Deleted in Colorectal Cancer (DCC) Gene Polymorphism is Associated with H. pylori Infection among Susceptible Malays from the North-Eastern Region of Peninsular Malaysia

Abstract

Background/Aims: Using genome-wide case-control association approach, the current study aimed to determine whether genetic polymorphism(s) is/are associated with H. pylori infection among ethnic Malays from the north-eastern region of Peninsular Malaysia, a region with an exceptionally low prevalence for H. pylori infection and gastric cancer. Methodology: Twenty-three Malay subjects positive for H. pylori confirmed with urease test and histology were enrolled as "cases" and 37 subjects negative for H. pylori were "controls". Both groups were matched for age and environmental risks. Extracted DNA samples (QIAGEN, Germany) from the venous blood of study subjects were genotyped using the Human Mapping 50k xba1 array (Affymetrix, USA). High throughput downstream analyses were then used to determine the significant SNP(s) associated with H. pylori infection. Results: Out of 20,361 SNPs filtered using the genotype association test, the top 1% (203) significant SNPs were selected for functional enrichment analysis. Of the 15 "enriched" SNPs, the rs10502974 which was located within the intronic region of Deleted in Colorectal Cancer (DCC) gene was the SNP most significantly associated with H. pylori infection (p=0.00549). Conclusions: Ethnic Malays is genetically susceptible to H. pylori infection and is possibly mediated through a genetic variation in the DCC gene.

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GASTROINTESTINAL
Hepato-Gastroenterology 2013; 60:124-128doi 10.5754/hge12471
© H.G.E. Update Medical Publishing S.A., Athens

ABSTRACT
Background/Aims: Using genome-wide case-control
association approach, the current study aimed to de-
termine whether genetic polymorphism(s) is/are as-
sociated with H. pylori infection among ethnic Malays
from the north-eastern region of Peninsular Malaysia,
a region with an exceptionally low prevalence for H.
pylori infection and gastric cancer. Methodology:
Twenty-three Malay subjects positive for H. pylori
confirmed with urease test and histology were en-
rolled as “cases” and 37 subjects negative for H. py-
lori were “controls”. Both groups were matched for
age and environmental risks. Extracted DNA samples
(QIAGEN, Germany) from the venous blood of study
subjects were genotyped using the Human Mapping
Key Words:
H. pylori; DCC
gene; Single
nucleotide
polymorphism;
Genome wide
association
study,
Οriginal Paper
Deleted in Colorectal Cancer (DCC)
Gene Polymorphism is Associated with
H. pylori Infection among Susceptible
Malays from the North-Eastern Region
of Peninsular Malaysia
Sathiya Maran1, Yeong Yeh Lee2, Shuhua Xu3,
Nur-Shafawati Rajab1, Norhazrini Hasan4, Nazri Mustaffa2, Noorizan Abdul Majid5 and
Zilfalil Bin Alwi5
1Human Genome Center, 2Department of Medicine,
4Department of Immunology and
5Department of Paediatrics, School of Medical Sciences,
Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
3Chinese Academy of Sciences and Max Planck Society Partner Institute for
Computational Biology, Shanghai Institutes for Biological Sciences, Chinese
Academy of Sciences, Shanghai, China
Corresponding author: Yeong Yeh Lee, MD MRCP (UK) DTM&H MMed FRCPE FACP, School of Medical Sciences,
Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia;
Tel.: +6097663000, Fax: +6097648277; E-mail: justnleeyy@gmail.com
50k xba1 array (Affymetrix, USA). High throughput
downstream analyses were then used to determine
the significant SNP(s) associated with H. pylori infec-
tion. Results: Out of 20,361 SNPs filtered using the
genotype association test, the top 1% (203) significant
SNPs were selected for functional enrichment analysis.
Of the 15 “enriched” SNPs, the rs10502974 which was
located within the intronic region of Deleted in Colo-
rectal Cancer (DCC) gene was the SNP most signifi-
cantly associated with H. pylori infection (p=0.00549).
Conclusions: Ethnic Malays is genetically susceptible
to H. pylori infection and is possibly mediated through
a genetic variation in the DCC gene.
INTRODUCTION
In Asia, the prevalence of H. pylori remains high with
rates above 70% reported from China, Korea, Vietnam
and Turkey (1-3). Compelling evidence from epidemio-
logical studies exist for H. pylori as the carcinogen for
the development of non-cardia gastric cancer (4). The
inter-relationship between H. pylori infection, gastric
cancer and genetic susceptibilities between different
populations is unknown. It is however known that a high
prevalence of H. pylori infection and gastric cancer runs
in parallel with the exception of the Indian population.
Despite having a high prevalence of H. pylori infection,
the gastric cancer rate in the Indians is paradoxically
low (5). There are populations with a low prevalence
of H. pylori infection and also a low incidence of gas-
tric cancer, for example the Malay population from the
north-eastern region of Peninsular Malaysia (6-8); the
reasons for this remain largely elusive.
There is evidence that ethnic Malays are susceptible
to H. pylori infection but environmental factors, and in
particular diet, may confer some protection (9). That
local practices may limit H. pylori infection was sup-
ported by a lower prevalence rate of H. pylori infec-
tion observed in both Chinese and Indian immigrants
in Kelantan compared to other larger cities (15.8% in
Kelantan compared to 76.1% in Kuala Lumpur) (7,10).
It is of interest that the incidence rate for oesophageal
and gastric cancer among the Malays are considerably
lower than that of Western Europe and North America
(11,12). This suggests that there may be intrinsic genet-
ic factors within the ethnic Malays that confer protec-
tion against the bacterium.
Two recent studies comparing the genetics of H. py-
lori strains obtained from members of the three major
ethnic groups resident in Malaysia supported the notion
that H. pylori was introduced to the Malays from the
immigrant Han Chinese and South Indian populations
(13,14). Whether the ethnic Malays have inherent ge-
netic susceptibilities to H. pylori infection is not known.
The current study aimed to determine the gene(s) in
which variant(s) can increase the risk of H. pylori infec-
tion among ethnic Malays from the north-eastern region
of Peninsular Malaysia using a genome-wide case-con-
trol association study.
METHODOLOGY
Study subjects
Malay subjects (age range 20-80 years) requiring

