program (2012CB944600). The funders had no role in study design, data
collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
. These authors contributed equally to this work.
The APOA5 gene is located approximately 27 kb downstream
from the APOA1/C3/A4 gene cluster on human chromosome
11q23 [1,2]. The protein product of the APOA5 gene, apoA-V, is
a component of several lipoprotein fractions, including very
lowdensity lipoprotein (VLDL), high-density lipoprotein, and
chylomicrons . Although the exact function of apoA-V is not yet
clear, it was demonstrated to be able to reduce triglyceride (TG)
levels by activating lipoprotein lipase, thus inhibiting VLDL-TG
production and stimulating VLDL-TG hydrolysis .
Five single nucleotide polymorphisms (SNPs), including
rs662799 (21131 T.C), rs651821 (23 A.G), rs3135506
(S19W, c.56C.G), rs2072560 (715 G.T, which was previously
referred to as IVS3+476G.T), and rs2266788 (1891 T.C,
c.158C.T, which was previously referred to as c.1259T.C), were
initially identified to be associated with plasma TG levels in
Caucasians . Except for rs3135506, the other four SNPs
were in almost complete linkage disequilibrium (LD), with r2
ranging from 0.87 to 1, resulting in the three following haplotypes:
haplotype APOA5*1, which is the wild-type haplotype as defined
by the presence of major alleles at all of the sites; haplotype
APOA5*2, which is defined by the rare alleles at four sites,
including rs662799, rs651821, rs2072560, and rs2266788; and
haplotype APOA5*3, which is distinguished from APOA5*1 by
the rare allele of the SNP rs3135506 [5,6]. Compared with the
most common haplotype APOA5*1, the haplotypes APOA5*2
and APOA5*3 were also associated with higher TG levels in
Caucasians . However, further studies in East Asians
revealed contrasting results, indicating that the SNP rs3135506
and haplotype APOA5*3 were rare and not associated with TG
levels in this population . The frequencies of the minor
alleles of the five SNPs vary significantly in East Asians compared
with those in Caucasians. The minor allele frequencies (MAFs) of
the five SNPs were in the range of 0.06 to 0.08 in the Caucasians;
however, the MAFs of rs662799, rs651821, rs2072560, and
rs2266788 increased to 0.20 to 0.30, and the MAF of rs3135506
decreased to less than 0.01 in the East Asians [5,6,1115]. The LD
patterns of the five SNPs in East Asians also differed from those in
Caucasians. Tight LDs between rs662799 and rs651821 (r2$0.99),
and also between rs2072560 and rs2266788 (r2$0.9) were
observed in East Asians, whereas the LDs between rs662799/
rs651821 and rs2072560/rs2266788 were less prominent, with r2
ranging from 0.6 to 0.7 in this population [13,14]. The differing
LD patterns also made the haplotype APOA5*4 defined by the
common allele of rs662799/rs651821 with the rare allele of
rs2072560/rs2266788, which was not detected in Caucasians, can
be observed in East Asians. The haplotype APOA5*4 was also
associated with familial combined hyperlipidemia . To date,
the mechanism of the SNPs or haplotypes that are associated with
TG levels have not been elucidated and the causal SNPs remain to
be identified. Moreover, another emerging SNP, rs2075291 (c.553
G.T, G185C), was also found to be associated with TG levels in
East Asians only . The combined effects of rs2075291 in
addition to the aforementioned five SNPs on TG levels need to be
The Uyghur population, who reside in the Xinjiang
Autonomous Region in China, represent a classic admixture population
with a genetic background of Caucasians (40%) and East Asians
(60%) [20,21]. Because this population was recently admixed, the
increased extent of LD between markers may facilitate the
genomic mapping of complex disease genes. In addition, the
population stratification is extremely low among Uyghurs in
different areas of Xinjiang (Fst = 0.0009), minimizing potential
confounding effects due to stratification in genetic association
studies [21,22]. Notably, Uyghurs show a higher prevalence of
hypertriglyceridemia compared with the Hans and Kazaks, who
also live in the same area [23,24]. All of these advantages provide
us with an opportunity to map the genetic variants of TG levels in
this ethnic group. However, the genetic architectures that
modulate TG levels in uyghurs remain unknown. Therefore, we
performed a cross-sectional study to evaluate the genotype and
haplotype frequencies of the SNPs in APOA5 and their
associations with plasma TG levels in the Uyghur population.
