BMC Gastroenterology BioMed Central

Research article Open Access

Genetic factors associated with intestinal metaplasia in a high risk
Singapore-Chinese population: a cohort study
Feng Zhu1, Marie Loh2, Jeffrey Hill3, Sumarlin Lee2, King Xin Koh2,
Kin Wai Lai2, Manuel Salto-Tellez2,4, Barry Iacopetta5, Khay Guan Yeoh1,
Richie Soong*2,4 and the Singapore Gastric Cancer Consortium

Address: 1Department of Medicine, National University of Singapore, Singapore, Singapore, 2Cancer Science Institute of Singapore, National
University of Singapore, Singapore, Singapore, 3Experimental Therapeutics Centre, Agency for Science, Technology and Research (A*STAR),
Singapore, Singapore, 4Department of Pathology, National University of Singapore, Singapore, Singapore and 5School of Surgery, The University
of Western Australia, Perth, Australia
Email: Feng Zhu - [email protected]; Marie Loh - [email protected]; Jeffrey Hill - [email protected];
Sumarlin Lee - [email protected]; King Xin Koh - [email protected]; Kin Wai Lai - [email protected]; Manuel Salto-
Tellez - [email protected]; Barry Iacopetta - [email protected]; Khay Guan Yeoh - [email protected];
Richie Soong* - [email protected]; the Singapore Gastric Cancer Consortium - [email protected]
* Corresponding author

Published: 13 October 2009 Received: 19 June 2009

Accepted: 13 October 2009
BMC Gastroenterology 2009, 9:76 doi:10.1186/1471-230X-9-76
This article is available from: http://www.biomedcentral.com/1471-230X/9/76
© 2009 Zhu et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract
Background: Intestinal metaplasia (IM) is an important precursor lesion in the development of
gastric cancer (GC). The aim of this study was to investigate genetic factors previously linked to
GC risk for their possible association with IM. A total of 18 polymorphisms in 14 candidate genes
were evaluated in a Singapore-Chinese population at high risk of developing GC.
Methods: Genotype frequencies were compared between individuals presenting with (n = 128)
or without (n = 246) IM by both univariate and multivariate analysis.
Results: Carriers of the NQO1 609 T allele showed an association with IM in individuals who were
seropositive for Helicobacter pylori (HP+; OR = 2.61, 95%CI: 1.18-5.80, P = .018). The IL-10 819 C
allele was also associated with IM in HP+ individuals (OR = 2.32, 95%CI: 1.21-4.43, P = 0.011), while
the PTPN11 A allele was associated with IM in HP- individuals (OR = 2.51, 95%CI: 1.16-5.40, P =
0.019), but showed an inverse association in HP+ subjects (OR = 0.46, 95%CI: 0.21-0.99, P = 0.048).
Conclusion: Polymorphisms in NQO1, IL-10 and PTPN11, in combination with HP status, could be
used to identify individuals who are more likely to develop IM and therefore GC.

Background programs began in the 1960's and led to a significant

Gastric cancer (GC) is the second leading cause of cancer- increase in the proportion of GC diagnosed at an early
related mortality worldwide, with more than 700,000 stage from 8% in 1960-1964 to 50% in 1975-1979. How-
deaths annually[1]. The late presentation of this disease is ever, more cost-effective screening programs that target
the main reason for the high mortality and highlights the high risk groups are needed because of the limited
importance of early detection[2]. In Japan, mass screening resources available in many Asian countries. Positive

