c Indian Academy of Sciences

ONLINE RESOURCES

Polymorphisms of seven genes involved in lipid metabolism

in an unselected Mexican population
BLANCA E. ROS-GONZLEZ1,2 , KARLA E. LUVANO-ORTEGA1 , ANA M. SALDAA-CRUZ1,2 ,
JUAN R. GONZLEZ-GARCA1 and MARA TERESA MAGAA-TORRES1
1

Divisin de Gentica, Centro de Investigacin Biomdica de Occidente, Instituto Mexicano del Seguro Social, and
2
Doctorado en Gentica Humana, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara,
Guadalajara, Jalisco 44340, Mxico
[Ros-Gonzlez B. E., Luvano-Ortega K. E., Saldaa-Cruz A. M., Gonzlez-Garca J. R. and Magaa-Torres M. T. 2011 Polymorphisms of
seven genes involved in lipid metabolism in an unselected Mexican population. J. Genet. 90, e114e119. Online only: http://www.ias.ac.in/
jgenet/OnlineResources/90/e114.pdf]

Introduction
Dyslipidemia is a multifactorial disorder caused by interactions between genetic and environmental factors. It is
characterized by hypertriglyceridemia, a low serum concentration of high density lipoprotein (HDL) cholesterol,
and a high serum concentration of low density lipoprotein
(LDL) cholesterol. These conditions play important roles
in the development of cardiovascular disease, hypertension,
metabolic syndrome, and atherosclerosis. Genetic variation
accounts for about 4383% of the variability of lipid levels in plasma (Chang et al. 2010). The most studied polymorphisms and/or mutations are situated in coding regions
of genes involved in lipid synthesis and degradation. Several worldwide population association studies have yielded
inconsistent results, mainly due to ethnic differences and
environmental factors (Aguilar-Salinas et al. 2009; Li et al.
2011).
Some of the single nucleotide polymorphisms (SNPs) that
modify lipid metabolism are APOA5 p.S19W (c.56C>G),
APOB p.E4181K (c.12541G>A), APOC3 *3238G>C,
FABP2 p.A55T (c.163G>A), LDLR c.1959C>T (p.V653V),
LIPC 514C>T, and LPL p.S474X (c.1421C>G). These
genetic variations were assigned according to the nomenclature proposed by den Dunnen and Antonarakis (2001).
Diverse effects and/or associations that have been reported
with these polymorphisms are summarized in table 1. In
Mexico, some of these polymorphisms have been associated
with dyslipidemias (Keebler et al. 2009), insulin sensitivity/resistance (Goodarzi et al. 2007), and obesity and cardio-

For correspondence. E-mail: maganamt@yahoo.com.mx.

vascular disease risk (Martnez-Lpez et al. 2007); however,

the allelic and genotypic frequencies in the general population remain unknown. The aim of this study was to analyse
10 polymorphisms distributed in seven genes implicated in
lipid metabolism in an unselected population from the west
Mexican.

Materials and methods

Subjects

We studied 142 individuals from an unselected mestizo

Mexican population, mainly from Jalisco and Michoacan
states (western Mexico). Individuals signed an informed
consent according to the recommendations of the institutional ethics committee. Genomic DNA was obtained by the
Millers method (Miller et al. 1988) from peripheral blood
collected in tubes containing EDTA.

DNA analysis

Genotyping was performed by polymerase chain reaction (PCR), PCR-articial introduction of a restriction
site (APOA5 p.S19W), by PCR-restriction fragment length
polymorphisms (PCR-RFLPs) (APOB p.E4181K, APOC3
*3238G>C, LDLR c.1959C>T and LPL p.S474X) and by
sequencing of PCR products (FABP2 and LIPC 514C>T)
using the ABI PRISM 310 sequencer. The amplified 456-bp
FABP2 fragment contains four described polymorphisms:
c.115A>G (p.A32A), p.E52D (c.156A>T), p.A55T (c.163G>
A) (reference SNP rs1799883, http://www.ncbi.nlm.nih.
gov/projects/SNP/snp_ref.cgi?rs=1799883) and c.216G>A
(p.N72N) (reference SNP rs4834770, http://www.ncbi.

Keywords. lipids; linkage disequilibrium; deviation of HardyWeinberg equilibrium; Mexican population; snps.
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e114

Blanca E. Ros-Gonzlez et al.