Our study sample consisted of 1174 unrelated Uyghur subjects
(404 men and 770 women with a mean age of 51.5611.2 years)
who were recruited from March to May of 2005 and April of 2006
from four villages in the Tulupan District of the Xinjiang Uyghur
Autonomous Region. All of the participants were of Uyghur
ancestry and had resided in Xinjiang for over 20 years. Subjects
who reported receiving lipid-lowering medications for the
treatment of dyslipidemia and who reported having tumors,
autoimmune diseases, or hematological diseases were excluded.
Written informed consent was obtained from each participant, and
all of the protocols were approved by the Human Ethics
Committee of Fudan University.
A standard questionnaire was administered by trained staff to
obtain information on demographic characteristics, personal
medical history, and lifestyle risk factors, etc. Ever smokers were
those who had smoked regularly for at least 6 months. Alcohol
consumption was defined as a dichotomous variable, and
individuals who consumed more than 3 drinks per week were
considered to be ever drinkers. All of the participants received a
physical examination and blood tests at a local hospital after
overnight fasting. A standardized mercury sphygmomanometer
was used to measure systolic blood pressure (SBP) and diastolic
blood pressure (DBP), and these measurements were obtained by
two cardiologists. For the body weight and height measurements,
the subjects wore only light indoor clothing and no shoes. BMI was
calculated by dividing weight (kg) by height squared (m2). The
waist circumference was measured midway between the caudal
point of the costal arch, as palpated laterally, and the iliac crest.
The blood specimens were drawn after overnight fasting,
immediately subjected to centrifugation, and analyzed within 8 h
for glucose (Glu), TG, and total cholesterol (TC). The clinical
characteristics of the studied population are summarized in
DNA extraction, SNP selection and genotyping
Genomic DNA was extracted from EDTA-anticoagulated
peripheral blood using a standard method. As previously
mentioned, there were 6 SNPs, including rs662799, rs651821,
rs3135506, rs2072560, rs2266788, and rs2075291, that were
reported to be associated with TG levels in Caucasians or East
Asians. As rs662799 and rs651821, as well as rs2072560 and
rs2266788, were in strong LD in both Caucasians and East Asians,
indicating they may be representative of each other. We only
selected two SNPs, rs662799 and rs2266788, from the four SNPs
in an effort to be cost efficient. The genotyping of the four SNPs in
APOA5, including rs662799, rs3135506, rs2075291, and
rs2266788, was performed using the TaqMan SNP Genotyping
Assay (Applied Biosystems, Foster City, CA, USA). All of the
genotyping success rates for these four loci were .99%. To assess
reproducibility, 1% of the samples were analyzed in duplicate, and
their genotypes were found to be 100% concordant.
Deviations from HardyWeinberg equilibrium for the genetic
variants were tested by a chi-squared test. Pair-wise Dand r2 for
all of the studied SNPs were calculated, and linkage disequilibrium
structures were constructed by the Haploview software . The
haplotypes and their frequencies were inferred using the PHASE
version 2.1.1 software (www.stat.washington.edu/stephens/phase/
download.html) and haplotype-based association analysis was
conducted based on the inferred haplotype data. For the function
prediction of the SNP rs2075291, two in silico tools (PolyPhen and
SIFT) were applied using the SeattleSeq Genomic Variation
). All of the other data analyses were performed with the SAS
statistical software (release 9.1; SAS Institute Inc, Cary, NC, USA).
The plasma TG levels were log-transformed to obtain
approximate normal distributions for performing the statistical tests. A
linear regression analysis was performed to identify any
associations between the SNPs, haplotypes and plasma TG levels and the
analysis was performed either without or with adjustments for
confounding risk factors in the regression model. The variances
that were explained by the APOA5 SNPs or haplotypes were
estimated by subtracting the total coefficient of determination (R2)
based on the regression model without the APOA5 genotype from
Values shown are numbers (frequencies) for categorical variables and mean 6 standard deviation for continuous variables.
$calculated by dividing weight (kg) by height squared (m2).
that of the same model incorporating the APOA5 genotype and
adjusting for age, gender, BMI, smoking, and drinking. Because
the minor allele frequency of rs3135506 was low, we combined the
heterozygotes and homozygotes of the minor allele to increase the
statistical power (dominant genetic model). For the other SNPs, an
additive genetic model of the minor allele was assumed. For the
SNP association analysis, a pre-specified threshold of P,0.0125
was used for the multiple correction significance (corresponding to
P,0.05 after adjusting for four loci) while P,0.05 was considered
to be significant in the other analyses.
