DSpace at VNU: Genetic variation of FUT2 in a Vietnamese population: identification of two novel Se enzyme-inactivating mutations

ORIGINAL ARTICLE
Genetic variation of FUT2 in a Vietnamese population:
identification of two novel Se enzyme–inactivating mutations

_3485

1..8

Mikiko Soejima, Ryo Fujimoto, Tetsuro Agusa, Hisato Iwata, Junko Fujihara, Haruo Takeshita,
Tu Binh Minh, Pham Thi Kim Trang, Pham Hung Viet, Tamiko Nakajima, Joji Yoshimoto,
Shinsuke Tanabe, and Yoshiro Koda

BACKGROUND: The human FUT2 gene encodes a
secretor-type a(1,2)fucosyltransferase, and many
population-specific polymorphisms have been reported
in the coding region.
STUDY DESIGN AND METHODS: Direct sequencing,
real-time polymerase chain reaction, and high-resolution
melt (HRM) analysis were done to detect singlenucleotide polymorphism (SNPs) and copy number
variations (CNVs) in a Vietnamese population. The
impacts of two novel mutations on the encoded enzyme
were examined by a transient expression study.
RESULTS: The major nonfunctional allele in the 294
Vietnamese was se357,385, whereas no CNV was
detected. Two novel SNPs, 818C>A (Thr273Asn) and
853G>A (Ala285Thr), distributed at low frequency, were
shown to remarkably affect the enzyme activity.
CONCLUSION: The allelic polymorphism of FUT2 in
Vietnamese is similar to that of other East and Southeast Asian populations. This result may reflect the
history and gene flow of this population. In addition,
HRM analysis seems to be a simple and effective

method for screening rare SNPs of FUT2 in a large
number of samples.

[Correction statement added after online publication
21-Dec-2011: Thr273Ala has been updated to Thr273Asn
throughout.]

T

he secretor-type a(1,2)fucosyltransferase, encoded by FUT2, regulates the expression of the H
antigen (essential precursor of A and B antigens)
not on red blood cells but on the surface
of mucosa and in body fluids and hence determines the
secretor status of the ABO(H) antigens. Secretors who have
the antigens in saliva and other body fluids have at least
one functional FUT2 allele (Se), while homozygotes of nonfunctional FUT2 alleles (se) become nonsecretors who do
not express the antigens in saliva and other body fluids.1,2
As shown in Table 1, many single-nucleotide polymorphisms (SNPs) and genetic recombination in the coding

ABBREVIATIONS: CNV(s) = copy number variation(s);
DHPLC = denaturing high-performance liquid chromatography;
HRM = high-resolution melt; SIFT = Sorting Intolerant From
Tolerant; SNP(s) = single-nucleotide polymorphism(s).
From the Department of Forensic Medicine and Human Genetics, Kurume University School of Medicine, Kurume, Japan; the
Center for Marine Environmental Studies (CMES), Ehime University, Matsuyama, Japan; the Department of Legal Medicine,
Shimane University Faculty of Medicine, Izumo, Japan; the
Center for Environmental Technology and Sustainable Development (CETASD), Hanoi University of Science, Vietnam National
University, and the Vietnam Environment Administration (VEA),
Ministry of Natural Resources and Environment (MONRE),
Hanoi, Vietnam; and the Department of Legal Medicine, Gunma

University, Graduate School of Medicine, Maebashi, Gunma,
Japan.
Address reprint requests to: Yoshiro Koda, Department of
Forensic Medicine and Human Genetics, Kurume University
School of Medicine, Kurume 830-0011, Japan; e-mail: ykoda@
med.kurume-u.ac.jp.
This work was supported by grants-in-aid for Scientific
Research from the Ministry of Education, Science, Culture and
Sports of Japan.
Received for publication July 18, 2011; revision received
October 16, 2011, and accepted October 28, 2011.
doi: 10.1111/j.1537-2995.2011.03485.x
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SOEJIMA ET AL.