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125Hepato-Gastroenterology 60 (2013)
upper endoscopy for gastrointestinal symptoms were
screened for study eligibility. Only subjects presented
with similar symptoms (including dyspepsia and/or
abdominal discomfort) and requiring the upper endos-
copy examination to exclude gastro-duodenal ulcer dis-
ease were included to ensure no ascertainment bias.
All Malay subjects included into the study must have
been born in Kelantan, resided within the region for at
least 3 generations and from different families but with
similar socio-economic and sociocultural backgrounds.
Study subjects positive for H. pylori infection on con-
firmed with urease test and histology were categorized
as “cases” and subjects negative for H. pylori infection
were categorized as “controls”. Subjects satisfying the
above inclusion criteria were recruited into the study.
Exclusion criteria included an intake of antibiotics 3
months prior to upper endoscopy test, positive family
history of H. pylori infection and gastric cancer, previ-
ous history of H. pylori infection, and chronic psychiat-
ric and medical conditions including cancer. Informed
consent was obtained from all subjects prior to their
enrolment in the study.
The exceptionally low rate H .pylori infection within
the region severely limits the number of H. pylori posi-
tive that could be collected. Only 23 Malay subjects were
eventually included as “cases”. A larger sample size for
the “controls” were sought to compensate for a low
sample size for the “cases”. In order to control for en-
vironmental risks, only subjects matched for age, socio-
economic and sociocultural backgrounds were included.
Only 37 Malay subjects were eventually included as
“controls” as a result of strict inclusion criteria along
with drop-out subjects who did not consent to the study
and exclusion of poor blood samples. The study was ap-
proved by the Human Research and Ethics Committee of
Universiti Sains Malaysia.
Genomic DNA preparation
All recruited subjects were called up by one of the
investigators (SM) to have their 1mL of venous blood
taken during the study day. Unlike conventional meth-
od for DNA extraction, 1mL of blood was sufficient for
commercially available kits. The blood was collected in
EDTA bottle and was transported immediately to a fa-
cility (Human Genome Centre, Universiti Sains Malaysia,
Kelantan) to be stored at 4°C. Subsequently, DNA for all
recruited cases and controls was isolated using QIAamp
DNA Blood Mini Kit (QIAGEN, Hilden, Germany).
Affymetrix 50k xba1 SNP Genotyping
The isolated DNA from all recruited cases (n=23)
and controls (n=37) were processed and genotyped
using the Affymetrix 50k xba1 array (Affymetrix, USA)
according to the instructions provided in the Affym-
etrix GeneChip Human Mapping 100K Assay Manual
(15). DNA samples with <90% genotype call rate were
dropped from the analysis. Single nucleotide polymor-
phisms (SNPs) that had a minor allele frequency of <5%,
that failed to genotype in >5% of samples, and with a
Hardy-Weinberg Equilibrium p value of <0.5 were also
excluded from subsequent analysis.
Data and statistical analysis
Genotype calling to assess for the normalization of
the SNPs was performed with the Bayesian Robust Line-
ar Model with Mahalanobis distance classifier (BRLMM)
algorithm from the Affymetrix® Genotyping Console™
software version 4.0 (Affymetrix, USA). Quality control
for genetic markers was assessed with the Genotype fil-
tering tool of SVS Golden Helix Bioinformatics Tools ver-
sion 7.4 (Golden Helix Inc, Montana). The genotype as-
sociation test between the genes and H. pylori infection
was evaluated for every single SNP in each gene with
SVS Golden Helix Bioinformatics Tools. False Discovery
Rate (FDR) and Bonferroni adjustments were then used
for multiple hypothesis testing.
Enrichment analysis to determine the most signifi-
cant SNP(s) associated with H. pylori infection were
carried out using The Database for Annotation, Visuali-
zation and Integrated Discovery (DAVID) software ver-
sion 6.7 (SAIC-Frederick Inc, Frederick, MD, USA). Data
analysis using SVS Golden Helix Bioinformatics Tools
and enrichment analysis using the DAVID software are
computational techniques that enable analyzing, visual-
izing and publishing of important discoveries on genet-
ic, phenotypic and clinical data more validly and much
easier (16). The “enriched” SNPs were then tested using
the FAMHAP program (IMBIE, Bonn, Germany) which
calculates the statistical significance by simulations.
RESULTS
A total of 56,000 SNPs were generated using the
Affymetrix GTC software. Further filtering of these SNPs
with the SVS Golden Helix Software resulted in 20,361
SNPs which were different between study groups. Out of
20,361 SNPs from the genotype association test, the top
1% (203) significant SNPs showing the lowest p values
were selected for functional gene enrichment analysis.
Gene enrichment analysis which utilized the “An-
notation Clustering Analysis” tool within the DAVID
software allowed a division of 80 annotation clusters
of genes based on enrichment scores. The annotation
cluster with the highest enrichment score of 3.89 was
then chosen to determine the significant SNP(s) of
which this cluster has 14 GOTERMS (Table 1). Out of
the 14 GOTERMS obtained, the GOTERM of “Cell Projec-
tion Morphogenesis” with the most significant p value
= 1.67×10-6 (modified Fisher Exact test) was selected.
The group with “Cell Projection Morphogenesis” con-
sisted of 15 SNPs; the x2 p value of these SNPs was deter-
mined using the FAMHAP program (17) (Table 2). Mean-
while, the functions of these SNPs were determined
using the DAVID’s “Functional Annotation Chart” tool
(18) (Table 2). Of these 15 SNPs, the SNP rs10502974
(p=0.00549) was significantly shown to have an associ-
ation with H. pylori infection. The SNP rs10502974 was
mapped to the chromosome 18q21within the intronic
region of the Deleted in Colorectal Carcinoma (DCC)
gene (19).
DISCUSSION
Genome wide association study using the Affymetrix
50k xba1 array can generate a large number of SNPs,
but this is not useful to detect any association with dis-
eases or infection. These SNPs can be “enriched” using
computational techniques, in our case the DAVID bioin-
formatics software was used to identify the most signifi-
cant SNP(s) associated with H. pylori infection among
the susceptible Malays. There were 15 candidate SNPs
after enrichment analysis and the rs10502974 was the
most significant SNP associated with H. pylori infection.
In the current study, the location for SNP rs10502974
was found to be in the intronic region of 18q21.3 of DCC
gene (19). Intronic polymorphisms harbor functional
polymorphisms which can influence the expression of
genes that host them (20,21).
The DCC gene encodes a 170 to 190kDa protein of the
Immunoglobulin superfamily. The role of DCC gene as a
tumor suppressor in particular colorectal cancer has re-
mained controversial over many years. It is known that
DCC and netrin-1 are essential for axonal guidance but
more recently DCC has been found also to function as a
dependence receptor and to induce apoptosis via this
mechanism (22,23). Adhesion of the H. pylori bacteri-
um to gastric epithelial cells is recognized as one of the
essential steps for the H. pylori infection in human be-
ings (24). In 2006, Martin et al. showed that the protein
products from the DCC gene could stimulate cell-cell
DCC gene and H. pylori in Ethnic Malays