To compare the frequencies of the minor allele of SNPs and
haplotypes in Uyghurs with those in Caucasians and East Asians,
the frequencies of the studied SNPs in the NCBI and Hapmap
databases were collected and the PubMed, HugeNavigator, and
Science Citation Index (ISI Web of Science) databases were
searched to collect all of the publications involving the APOA5
(last search update: 30th March 2014). The following key words
were used: apolipoprotein A5, OR APOA5, in combination
with polymorphis*, OR SNP*, OR single nucleotide, OR
variant*, OR genotype*, OR mutation*. The references
lists were further retrieved from identified publications to avoid
missing any relevant articles. Only the studies met the following
criteria were included: (1) the study were conducted in Caucasians
or East Asians; (2) the three genotypes of rs662799, rs3135506,
rs2075291, or rs2266788 were reported or the MAF of the SNPs
and the frequencies of the haplotypes were available; (3) the
genotype distributions should meet the HardyWeinberg
equilibrium; (4) data were used from only apparently healthy individuals
(ie, people selected from the hospital without known coronary or
other diseases or from the general population). Animal studies,
case reports, review articles, reports with incomplete data, and
family studies were excluded. The genotype distributions of the
SNPs and haplotypes were extracted and the MAF of the SNPs
and the frequencies of the haplotypes were derived from weighted
averages of the frequencies that were reported in the articles in
addition to the NCBI and Hapmap databases.
Frequencies of studied polymorphisms and haplotypes
in uyghur population
The distributions of the genotypes of the four SNPs and the
haplotypes that were derived from them are presented in Tables 2
and 3. The genotypes at all of the sites were consistent with
HardyWeinberg equilibrium. The minor allele frequencies of rs662799,
rs3135506, rs2075291, and rs2266788 were 0.19, 0.03, 0.03, and
0.16, respectively. The pairwise LD between the four SNPs in the
total Uyghur population, which was expressed as D and r2, is
presented in Figure 1. The LD between rs662799 and rs2266788
in Uyghurs was stronger than that in East Asians but weaker than
that in Caucasians (r2 = 0.75, D = 0.97). However, the LDs
between the SNP rs3135506 or rs2075291 with the other three
SNPs were weak with r2 ranging from 0.002 to 0.13. We identified
four major haplotypes as follows: TGGT (APOA5*1), CGGC
(APOA5*2), TCGT (APOA5*3), and CGTT (APOA5*4, the four
SNPs were ordered from 59 to 39) with frequencies of greater than
0.01. The most common haplotype, TGGT, represented 77.1% of
all of the haplotypes; the other three haplotypes, CGGC, TCGT,
and CGTT, accounted for 15.4%, 3.5%, and 3.2%, respectively.
In total, these four haplotypes accounted for 99.2% of all of the
haplotypes in this population.
To compare the frequencies of the studied SNPs and haplotypes
in Uyghurs to those in Caucasians and in East Asians, we searched
the online databases and a total of 67 eligible studies were
identified, including 20 studies involving Caucasians and 47 with
East Asians (data not shown). Over half of them described the SNP
rs662799, involving 10 reports on Caucasians and 33 on East
Asians. However, studies involving the SNP rs3135506 in East
Asians and rs2075291 in Caucasians were rare. Based on the data
from these studies, in addition to the NCBI and Hapmap
databases, the APOA5 polymorphisms and haplotypes frequencies
in different populations and the frequencies that were obtained in
the general Uyghur population in the present study were
demonstrated in Figures 2 and 3. The frequencies of the four
SNPs in Uyghurs were in between those in Caucasians and in East
Asians. The C allele of rs662799, C allele of rs2266788, and T
allele of rs2075291 were more prevalent in Uyghurs compared
with those in Caucasians and less prevalent compared to those in
East Asians whereas the trend was opposite for the C allele of
rs3135506 (all P for trend ,0.05). The frequencies of the
haplotypes conducted by the four SNPs in Uyghurs were also in
between those in Caucasians and in East Asians although only
marginal levels of significance were detected (P for trend ranging
from 0.059 to 0.073).