TABLE 1. Characteristic FUT2 SNPs and alleles in several populations
Allele
Functional
Se
Se40
Se278,357

Prevalence

Reference

40A>G
278C>T 357C>T

No change
Ile14Val
Ala93Val

Many populations
Africans
Iranians, Sri Lankans, Israelis

357C>T
357C>T 480C>T

No change
No change

375A>G

No change

400G>A
481G>A

Val134Ile
Asp161Asn

Many populations
Africans, South and West
Asians, Europeans
New Guineans, African,
Samoans
New Guineans, Samoans
Africans

Koda et al.9,10
Liu et al.,11 Soejima et al.21
Koda et al.,7 Soejima and
Koda,18 Storry et al.22
Koda et al.9,10
Liu et al.,11 Soejima et al.21

Se357
Se357,480
Se375

302C>T

Ile101Pro

South Asians

se357,385

385A>T

Ile129Phe

East and Southeast Asians

se357,571

357C>T 571C>T

Arg191Ter

Samoans, Taiwanese

se357,480,778del
se428

357C>T 480C>T 778delC
428G>A plus 6

Frame shift 259, 275Ter
Trp143Ter

628C>T
849G>A

Arg210Ter
Trp283Ter

Africans
Europeans, Iranians, Africans,
South and West Asians
Japanese, Thai, Taiwanese

Taiwanese

Se400
Se481
Nonfunctional
se302

se628
se849
Recombinant
sefus
sedel
sedel2
sedel3

SNP

Amino acid change

Hybrid of Sec1 and FUT2

Japanese

Alu-Alu recombinations
Alu-Alu recombinations
Alu-Alu recombinations

South Asians
Samoans, New Guineans
Chinese

region of the FUT2 locus have been identified, and some of
them appear in a population-specific manner.3-24
Polymerase chain reaction (PCR)–high-resolution
melt (HRM) is based on the analysis of melting properties
of formed heteroduplexed amplicons and is similar to
other heteroduplex detection-based techniques such as
denaturing high-performance liquid chromatography
(DHPLC).25 We previously introduced DHPLC for FUT2
genotyping.18,21 Compared to DHPLC, HRM analysis is a
closed-tube post-PCR method without optimization of
column temperature for each amplicon and is suitable
for high-throughput assays because of its rapidity and
simplicity.
In this study, we analyzed the genetic variation in the
FUT2 coding region in Vietnamese, a Southeast Asian
population, to further understanding of the allelic variation of FUT2. In addition, we introduced and evaluated
HRM analysis as a method for genotyping the FUT2 gene.

Koda et al.7
Koda et al.7
Liu et al.,11 Soejima et al.,21
Pang et al.,15 Soejima and
Koda15,18,19
Chang et al.,4 Koda et al.,6
Liu et al.,12 Pang et al.,16
Peng et al.17
Henry et al.,5 Pang et al.,15
Yu et al.23,24
Liu et al.,11 Soejima et al.,21

Koda et al.,10 Liu et al.,11
Oriol et al.14
Chang et al.,3,4 Koda et al.6
Yu et al.23,24
Koda et al.,6 Liu et al.,12
Mitani et al.13
Koda et al.,8 Pang et al.15
Koda et al.,8 Pang et al.15
Soejima and Koda20

were obtained from 294 randomly selected Vietnamese
individuals in rural areas of Hoa Hau and Liem Thuan in
Ha Nam Province; Thach Hoa, Thanh Van, and Son Dong
in Ha Tay Province; and Van Phuc in Hanoi in the Red River
Delta, Vietnam.26 All samples were kept at -25°C in a
freezer of the Environmental Specimen Bank (es-BANK) in
Ehime University.27 Genomic DNAs were isolated by using
blood kits (Gentra Puregene, Qiagen, Tokyo, Japan).