Table 1. Polymorphisms associated with lipid metabolism.
Gene polymorphism
(variant nucleotide)

Ref. Seq.
(rs)

Chromosome

APOA5 p.S19W
(C>G)
APOB p.E4181K
(G>A)

3135506

11q23

19W

1042031

2q24.1

4181K

APOC3 *3238G>C
FABP2 p.A55T
(G>A)

5128
1799883

11q23
4q2-q31

*3238 C
55T

LDLR c.1959C>T

5925

19p13-p13.3

1959T

LIPC 514C>T

1800588

15q21

514T

LPL p.S474X
(C>G)

328

8p22

474X

Allele

Effect and/or associations

Low lipoprotein lipase (LPL) activity and therefore high plasma
triglyceride levels (Smith et al. 2010).
More frequent in patients with premature coronary artery disease.
Associated with a reduction of total cholesterol levels, apoprotein B
and nonHDL cholesterol (Genest et al. 1990; Benn et al. 2008).
Associated with hypertriglyceridemia (Liu et al. 2005)
Two-fold afnity for longchain fatty acids. Increase in fat oxidation and in
insulin resistance. High diastolic pressure and elevated LDL cholesterol
levels homozygous form (Baier et al. 1996; Albala et al. 2006).
Even though there is no amino acid change, it is associated with
low levels of triglycerides and LDL cholesterol (Liu et al. 2003).
Diminished transcriptional activity. Increased triglyceride contained
in HDL and LDL particles (Deeb and Peng 2000).
Increased protein lipolytic function. Low triglyceride levels.
High HDL cholesterol levels. Atheroprotection (Rip et al. 2006).

Polymorphisms were named according to the nomenclature proposed by den Dunnen and Antonarakis (2001) (http://www.hgmd.cf.ac.
uk/docs/mut_nom.html).

nlm.nih.gov/projects/SNP/snp3D.cgi?rs num=rs4834770). All

the primers, except APOA5 p.S19W site (Talmud et al.
2002), were designed with Oligo version 4.0 software.
Each PCR reaction contained 200 ng of genomic DNA,
0.46 pg of each primer, 0.204 mM dNTPs, 1 Tris-HCl
buffer, 0.04 U/L Taq polymerase, and 1.5 mM MgCl2
for all polymorphisms, except FABP2 p.A55T and LDLR
c.1959C>T, where 1.75 mM of MgCl2 was used. The nal
reaction volume was 15 L. Additionally the FABP2 p.A55T
polymorphism was conrmed by PCR-RFLP analysis using
ve units of enzyme HhaI. Enzymes and primers used are
shown in table 2. PCR products and digested fragments were
resolved using 6% and 8% polyacrylamide gels, respectively,

that were stained with silver to visualize. The PCR assays

included at least one negative control to rule out DNA contamination. Genotypes were interpreted by two people, based
on the expected fragments (table 2). In addition, samples
previously genotyped by sequencing (wildtype homozygous,
heterozygous and homozygous mutant) were used as positive
control for restriction assays.
Statistical analysis

Allele and genotype frequencies were determined by counting. The HardyWeinberg equilibrium was calculated using
a chi-square test. The linkage disequilibrium between pairs

Table 2. Enzymes and primers used in this study.

Enzymed

Primers

APOA5 p.S19W

-TaqI

APOB p.E4181K

EcoRI

APOC3 *3238G>C

SacIa

F:5- GGCTCTTCTTTCAGGTGGGTCTCCG-3
R:5- GCCTTTCCGTGCCTGGGTGGT -3
F:5- GCCATTAGGCAAATTGATGA-3
R:5- GAAACTGGAATCTGGGGAAG-3
F:5- CCAGTGAAGTTGAGAGGGTG -3
R:5- ACCCACAGAACAGCCTCG -3
F:5- TAC CGA GTT TTC TTC CCA CCC -3
R:5- TTA AAT ATC CTG CCA ATT TGT GC -3
F:5- TCT TCC TTG CTG CCT GTT TAG G -3
R:5- GGG CAG AAG AAG CGG AGT CA -3
F:5- CCT ACC TGA TTT TGC TGA GTG GC -3
R:5- TGG AAA TTC TGC CAA AGG TCG -3
F:5- ACC AGG TTA GGC TCT CAA ATT ACC C -3
R:5- GGC AAG CTG CTG GTG ATG GG -3

Polymorphism

FABP2b

LDLR c.1959C>T
LIPC 514C>T
LPL p.S474X
a Isoschizomer

AvaII

MnlI

PCR products (bp) Digested fragments (bp)