Association between APOA5 gene SNPs/haplotypes and
plasma TG levels in Uyghur population
The mean TG levels were compared with respect to the
genotypes of the SNPs and haplotypes in the general Uyghur
population to estimate the impact of the APOA5 gene SNPs and
haplotypes on TG levels. As shown in Table 2, the SNPs rs662799
and rs2266788 were significantly associated with TG levels at a
multiple correction threshold level of P,0.0125 after controlling
for age, sex, smoking and drinking. The other two SNPs,
rs3135506 and rs2075291, were also associated with TG level,
whereas the associations were not significant after multiple
corrections. Compared with the most common haplotype TGGT,
the haplotypes CGGC, TCGT, and CGTT were all significantly
associated with TG levels (all adjusted P,0.0125, Table 3).
Figure 4 shows the percentage increase of the TG means
between the TG-raising minor allele carriers and the homozygotes
of the normal allele for all four SNPs and also between the
TGraising haplotypes and the most common TGGT haplotype.
Compared with non-carriers, carriers of the TG-raising minor
allele of the four SNPs had 16.0%, 15.1%, 17.1%, and 12.4%
higher TG levels for the SNP rs662799, rs3135506, rs2075291,
and rs2266788, respectively. The effects of the three haplotypes on
TG were in the range of 16.1% to 19.8%, with the haplotype
CGTT, which was defined by the rare allele rs662799 and
rs2075291, exhibiting the strongest TG-raising effect. The
proportions of variance in TG explained by individual SNPs were
2.5%, 0.3%, 0.4%, 1.9% for rs662799, rs3135506, rs2075291, and
rs2266788, respectively. To evaluate the combined effect of the
four SNPs, we estimated the proportions of variance explained by
the calculated haplotypes. The haplotypes explained 3.0% of the
variances in TG levels in this population. With respect to other
metabolic traits (TC, Glu, BMI, waist, SBP, and DBP), no
significant associations were found with the exception that the T
allele of the SNP rs2075291 inferred higher waist circumferences
in this population (Table S1).
In this study, we aimed to identify the frequencies of the SNPs
and the haplotypes in the APOA5 gene and evaluated the effect of
them on the plasma TG levels in Uyghur population, which is an
admixture population of Caucasians and East Asians. We found
that the presence of the minor alleles at each of the four studied
SNPs in addition to the haplotypes constructed by them were
associated with increased TG levels. To the best of our knowledge,
this is the first study to correlate APOA5 polymorphisms and
haplotypes with plasma TG levels in the Uyghur population.
The association profiles between the SNPs at the APOA5 locus
and TG levels in Uyghurs differed from those in Caucasians and
East Asians. The APOA5 rs2075291 was previously found to
correlate strongly with TG levels in East Asians but not in
Caucasians or Turks [1618,26]. In the present study, we showed
that the TG levels were higher in Uyghurs with the GT genotype
compared with those possessing the GG genotype. Additionally,
numerous studies have found associations between rs3135506 and
TG levels in Caucasians but not in East Asians [27,28]. In this
study, we found that C carrier of rs3135506 had 15.1% higher TG
compared with non-carriers. Notably, the haplotype CGTT,
which was rare and not associated with TG in Caucasians, was
also associated with elevated TG levels in the studied population.
Different gene-gene or gene-environment interactions may
account for some of these discrepancies in addition to the different
MAFs of the SNPs among ethnicities. Significant trends were
observed for the MAFs of the four SNPs in APOA5 in Caucasians,
Uyghurs and East Asians, and their frequencies in Uyghurs were
in between those of Caucasians and East Asians. The MAF of
rs662799, rs3135506, and rs2266788 ranged from 0.06 to 0.08 in
Caucasians. However, the MAFs of rs662799 and rs2266788
increased to more than 0.20 and the MAF of rs3135506 decreased
to less than 0.01. Additionally, the MAF of rs2075291 was less
than 0.01 in Caucasians and increased to approximately 0.04 in
East Asians. The reasons for these differences were not clear. As
TG is a key energy source in humans, the TG-raising allele may
play an important role in human evolution . The TG-raising
allele frequencies were not consistently high or low in any one
population makes the TG levels were comparable in the world.