PCR amplification of coding region of FUT2 and
sequence analysis
The PCR amplification and subsequent direct sequencing
of FUT2 were performed as described previously.28 The
copy number variations (CNVs) including deletion alleles
(sedel, sedel2, and sedel3) and sefus were detected by real-time
PCR (TaqMan, Applied Biosystems, Tokyo, Japan), as
described previously.20 We also examined four known
CNVs by conventional PCR using three sets of primers, as
described previously.6,8,15,20

MATERIALS AND METHODS
DNA samples
This study protocol was approved by the ethical committees of Ehime University and Kurume University School of
Medicine. Because only DNA samples were available, we
could not examine either the secretor status or the Lewis
phenotypes of the subjects in this study. Blood samples
2

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Genotyping of 385A>T by TaqMan SNP
genotyping assay
The TaqMan predesigned SNP genotyping assay (Assay ID
C_8832449_10, Life Technologies, Tokyo, Japan) was
applied for genotyping of 385A>T of 294 Vietnamese
persons. The PCR procedure was carried out in a 96-well


FUT2 IN VIETNAM

plate with 20-mL volume composed of 10 mL of universal
probe master (FastStart, Roche Diagnostics, Tokyo, Japan),
0.5 mL probe-primer mix, and approximately 10 ng of
DNA. PCR conditions included 95°C for 10 minutes, followed by 45 cycles of 95°C for 15 seconds and 60°C for 60
seconds. To monitor the progression of amplification, we
measured the fluorescence at the end of each cycle using a
real-time PCR system (Mx3000P, Agilent Technologies,
Tokyo, Japan) equipped with excitation-emission filters of
492-516 nm (FAM) or 535-555 nm (VIC). Data were collected and analyzed using computer software (MxPro,
Version 4.10; Agilent Technologies, Tokyo, Japan).

PCR-HRM assay and analysis
To screen new mutations and SNPs with low frequencies,
we performed HRM analysis. The primer pairs used are
listed in Table 2. Fragment 1 was scanned for the 143-bp
region including 628C>T and Fragment 2 for the 116-bp
region including 818C>A, 849G>A, and 853G>A. The 20-mL
PCR procedure contained approximately 10 ng of
genomic DNA, 10 mL of high resolution melting master
(LightCycler 480, Roche Diagnostics), 2.5 mmol/L MgCl2,
and 250 nmol/L each primer. The amplification was performed on a real-time PCR platform (LightCycler 480
instrument II, Roche) and entailed an initial denaturation
step at 95°C for 10 minutes, followed by 45 cycles of denaturation at 95°C for 10 seconds and annealing at 60°C for 1
minute. Before the HRM step, the products were heated to
95°C for 1 minute and cooled to 60°C for 1 minute allowing
heteroduplex formation. HRM was carried out and the
data were collected over the range from 65 to 96°C,
increasing at 0.02°C/sec with 25 acquisitions/sec. Gene
scanning software (LightCycler 480, Roche Diagnostics)
was used for analysis of the melting curves obtained.
Briefly, the raw melting curve data were normalized by
manual adjustment of linear regions before (pre- or 100%
fluorescence) and after (post- or 0% fluorescence) the
melting transition. Temperature shifting was automatically performed using a default temperature shift threshold of 5% and 0.3 as the internal instrument sensitivity
settings. Samples with heterozygous SNPs can be distinguished from homozygous by the different shapes of normalized and temperature-shifted melting curves. The
curves were further automatically subtracted from
assigned reference curves to generate difference plots that
were automatically clustered into separate groups. All

samples of groups differentiated from the reference group

were further confirmed by PCR direct sequencing of the
full length of the coding region of FUT2, as mentioned
above.

Determination of FUT2 haplotypes
To determine the FUT2 haplotypes of the individuals who
were heterozygous for newly found mutations, we performed PCR cloning as described previously.28

Transient expression of FUT2 alleles
To examine the functional significance of the two novel
nonsynonymous mutations, transient expression study
was performed as described previously except the flow
cytometer used.28 The FUT2 alleles carrying newly found
mutations of FUT2 (818C>A and 853G>A), Se357 (wild-type
allele), or se357,385 (weak-secretor allele) were inserted into
pcDNA3.1(+). These constructs together with the pGL3
Promoter were then transfected into COS-7 cells. The cells
were immunostained using anti-H 1E3 antibody, which is
specific for H Type 1 antigen,29 and H antigen expression
on cell surfaces was examined using a flow cytometer
(FACSCanto II, Becton Dickinson, Franklin Lakes, NJ).
Transfection efficiency in each experiment was checked
by luciferase luminescence intensity. The experiments
were repeated eight times.