157

134/23

261

188/73

501

292/209

456

296

164/132

400

394

19/33/35/59/248c

of SstI. b FABP2 sites: c.115A>G, p.E52D, p.A55T and c.216G>A. c LPL p.S474X PCR product has three constitutive cuts
(19/33/35 bp).
units of enzyme were used in all digests. F, forward primer; R, reverse primer.
d Five

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Lipid metabolism polymorphisms

of loci were evaluated with the correlation of alleles test
(r 2 ) and were considered in disequilibrium when r 2 0.33
(Shifman et al. 2003). An exact test of population differentiation was carried out using the genotypic frequencies of
populations reported in the Hap Map (International Hap Map
Consortium 2003, http://www.ncbi.nlm.nih.gov/projects/SNP/
snp_ref.cgi? rs = 328, rs = 5925, rs = 1800588, 1799883,
1800775, 4783962, 5128, 1042031, 3135506) and our data.
One million steps of Markov chain length were considered,
and values were deemed signicant when P <0.05. FABP2
gene haplotypes were estimated by (maximum likelihood)
expectation-maximization algorithm, and the haplotypic distribution was analysed with the EwensWatterson homozygosity neutrality test. Statistical analyses were performed

with the Arlequin version 3.1 software (Excofer et al.

2005).

Results
We analysed 10 SNPs in 142 unrelated individuals;
however, not all sites could be identied in every DNA sample (table 3). All 131 individuals analysed were monomorphic for the wildtype allele at sites FABP2 c.115A>G and
p.E52D. Genotypic and allelic frequencies of the other eight
polymorphic sites are in table 3. The most common mutated
alleles were LDLR c.1959T (55.7%) and LIPC 514T
(51.6%); in contrast, the LPL p.474X allele was seen the least
(8.8%).

Table 3. Genotypic and allelic frequencies of the polymorphisms studied in the Mexican population.
Polymorphism
APOA5
p.S19W

APOB
p.E4181K

APOC3a
*3238 G>C

FABP2c
p.A55T

FABP2c
c.216G>A

LDLRb
c.1959C>T

LIPC
514C>T

LPL
p.S474X

Genotypes

(%)

n = 131
SS 84
SW 41
WW 6

64.1
31.3
4.6

n = 142
EE 102
EK 36
KK 4

71.8
25.4
2.8

n = 127
GG 92
GC 34
CC 1

72.4
26.8
0.8

n = 131
AA 73
AT 23
TT 35

55.7
17.6
26.7

n = 131
GG 45
GA 32
AA 54

34.4
24.4
41.2

n = 132
CC 29
TC 59
TT 44

22.0
44.7
33.3

n = 125
CC 24
CT 73
TT 28

19.2
58.4
22.4

n = 130
SS 109
SX 19
XX 2

83.8
14.6
1.5

Alleles

(%)

n = 262
S 209
W 53

79.8
20.2

n = 284
E 240
K 44

84.5
15.5

n = 254
G 218
C 36

85.8
14.2

n = 262
A 169
T 93

64.5
35.5

n = 262
G 122
A 140

46.6
53.4

n = 264
C 117
T 147

44.3
55.7

n = 250
C 121
T 129

48.4
51.6

n = 260
S 237
X 23

91.2
8.8

All individuals (n = 131) were monomorphics for the wildtype allele at sites FABP2 c.115A>G and p.E52D.
Usually named a SstI and b AvaII. c Departure from the HardyWeinberg equilibrium.
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Blanca E. Ros-Gonzlez et al.

We established haplotypes with polymorphic sites FABP2
p.A55T (G>A) and c.216G>A. The following four possible
nucleotide base combinations were observed: GG (n = 121,
46.2%), AA (n = 92, 35.1%), GA (n = 48, 18.3%) and
AG (n = 1, 0.4%). Statistical analyses of the genotypic frequencies revealed that all the polymorphisms were within
HWE expectations (P>0.05), except the FABP2 p.A55T and
c.216G>A sites, which showed a signicant loss of heterozygosity (P<0.0001). The exact test of linkage disequilibrium was performed for the loci pairs FABP2 p.A55T versus
c.216G>A and APOA5 p.S19W versus APOC3 *3238G>C.
Only the rst pair were in disequilibrium (r 2 = 0.46, P <
0.0001).