The LD patterns of the APOA5 SNPs in Uyghurs also differed
from those in Caucasians and East Asians, with the LD between
rs662799 and rs2266788 was stronger than that in East Asians but
weaker than that in Caucasians. The different LD patterns in
addition to the MAFs of the SNPs in APOA5 led to the different
haplotype profiles in this population. We found that the frequency
of the haplotype CGGC (APOA5*2), which was defined by the
rare alleles rs662799 and rs2266788, was 15.4% and was
associated with 16.1% higher TG levels in Uyghurs. These results
are consistent with those that have been reported in Caucasians
and East Asians [7,30,31], indicating that the association between
this haplotype and TG levels is irrespective of ethnicities.
Meanwhile, we found that the haplotype CGTT (APOA5*4),
which was defined by the rare alleles of rs662799 and rs2075291
with a frequency of 3.2%, was also associated with 19.8% higher
TG levels. Our results are in concordance with previous studies
demonstrating that the haplotype APOA5*4 is associated with
16% higher TG levels in Taiwan Chinese  and with familial
combined hyperlipidemia in Hong Kong Chinese . However,
this haplotype had not been detected in Caucasians. The
frequency of the haplotype TCGT (APOA5*3), which was defined
by the rare allele of rs3135506, was similar to that of CGTT
(APOA5*4) and was associated with 19.0% of higher TG levels in
our population. The associations can also be observed in
Caucasians but not in East Asians [32,33].
The functions of the SNPs and haplotypes remain to be
elucidated. The SNP rs3135506 was found in the second exon of
the gene. The minor allele of this SNP was observed to lead to the
vitiated signal activity of APOA5 through amino acid replacement
lowering the amount of functioning protein . The SNPs,
rs662799 and rs2266788, belonged to the well-defined haplotype
APOA5*2, which was characterized by the rare allele of rs662799,
rs651821, rs2072560, and rs2266788. Tight LD can be observed
between the SNPs rs662799 and rs651821, and also between the
SNPs rs2266788 and rs2072560 in both Caucasians and East
Asians, suggesting that the haplotypes of these four SNPs can be
inferred if we simultaneously genotyped two SNPs of them, one of
rs662799/rs651821 and the other of rs2072560/rs2266788,
similar to what was carried out in the present study. The
welldocumented hypertriglyceridemic effects of APOA5*2 were found
to be partially due to the miR-binding site created by the rare
allele of rs2266788 which mediated the APOA5-induced
posttranscriptional downregulation . However, in our study, we
found that the haplotype CGTT (APOA5*4), defined by the rare
allele of rs662799 and rs2075291, was also associated with TG,
indicating that the SNP rs662799, together with rs2075291, may
also have relevant biological functions. Although many studies
aimed to demonstrate the function of the SNP rs662799 had been
carried out, its functional effects remain to be elucidated. Since
rs662799 is located within the promoter region of the APOA5
gene, it may affect mRNA translation, which could lead to lower
plasma apoA-V levels, thus affecting plasma lipid concentrations.
Indeed, some studies have found that subjects who are
homozygous for the major allele of rs662799 have significantly higher
plasma apoA-V levels compared with those who are homozygous
for the minor allele . However, the underlying mechanism
leading to these occurrences is unknown. Meanwhile, few studies
had been demonstrated the function of the SNP rs2075291. We
performed bioinformatic studies to determine the effect of this
SNP and found that the replacement of glycine with cysteine at
amino acid 185 caused by this polymorphism were damaging (the
SIFT and PolyPhen scores were 0.01 and 0.94, respectively). The
TG-raising effects of the haplotype CGTT (APOA5*4) were
induced by the SNP rs662799 or rs2075291 alone or by the
combination of them needed to be studied further.
In conclusion, our cross-sectional study revealed the essential
roles of the polymorphisms and haplotypes of APOA5 in the
dysregulations of TG levels in Uyghur population, which is an
admixture population of Caucasians and East Asians. The
functions of these SNPs and haplotypes require more extensive
investigations in the future.
Conceived and designed the experiments: XFW LJ. Performed the
experiments: SYL BH DW. Analyzed the data: SYL YW. Contributed
reagents/materials/analysis tools: XFW LJ. Contributed to the writing of
the manuscript: SYL XFW.
1. Pennacchio LA , Olivier M , Hubacek JA , Cohen JC , Cox DR , et al. ( 2001 ) An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing . Science 294 : 169 - 173 .
2. van der Vliet HN , Schaap FG , Levels JH , Ottenhoff R , Looije N , et al. ( 2002 ) Adenoviral overexpression of apolipoprotein A-V reduces serum levels of triglycerides and cholesterol in mice . Biochem Biophys Res Commun 295 : 1156 - 1159 .