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126 Hepato-Gastroenterology 59 (2012)
adhesion (25). Studies had also shown that expression
of cell adhesion proteins was significantly reduced in H.
pylori infected gastric tissues (26).
Alteration of tumor suppressor function of the DCC
gene in susceptible Malay individuals to H. pylori may
potentially increase the risk for developing gastric can-
cer. Studies had shown that there is aberrant methyla-
tion of the DCC gene observed in the course of gastric
carcinogenesis (27,28). The current study provides a
hint that there is a genetic link between H. pylori in-
fection and gastric cancer mediated by the DCC gene
variant among susceptible Malays and possibly other
susceptible populations. This will be validated and con-
firmed in subsequent gene expression studies which we
are currently performing.
There are limitations to be addressed in the current
study, such as its low sample size. The extremely low
H. pylori infection rate among the local Malays and the
strict inclusion and exclusion criteria severely limited
subject recruitment. However, the well-matched group
in terms of environmental risks compensates for the
size inadequacy. Furthermore the evidence that DCC
gene is involved in gastric carcinogenesis and is also
shown to be involved with H. pylori susceptibility in our
study suggests a possible genetic linkage between the
two. Secondly, further validation studies in a larger co-
hort are required to confirm the genome wide associa-
tion findings. Further studies involving post-transcrip-
tional protein analysis or gene expression analysis may
be needed to confirm the regulatory expression of DCC
gene. These studies are currently ongoing in our center.
In conclusion, the current study suggests that ethnic
Malays from the north-eastern region of Peninsular
Malaysia, a region known for extremely low prevalence
of H. pylori infection, are genetically susceptible to the
bacterium, possibly mediated through a genetic varia-
tion in the DCC gene.
TABLE 1. Composition or GOTERM annotation cluster with
the most significant enrichment score of 3.89
determined by DAVID software