Discussion
In different populations, the alleles APOA5 p.19W, APOC3
*3238C, LIPC 514T and FABP2 p.55T have been associated with high levels of cholesterol, HDL and/or triglycerides
in plasma (Deeb and Peng 2000; Liu et al. 2005; Albala et al.
2006; Smith et al. 2010). These alleles were frequent and
were seen at a range of 1452% in our population. Further,
mutant alleles APOB p. 4181K (15%), LDLR c.1959T(56%),
and LPL p.474X (9%), which have opposite effects on lipid
concentrations (Genest et al. 1990; Liu et al. 2003; Rip et al.
2006; Benn et al. 2008) from the above-mentioned alleles, also appear at high frequencies. These results reveal the
importance of integrating results from studies on multiple
polymorphisms and/or mutations with potential roles in the
development of dyslipidemia. Because some of these variants have opposite effects on the regulation of lipid levels in
plasma, analysis of singular polymorphisms could generate
ambiguous results.
The FABP2 p.A55T (alanine>threonine) site frequently
exhibits a G>A change; however, in some populations the C
and T variants, rendering proline and serine changes, respectively, have also been observed (Reference SNP rs1799883,
http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi? rs=
1799883). The Mexican population harboured only the G>A
change where the ancestral G allele was the most common
(66.1%).
Linkage disequilibrium analyses are useful in establishing the genetic basis of multifactorial diseases or complex
traits. Our unselected population showed linkage disequilibrium between FABP2 p.A55T and c.216 G>A, perhaps as a
result of the small number of nucleotides between them.
Evaluating HWE among alleles is a basic approach in
most population genetics studies. We detected a signicant
departure from HWE for the polymorphisms FABP2 p.A55T
and c.216G>A, where heterozygotes were under-represented
and mutant homozygotes were in excess. These deviations
are often interpreted as genotyping errors; however, we can
exclude this possibility at least for site p.A55T because it
was identied by two different methodologies (sequencing
and RFLPs), and in both instances the same results were

obtained. Other causes of departure from HWE are nonrandom mating, recent migrations, mixture of subpopulations with incomplete interbreeding, and selection. The rst
three causes can be dismissed because other polymorphisms
(at least 13) were analysed in the same population (mainly
from two different states: Jalisco and Michoacan) and all
were at HWE (Luvano et al. 2009). It is noteworthy that
a report in obese Mexican population also shows signicant
departure from HWE for FABP2 p.A55T site (P = 0.02)
(Martnez-Lpez et al. 2007). Thereby, we can suggest that
in our population these polymorphisms represent underdominant selection, where the new alleles reduce the tness of
the heterozygote alone (Jobling et al. 2004).
On the other hand, the GG haplotype (121 versus 190
45) was under-represented in the haplotype distributions of
the FABP2 p.A55T (G>A) and c.216G>A sites analysed by
the EwensWatterson homozygosity test. In contrast, the AA
(92 versus 51 34) and the GA (48 versus 15 16) haplotypes were over-represented in the sample. According to
the values proposed by Watterson (1978), F value was statistically signicant (0.08); which indicates that the FABP2
polymorphisms signicantly deviate, with an excess of heterozygosity, from the expectations of the standard neutral
model. These results suggest the presence of a type of
gene-specic selective force.

Comparison among populations

The Mexican (MEX) genotype frequencies obtained from

our study were compared with European (CEU), Chinese
(CHB), Japanese (JPT), Nigerian (YRI) and MexicanAmerican (MEX-A) populations (HapMap) (table 4). The
sites FABP2 p.A55T and LDLR c.1959C>T were not
reported in YRI and APOA5 p.S19W, LIPC 514C>T and
LPL p.S474X in MEX-A. MEX distribution frequencies for
polymorphism APOA5 p.S19W showed statistically significant differences with all the analysed populations (P <
0.001). MEX differed from the two Asian populations in
the sites APOB p.E4181K, FABP2 c.216G>A and LDLR
c.1959C>T (P < 0.05). Likewise, the distribution of the
LIPC 514C>T MEX polymorphism was different from
CEU (P < 0.001) distributions. LPL p.S474X and FABP2
p.A55T frequencies were similar among all populations (P >
0.05). The two Mexican populations (MEX and MEX-A)
showed similar frequencies in the analysed sites.
Along with others, our study illustrates the existence of
extensive inter-population and intra-population heterogeneity through the presence of European, Asian, and African
genes in the Mexican population. This mixture of at least
three ancestral roots in our population has been previously
reported (Magaa et al. 2007; Rubi-Castellanos et al. 2009).
In conclusion, eight genetic polymorphisms in a Mexican
population illustrated expected HWE distributions with the
exception of FABP2 p.A55T and c.216G>A sites. Therefore
it is important to consider these results in future gene-disease