3. Merkel M , Heeren J ( 2005 ) Give me A5 for lipoprotein hydrolysis ! J Clin Invest 115 : 2694 - 2696 .
4. van Dijk KW , Rensen PC , Voshol PJ , Havekes LM ( 2004 ) The role and mode of action of apolipoproteins CIII and AV: synergistic actors in triglyceride metabolism? Curr Opin Lipidol 15 : 239 - 246 .
5. Pennacchio LA , Olivier M , Hubacek JA , Krauss RM , Rubin EM , et al. ( 2002 ) Two independent apolipoprotein A5 haplotypes influence human plasma triglyceride levels . Hum Mol Genet 11 : 3031 - 3038 .
6. Lai CQ , Demissie S , Cupples LA , Zhu Y , Adiconis X , et al. ( 2004 ) Influence of the APOA5 locus on plasma triglyceride, lipoprotein subclasses, and CVD risk in the Framingham Heart Study . J Lipid Res 45 : 2096 - 2105 .
7. Olivier M , Wang X , Cole R , Gau B , Kim J , et al. ( 2004 ) Haplotype analysis of the apolipoprotein gene cluster on human chromosome 11 . Genomics 83 : 912 - 923 .
8. Talmud PJ , Hawe E , Martin S , Olivier M , Miller GJ , et al. ( 2002 ) Relative contribution of variation within the APOC3/A4/A5 gene cluster in determining plasma triglycerides . Hum Mol Genet 11 : 3039 - 3046 .
9. Aouizerat BE , Kulkarni M , Heilbron D , Drown D , Raskin S , et al. ( 2003 ) Genetic analysis of a polymorphism in the human apoA-V gene: effect on plasma lipids . J Lipid Res 44 : 1167 - 1173 .
10. Lee KW , Ayyobi AF , Frohlich JJ , Hill JS ( 2004 ) APOA5 gene polymorphism modulates levels of triglyceride, HDL cholesterol and FERHDL but is not a risk factor for coronary artery disease . Atherosclerosis 176 : 165 - 172 .
11. Li YY , Yin RX , Lai CQ , Li M , Long XJ , et al. ( 2011 ) Association of apolipoprotein A5 gene polymorphisms and serum lipid levels . Nutr Metab Cardiovasc Dis 21 : 947 - 956 .
12. Yin RX , Li YY , Lai CQ ( 2011 ) Apolipoprotein A1/C3/A5 haplotypes and serum lipid levels . Lipids Health Dis 10 : 140 .
13. Lai CQ , Tai ES , Tan CE , Cutter J , Chew SK , et al. ( 2003 ) The APOA5 locus is a strong determinant of plasma triglyceride concentrations across ethnic groups in Singapore . J Lipid Res 44 : 2365 - 2373 .
14. Liu ZK , Hu M , Baum L , Thomas GN , Tomlinson B ( 2010 ) Associations of polymorphisms in the apolipoprotein A1/C3/A4/A5 gene cluster with familial combined hyperlipidaemia in Hong Kong Chinese . Atherosclerosis 208 : 427 - 432 .
15. Chien KL , Fang WH , Wen HC , Lin HP , Lin YL , et al. ( 2008 ) APOA1/C3/A5 haplotype and risk of hypertriglyceridemia in Taiwanese . Clin Chim Acta 390 : 56 - 62 .
16. Kao JT , Wen HC , Chien KL , Hsu HC , Lin SW ( 2003 ) A novel genetic variant in the apolipoprotein A5 gene is associated with hypertriglyceridemia . Hum Mol Genet 12 : 2533 - 2539 .
17. Tang Y , Sun P , Guo D , Ferro A , Ji Y , et al. ( 2006 ) 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 185 : 433 - 437 .
18. Matsunaga A , Arishima H , Niimura H , Zhang B , Uehara Y , et al. ( 2007 ) 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 71 : 746 - 752 .
19. Yamada Y , Ichihara S , Kato K , Yoshida T , Yokoi K , et al. ( 2008 ) Genetic risk for metabolic syndrome: examination of candidate gene polymorphisms related to lipid metabolism in Japanese people . J Med Genet 45 : 22 - 28 .
20. Yao YG , Kong QP , Wang CY , Zhu CL , Zhang YP ( 2004 ) Different matrilineal contributions to genetic structure of ethnic groups in the silk road region in china . Mol Biol Evol 21 : 2265 - 2280 .