Prediction of effects of SNPs on enzyme activity
We also predicted the effect of each newly identified
amino acid substitution on protein by using PolyPhen-2
( and Sorting
Intolerant From Tolerant (SIFT; />PolyPhen-2 is a tool that predicts the possible impact of an

amino acid substitution on the structure and function of a
human protein using straightforward physical and comparative considerations. SIFT uses sequence and/or structure to predict the effect of an amino acid substitution on
protein function.

RESULTS
Sequence variation in FUT2
We encountered five SNPs including two novel SNPs,
818C>A (T273N) and 853G>A (A285T), in the coding region
of FUT2 by direct DNA sequencing in 94 randomly selected Vietnamese persons (Table 3). [Correction statement

TABLE 2. Amplified regions, primers used, and residing SNPs for HRM analysis
Region
Fragment 1
Fragment 2

Name
FUT2HRM-545F
FUT2HRM-687R
FUT2HRM-778F
FUT2HRM-893R

Sequence (5′ to 3′)
GCACCTTTGTAGGGGTCCAT
CACGAAGATGAGGGAGCTGT
CCTGCCAAAGATTTTGCTCTA
TAATTGGCCAGGTAGATGGTG

545
668
778

873

Position in FUT2
to 564 bp
to 687 bp (antisense)
to 798 bp
to 893 bp (antisense)

Residing SNPs
571C>T, 628C>T
818C>A, 849G>A, 853G>A

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SOEJIMA ET AL.

added after online publication 21-Dec-2011: T273A has
been updated to T273N.] We then determined the FUT2
haplotypes of the individuals with 818C>A (Thr273Asn)
and 853G>A (Ala285Thr) inserting them into a plasmid.
The results suggested that 818C>A (Thr273Asn) was on the
Se357 allele with 357C>T synonymous substitution, while
853G>A (Ala285Thr) was on wild-type Se allele. As mentioned below, functional analysis suggested both alleles to
be nonfunctional. Therefore, we designated these two
alleles as se357,818 and se853, respectively.

HRM analysis for FUT2 SNP detection
To evaluate the detection of three SNPs (818C>A, 853G>A,
and 849G>A) by HRM, we amplify a 116-bp region (Fragment 2) from 778 to 893 (Table 2) in 94 randomly selected
TABLE 3. Allele frequency of FUT2 in 94
Vietnamese
Allele frequency
Functional alleles
Se
Se357
Nonfunctional alleles
se357,385
se849
se357,818
se853

n
73
21
52
115
111
1
1
2

(%)
(38.8)
(11.2)
(27.7)

(61.2)
(59.0)
(0.5)
(0.5)
(1.1)

Vietnamese persons. The normalized temperature-shifted
melting curves and difference plot are shown in Fig. 1.
After the normalization procedure, we could discriminate
the two groups of se853/Se and se357,385/se849 (Group A), and
se357,818/Se357 (Group B) from the reference group. Because
se853/Se and se357,385/se849 showed the same pattern (Group
A), we cannot distinguish 853G>A (Ala285Thr) and
849G>A (Trp283Ter) substitutions in melting curve patterns. Subsequently, we performed this assay on 200 additional Vietnamese individuals, and two samples were
ascribed to group A. The direct sequencing of total coding
region of these two individuals showed the genotypes of
se357,385/se849 and se628/se849.
Because we encountered the previously reported
628C>T mutation (Arg210Ter) in one sample (se628/se849),
we then designed an HRM assay protocol to detect this
SNP. The amplicon (Fragment 1) encompassed the 143-bp
region from 545 to 687 (Table 2). As shown in Fig. 1, we
detected one group was distinguishable from the other.
We then observed five additional samples with same
melting curve as the se628/se849 sample, and sequencing
showed that all of them were heterozygous for 628C>T
(two se357,385/se628, one se357/se628, and two Se/se628). After
we added the seven individuals mentioned above, we
encountered seven alleles and six SNPs in 101 Vietnamese
persons by direct sequencing of the entire coding region of

FUT2 (Table 5).