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Lipid metabolism polymorphisms

Table 4. Frequencies of polymorphisms reported in the HapMap. These data were compared with those obtained in our study.
Genotype

CEU

CHB

JPT

YRI

MEX-A

APOA5
p.S19W

SS
SW
WW

n = 60
53
7

P < 0.01

%
88.3
11.7

n = 45
45

P < 0.01

%
100

n = 45
45

P < 0.01

%
100

n = 60
55
4
1
P < 0.01

%
91.6
6.7
1.7

APOB
p.E4181K

EE
EK
KK

n = 60
40
15
5
P = 0.19

%
66.7
25
8.3

n = 45
41
4

P < 0.01

%
91.1
8.9

n = 44
42
2

P < 0.01

%
95.5
4.5

n = 60
44
11
5
P = 0.66

APOC3
*3238
G>C

GG
GC
CC

n = 113
94
18
1
P = 0.09

%
83.2
15.9
0.9

n = 43
13
25
5
P < 0.01

%
30.2
58.2
11.6

n = 85
29
47
9
P < 0.01

%
34.1
55.3
10.6

FABP2
p.A55T

AA
AT
TT

n = 113
47
58
8
P = 0.57

%
41.6
51.3
7.1

n = 41
16
23
2
P = 0.70

%
39.0
56.1
4.9

n = 84
37
40
7
P = 0.53

%
44.0
47.7
8.3

FABP2
c.216
G>A

GG
GA
AA

n = 113
27
60
26
P = 0.41

%
23.9
53.1
23.0

n = 42
14
22
6
P = 0.05

%
33.3
52.4
14.3

n = 84
26
46
12
P = 0.02

%
31.0
54.8
14.3

LDLR
c.1959
C>T

CC
CT
TT

n = 60
20
25
15
P = 0.08

%
55.5
41.7
25.0

n = 44
27
14
3
P < 0.01

%
61.4
31.8
6.8

n = 45
28
17

P < 0.01

%
62.2
37.8

LIPC
514
C>T

CC
CT
TT

n = 60
34
21
5
P < 0.01

%
56.7
35.0
8.3

n = 45
16
23
6
P = 0.08

%
35.6
51.1
13.3

n = 44
7
22
15
P = 0.32

LPL
p.S474X

SS
SX
XX

n = 60
46
13
1
P = 0.48

%
76.7
21.7
1.7

n = 45
37
8

P = 0.82

%
82.2
17.8

n = 44
32
11
1
P = 0.18

%
73.3
18.3
8.3

n = 50
33
16
1
P = 0.64

%
66.0
32.0
2.0

n = 113
70
37
6
P = 0.04

%
62.0
32.7
5.3

n = 50
34
14
2
P = 0.41

%
68.0
28.0
4.0

n = 49
25
19
5
P = 0.32

%
51.0
38.8
10.2

n = 113
33
58
22
P = 0.07

%
29.2
51.3
19.5

n = 49
14
28
7
P = 0.07

%
28.6
57.1
14.3

n = 50
16
24
10
P = 0.06

%
32.0
48.0
20.0

%
15.9
50.0
34.1

n = 60
12
32
16
P = 0.74

%
20.0
53.3
26.7

%
72.7
25.0
2.3

n = 60
56
4

P = 0.22

%
93.3
6.7

P = P values obtained by comparing our frequencies versus the frequencies from other populations. CEU, European, CHB, Chinese, JPT,
Japanese; YRI, Nigerian populations (International Hap Map Consortium 2003, http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?
rs = 328, rs = 5925, rs = 1800588, 1799883, 1800775, 4783962, 5128, 1042031, 3135506).

association studies and to use appropriate statistical tests to

avoid misinterpretations.
Acknowledgements
We thank CONACYT and IMSS for scholarship to Blanca E. Ros
Gonzlez numbers 219039 and 2010058, respectively.

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Received 6 June 2011, in nal revised form 22 August 2011; accepted 13 September 2011
Published on the Web: 16 December 2011

Journal of Genetics Vol. 90, Online Resources

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