21. Xu S , Huang W , Qian J , Jin L ( 2008 ) Analysis of genomic admixture in Uyghur and its implication in mapping strategy . Am J Hum Genet 82 : 883 - 894 .
22. Bacanu SA , Devlin B , Roeder K ( 2002 ) Association studies for quantitative traits in structured populations . Genet Epidemiol 22 : 78 - 93 .
23. Wang L , Tao Y , Xie Z , Ran X , Zhang M , et al. ( 2010 ) Prevalence of metabolic syndrome, insulin resistance, impaired fasting blood glucose, and dyslipidemia in Uygur and Kazak populations . J Clin Hypertens (Greenwich) 12 : 741 - 745 .
24. Lin R , Wang X , Wang Y , Zhang F , Wang Y , et al. ( 2009 ) Association of polymorphisms in four bilirubin metabolism genes with serum bilirubin in three Asian populations . Hum Mutat 30 : 609 - 615 .
25. Barrett JC , Fry B , Maller J , Daly MJ ( 2005 ) Haploview: analysis and visualization of LD and haplotype maps . Bioinformatics 21 : 263 - 265 .
26. Hodoglugil U , Tanyolac S , Williamson DW , Huang Y , Mahley RW ( 2006 ) Apolipoprotein A-V: a potential modulator of plasma triglyceride levels in Turks . J Lipid Res 47 : 144 - 153 .
27. Chandak GR , Ward KJ , Yajnik CS , Pandit AN , Bavdekar A , et al. ( 2006 ) Triglyceride associated polymorphisms of the APOA5 gene have very different allele frequencies in Pune, India compared to Europeans . BMC Med Genet 7 : 76 .
28. Wright WT , Young IS , Nicholls DP , Patterson C , Lyttle K , et al. ( 2006 ) SNPs at the APOA5 gene account for the strong association with hypertriglyceridaemia at the APOA5/A4/C3/A1 locus on chromosome 11q23 in the Northern Irish population . Atherosclerosis 185 : 353 - 360 .
29. Lai CQ , Parnell LD , Ordovas JM ( 2005 ) The APOA1/C3/A4/A5 gene cluster, lipid metabolism and cardiovascular disease risk . Curr Opin Lipidol 16 : 153 - 166 .
30. Xu C , Bai R , Zhang D , Li Z , Zhu H , et al. ( 2013 ) Effects of APOA5 -1131T.C (rs662799) on fasting plasma lipids and risk of metabolic syndrome: evidence from a case-control study in China and a meta-analysis . PLoS One 8 : e56216 .
31. Eichenbaum-Voline S , Olivier M , Jones EL , Naoumova RP , Jones B , et al. ( 2004 ) Linkage and association between distinct variants of the APOA1/C3/ A4/A5 gene cluster and familial combined hyperlipidemia . Arterioscler Thromb Vasc Biol 24 : 167 - 174 .
32. Martinelli N , Trabetti E , Bassi A , Girelli D , Friso S , et al. ( 2007 ) The -1131 T. C and S19W APOA5 gene polymorphisms are associated with high levels of triglycerides and apolipoprotein C-III, but not with coronary artery disease: an angiographic study . Atherosclerosis 191 : 409 - 417 .
33. Wang J , Ban MR , Zou GY , Cao H , Lin T , et al. ( 2008 ) Polygenic determinants of severe hypertriglyceridemia . Hum Mol Genet 17 : 2894 - 2899 .
34. Talmud PJ , Martin S , Taskinen MR , Frick MH , Nieminen MS , et al. ( 2004 ) APOA5 gene variants, lipoprotein particle distribution, and progression of coronary heart disease: results from the LOCAT study . J Lipid Res 45 : 750 - 756 .
35. Caussy C , Charriere S , Marcais C , Di Filippo M , Sassolas A , et al. ( 2014 ) An APOA5 39 UTR variant associated with plasma triglycerides triggers APOA5 downregulation by creating a functional miR-485-5p binding site . Am J Hum Genet 94 : 129 - 134 .
36. Ishihara M , Kujiraoka T , Iwasaki T , Nagano M , Takano M , et al. ( 2005 ) A sandwich enzyme-linked immunosorbent assay for human plasma apolipoprotein A-V concentration . J Lipid Res 46 : 2015 - 2022 .