Fig. 1. PCR-HRM analysis of two partial coding regions of the FUT2 gene. Typical results for Fragment 1 and Fragment 2 are shown.
Normalized and temperature-shifted melting curves (top) and normalized and temperature-shifted difference plot (bottom).
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FUT2 IN VIETNAM

Functional analyses of alleles containing two
novel nonsynonymous mutations
The expression of H antigen in the COS-7 cells transfected
with pcDNA3.1-se357,818 (1.65 Ϯ 0.45%) and pcDNA3.1se853 (1.65 Ϯ 0.45%) was almost undetectable, as was the
expression in COS-7 cells transfected with plasmid
pcDNA3.1 (1.76 Ϯ 0.96%, n = 8, negative control). Under
the same conditions, the percentage of H-antigen–
positive cells of transfectants of pcDNA3.1-Se357 and
pcDNA3.1-se357,385 were 30.54 Ϯ 3.11% (wild type, positive
control) and 6.13 Ϯ 1.70%, respectively (n = 8). The mean
values of the luciferase luminescence intensities
(relative light unit) representing transfection efficiency
did not show significant difference: 86201, 62047, 88420,
52461, and 77753 for pcDNA3.1-se357,818, pcDNA3.1-se853,
pcDNA3.1, pcDNA3.1-Se357, and pcDNA3.1-se357,385, respectively. These results suggested that both of se357,818 and
se853 were nonsecretor alleles.

constitute recombination-promoting motifs, have probably played an important role in initiating homologous
recombination events involving the FUT2 locus.32,33 By

using a TaqMan probe–based CNVs assay, however, we
found no known CNVs including sefus, sedel, sedel2, and
sedel3 and other possible recombinants in the present
population.
To estimate the proportion of nonfunctional alleles
and nonsecretors (weak secretors), we determined genotypes of 385A>T (Ile129Phe) by TaqMan SNP genotyping
assay of 294 individuals. The result obtained by this assay
was fully consistent with that by PCR direct sequencing for
101 (the first 94 randomly selected plus the additional
seven) samples. The number of individuals with A/A, A/T,
and T/T were 65, 139, and 90, respectively. Together from
the results of HRM analysis, we observed 257 secretor
(43.7%), 319 weak secretor (54.3%), and 12 nonsecretor
alleles (2.0%), respectively. From the genotyping results,
we estimated 197 secretors (67.0%), 97 weak secretors
(32.7%), and 1 nonsecretor (0.3%) in this population.

Significance of novel nonsynonymous mutations
The results of transient expression studies suggested that
both 818C>A (Thr273Asn) and 853G>A (Ala285Thr) are
expected to result in amino acid changes in the catalytic
domain of the enzyme and inactivate or at least significantly reduce the encoded enzyme activity. In addition,
both changes may give rise to a difference in polarity and
are predicted to be “probably damaging” by PolyPhen2 ( and as
“affecting protein function” by SIFT ( />Table 4).31 These results also supported the results of the
transient expression study of the FUT2 allele containing
two new mutations.

Haplotype variation at FUT2
In total, six FUT2 alleles were inferred in 94 Vietnamese

individuals (Se, Se357, se357,385, se849, se357,818, and se853) and
the major nonfunctional allele is se357,385 (Table 3), which is
the predominant allele in other East and Southeast Asian
populations.4,6,10,12,17 In addition, FUT2 had at least four
recombination alleles (Table 1). For the formation of these
recombination alleles, local DNA sequences that are
capable of forming non–B-DNA conformations, or which

DISCUSSION
In this study, we seemed to successfully detect several rare
SNPs using this HRM analysis, although there is a possibility of failing to detect the homozygotes of a mutant
allele because of the difficulty in differentiation by melting
curve analysis. However, to increase the sensitivity of the
assay, homozygote mutants can be differentiated from
wild-type and heterozygote mutant samples by spiking
the sample with low amounts (10%-20%) of wild-type
DNA. Therefore, HRM analysis seems to be a simple and
effective method of screening for rare SNPs of the FUT2
gene in a large number of samples.
We compared the frequencies of the polymorphisms
observed in this study with that of the geographically
closer populations already studied (Table 5). The FUT2
gene shows genetic variation in a population-specific
manner and that of Vietnam also may reflect the present
geographic location and the history of human migration.
As discussed previously, the frequencies of nonsecretor (or weak secretor) status in inhabitants of low latitudes
are much higher than in inhabitants of high latitudes.28
Recent studies also suggested that the frequency of weak