Annotation
Cluster 13.89
Enrichment Score:
CategoryTermp value
Fold
Enrichment
GOTERM_BP_FAT
Cell projection
morpogenesis
Cell part
morphogenesis
1.67x10-06
5.019
GOTERM_BP_FAT2.80x10-06
4.803
GOTERM_BP_FATCell morphogenesis
Cell projection
organization
Axon guidance
Neuron projection
morphogenesis
Neuron projection
development
Cellular component
morphogenesis
Axonogenesis
2.83x10-05
3.684
GOTERM_BP_FAT4.14x10-05
3.564
GOTERM_BP_FAT4.63x10-05
6.896
GOTERM_BP_FAT5.70x10-05
4.619
GOTERM_BP_FAT 6.70x10-05
4.163
GOTERM_BP_FAT9.75x10-05
3.304
GOTERM_BP_FAT1.21x10-04
4.672
GOTERM_BP_FAT
Cell morphogenesis
involved in
differentiation
1.91x10-04
4.032
GOTERM_BP_FAT1(5.6)0 1(5.6)
GOTERM_BP_FAT
Cell morphogenesis
involved in neuron
differentiation
2.32x10-04
4.315
GOTERM_BP_FAT Neuron development8.76x10-04
3.144
GOTERM_BP_FAT Neuron differentiation0.0072.433
GOTERM_BP_FATCell motion0.1231.726
ACKNOWLEDGEMENTS
This work was supported by Fundamental Research
Grant Scheme (FRGS) 203/PPSP/6171121, 1001/
PPSP/812016 and 1001/PPSP/8122022 Universiti
Sains Malaysia. Shuhua Xu was supported by the
National Science Foundation of China (30971577,
31171218) and Shanghai Rising-Star Program
(11QA1407600). Shuhua Xu also gratefully acknowl-
edges the support of K.C. Wong Education Foundation,
Hong Kong. We also would like to thank Wenfei Jin
and Dongsheng Lu from Chinese Academy of Sciences
and Max Planck Society Partner Institute for Computa-
tional Biology for their remarkable help in GWAS data
analysis.
Sathiya Maran, Yeong Yeh Lee et al.