TABLE 4. Novel SNPs identified in this study and their putative effects on encoded enzymes

SNPs

CG site

818C>A
853G>A

CG

Amino
acids

Domain

Amino acid change
from
to

Thr273Asn

Catalytic

Polar

Polar

Ala285Thr

Catalytic

Nonpolar

Polar

PolyPhen-2
prediction28 (score)
Probably
damaging (0.999)
Probably
damaging (0.968)

SIFT
prediction29 (score)
Affect protein
function (0.00)
Affect protein
function (0.00)

Allele
se357,818
se853

Expression
level (%) (n = 8)
1.65 Ϯ 0.45
1.88 Ϯ 0.81

[Correction statement added after online publication 21-Dec-2011: Amino acid change columns have been updated. PolyPhen-2 prediction
(score) for 818C>A has been updated to 0.999 and the SIFT prediction (score) has been updated to 0.00.]

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ACKNOWLEDGMENTS
We thank Ms Kimiko Kimura for helpful suggestions and techni-

0
0.9
0.7
0

0

cal assistance and Ms. Katherine Ono for the English editing of
the manuscript. The authors thank the staff of the CETASD, Hanoi
University of Science, for their help in sample collection.

1.2

685-687
0

688-690
0

818
C>A
0.5
0.2

849
G>A
0.5
0.5
0
1.6
0.9
6.8
1.5
0

0

853
G>A
1.1
0.3

Reference
This study (direct sequencing)
This study (real-time PCR)
Chang et al.3

Liu et al.12
Chang et al.3
Chang et al.3
Chang et al.3
Pang et al.16

secretor allele (se357,385) seems to be increased relative
recently by nonneutral evolution such as a directional
selection.10,34 Nonsecretors have an increased incidence of
Crohn’s disease, urinary tract infections, and vaginal
candidiasis, but a reduced incidence of infection by
certain genotypes of noroviruses and Helicobacter pylori,
and they usually have a slow disease progression of
human immunodeficiency virus Type 1 infection.35-40
These results suggested that a mixture of secretors and
nonsecretors (and/or weak secretors) may be advantageous for human survival during different pathogen outbreaks, and weak secretors, particularly in inhabitants of
low latitudes, may have the benefits of both secretors and
nonsecretors.

0

0.3

658
C>T
0

CONFLICT OF INTEREST

628

C>T
0
1.0
0
0
0.4
0
0
0

There are no conflicts of interest to declare.

571
C>T
0

0.7
1.0
0.6
13.3
3.3
1.2

428
G>A
0

0
0
0

0
0
2.4

posing that the Se gene is a structural gene closely linked
to the H gene. Am J Hum Genet 1981;33:421-31.
3. Chang JG, Ko YC, Lee JC, Chang SJ, Liu TC, Shih MC, Peng

1. Clausen H, Hakomori S. ABH and related histo-blood
group antigens; immunochemical differences in carrier

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* 685-687 = 685-687GTG>del. 688-690 = 688-690GTC>del.
† Blank cells represent site not explored.

0.6
0
0
0

84.4
83.1
88.9
85.5
89.3
92.9
Han-South (1)
Han-South (2) (Guangzhou)
Thai

Filipino
Indonesian (1)
Indonesian (2) (Surabaya)

Sample size (2N)
188
588
154
308
530
234
270
84

302
C>T
0
†
0

357
C>T
87.2

isotypes and their distribution. Vox Sang 1989;56:1-20.
2. Oriol R, Danilovs J, Hawkins BR. A new genetic model pro-

385
A>T
59.0

54.3
43.5
48.1
50.94
34.19
48.52
63.1

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TABLE 5. Frequencies of derived state of substitutions in FUT2 in Vietnamese and neighboring Asian populations

SOEJIMA ET AL.

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