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127Hepato-Gastroenterology 60 (2013)
TABLE 2. Possible variant genes of interest associated with H. pylori infection in Malays analysed using the DAVID
software.

SNP IDrsID Associated Gene Chromosome

χ2 p value*

Function
SNP_A-1753707rs10496563GLI family zinc finger 22q14 0.067
regulation of epidermal proliferation
and skin tumorigenesis
SNP_A-1647724rs1268328
RAB3A interacting protein
(rabin3)
12q14.3 0.864
involved in mediating polarized
membrane transport
SNP_A-1661578rs9319171SLIT and NTRK-like family 13q31.1 0.494suppresses neurite outgrowth
SNP_A-1671688 rs4474385 ankyrin G10q21 0.418
cell motility, activation, proliferation,
contact and the maintenance of
specialized membrane domains
lipid transport, epithelial cell
differentiation, tumorigenesis, and
apoptosis
SNP_A-1681788rs10503813 clusterin 8p21-p120.389
SNP_A-1699297 rs10502974 DCC18q21.30.00549 tumor suppressor
SNP_A-1698719 rs1533949 zygin II2q21 0.761axonal outgrowth and fasciculation
SNP_A-1758143rs221493 neurexin 314q31 0.556
involved in cell recognition molecules in
the nerve terminal
SNP_A-1677344 rs10487849
Neuronal cell adhesion
molecule
7q31.1-q31.2 0.13axon growth
SNP_A-1749641 rs2120441one cut homebox 115q21.1-q21.20.153regulator of hepatocyte specific genes
SNP_A-1721159 rs1941158protein tyrosine phosphatase18p11.20.552 signal transduction and growth control
SNP_A-1751019rs10435337reelin7q220.891
modulating the structure and function
of retinal synaptic circuitry and of the
central nervous system and synaptic
plasticity
involved in axonal guidance during
neural development
SNP_A-1667186rs200032SEMA5A5p15.20.206
SNP_A-1657528rs2896092
tetratricopeptide repeat
domain 8
14q31.30.469 planar cell polarity
*All markers were run in the FAMHAP program. The p values represent simulated overall significance for the particular marker corrected for multiple testing.
The DCC variant gene with the most significant p value is highlighted with a red box.
DCC gene and H. pylori in Ethnic Malays

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128Hepato-Gastroenterology 60 (2013)
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