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assessment of Helicobacter pylori (HP) infection can help to 2004 and December 2006 were used for genotyping in the
identify high risk individuals since this is a proven risk fac- present study.
tor for GC[3,4]. Various genetic factors have also been
associated with an increased risk for the development of Three biopsies from the antrum, body and cardia were
GC [5-8]. These polymorphisms could be used in con- collected for histopathological examination during each
junction with HP status and together with dietary and endoscopic surveillance episode. IM was diagnosed from
environmental factors to target screening programs mucosal biopsies in three locations (antrum, body and
towards individuals deemed to be at high risk. cardia) for each subject and by consensus amongst three
pathologists according to the updated Sydney System for
GC is thought to arise via a multi-step pathway that the classification and grading of gastritis [28]. In cases
involves intestinal metaplasia (IM) as a precursor where H. pylori was identified in biopsies, eradication
lesion[9]. It has been estimated that 0.25-1.1% of IM therapy was administered according to standard clinical
lesions will progress to GC annually, representing an 18- guidelines. For 339/374 (91%) individuals, the HP status
78-fold increased lifetime risk of developing this disease was determined using the Helicoblot2.1 serology test
in comparison to the general population[10,11]. In the (Genelabs Diagnostics, Singapore). In individuals where
present study, we have investigated a panel of 18 poly- this test was not performed, the HP status was determined
morphisms in 14 candidate genes for their association from histological examination of biopsies from the
with IM precursor lesions in a Singapore-Chinese popula- antrum, body and cardia, as well as from past medical his-
tion considered to be at increased risk of GC because of tory. Blood samples (8 mls) were collected into Vacu-
age greater than 50 years. These polymorphisms were cho- tainer CPT tubes (Becton Dickinson, Franklin Lakes, NJ)
sen for study because previous research has shown them and the mononuclear cells isolated and stored at -80°C
to be risk factors for GC. They included SNPs in genes prior to DNA extraction using Tri-Reagent (MRC Inc,
involved in the immune response (IL-1β, IL-10, PTPN11) Cincinnati, OH).
[12-14], folate metabolism (FR-α, MTHFR)[15,16], cell
growth (EGF, HER2) [17-19], cell survival (STCH)[20], Helicoblot2.1 serology test
cell invasion (MMP2)[21] and DNA damage or repair This serological assay uses a Western Blot nitrocellulose
(NQO1, SULT1A1, TP53, ADPRT) [22-26]. strip containing electrophoretically separated proteins
from a bacterial lysate of an ulcer-causing type strain of H.
Methods pylori and a recombinant antigen of H. pylori (Genelabs
Subjects Diagnostics, Singapore). When incubated with diluted
Subjects were recruited from the Gastric Cancer Epidemi- serum/plasma, specific antibodies to the various antigens,
ology and Molecular Genetics Program (GCEP). This if present, will bind to the H. pylori antigens on the strip.
project is a prospective cohort study aiming to enroll These bound antibodies appear as dark bands upon reac-
4,000 Singapore-Chinese subjects aged more than 50 tion with goat anti-human IgG conjugated with alkaline
years from four major public hospitals in Singapore phosphatase and a 5-bromo-4-chloro-2-indolyl-phos-
(National University Hospital, Tan Tock Seng Hospital, phate/nitroblue tetrazolium substrate solution. In order
Singapore General Hospital, Changi General Hospital). It to identify the various bands present, the strip is com-
offers screening by endoscopy and systematic follow-up pared with reference strips of non-reactive (negative) and
for a minimum of 5 years [27]. Chinese subjects older reactive (positive) controls run concurrently. Determina-
than 50 years of age who met the following criteria were tion of H. pylori seropositivity was based on criteria rec-
eligible to enroll in the study: (i) symptoms of dyspepsia ommended by the kit manufacturer. They consist of (1),
(ie. bloating, distension, nausea, stomach pain etc), (ii) 116 kD (CagA) positive band present with one or more of
family history of gastric cancer, or (iii) a medical condi- the following bands: 89 kD (VacA), 37 kD, 35 kD, 30 kD
tion that required them to undergo gastroscopy. They (UreA) and 19.5 kD together, or with the current infection
must also be able to attend all study visits assigned to marker, (2) the presence of any one band at 89 kD (VacA),
them. Subjects who could not undergo gastroscopy, had a 37 kD or 35 kD, with or without current infection marker,
history of stomach cancer or surgery, had a disabling ill- or (3) the presence of both 30 kD and 19.5 kD with or
ness, or were unable to provide informed consent were without current infection marker.
ineligible for the study. Clinical information including
demographics, medical history and family history were Selection of gene polymorphism panel
obtained. Informed consent was obtained from all sub- A systematic literature search in PubMed was carried out
jects and the study was approved by the institutional using the terms "gastric cancer" and "polymorphism".
review boards of all hospitals involved. Blood samples From a total of 78 candidate polymorphisms identified,
from 374 individual subjects collected between April 18 were found to be significantly associated with the risk

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of GC and were therefore included in the current investi- at the appropriate annealing temperature and 30 seconds
gation of IM. at 72°C, before conclusion with 7 minutes at 72°C.

Genotyping Pyrosequencing was performed by incubating the PCR

Table 1 shows the PCR primers, annealing temperatures products with 3 μl of streptavidin magnetic beads (Amer-
and product sizes for 17 SNPs investigated in this study by sham Pharmacia Biotech, Uppsala, Sweden) and 1× bind-
pyroseqeuncing. The 86-bp variable number of tandem ing buffer (10 mM Tris-HCl, 2 M NaCl, 1 mM EDTA, 0.1%
repeats (VNTR) polymorphism in ILRN was genotyped Tween 20) and mixing for 10 minutes at 37°C. The prod-
using PCR followed by size analysis using gel electro- uct mix was then denatured by 5 seconds incubation in
phoresis. The primers and PCR conditions were the same 0.2 M NaOH solution and washed in annealing buffer (20
as previously reported[29]. Polymorphisms were recorded mM Tris-acetate, 2 mM magnesium acetate) for 10 sec-
in their most commonly used notation for easy cross-ref- onds. The single-stranded products were transferred to an
erencing. For PCR, 50 ng DNA was amplified in a 25 μl annealing buffer containing 15 pmol of the sequencing
reaction containing 1 × FastStart Reaction Buffer, 2 mM primer (Table 1) and incubated for 2 minutes at 80°C in
magnesium chloride, 10 μM deoxynucleotide mix, 500 a Hybaid Maxi 14 hybridization oven (Thermo Electron,
nM each of the forward and reverse primers and 1 unit USA). Pyrosequencing was then performed on a
FastStart Taq Polymerase (Roche Diagnostics, Mannheim, PSQ96MA pyrosequencer instrument (Biotage AB, Upp-
Germany). PCR cycling comprised of 4 minutes at 95°C, sala, Sweden). Samples that failed to give a genotype
followed by 35 cycles of 30 seconds at 95°C, 30 seconds result after the first analysis were repeated up to two times.

Table 1: PCR primers and dispensation sequences for pyrosequencing of 17 SNPs evaluated for association with IM.

PCR Pyrosequencing

Locus Forward Primer Reverse Primer °C bp Sequencing Primer Dispensation

IL10 -- 1082 A/G CTCAATCAAAGGATCCCC AGGCTGGATAGGAGGTCC 60 253 ACACTACTAAGGCTTCT cgagcagta

AGAGAC CTTACT TTG
IL10 -- 819 T/C GGCCAATTTAATCCAAGG TCTGCACTTGCTGAAAGC 60 207 CCTTGTACAGGTCATGT gtcgatctc
TTT TTCTTA AA
IL-1B -- 511 T/C CATGAGATTGGCTAGGGT GCCCTCCCTGTCTGTATT 60 230 CAATTGACAGAGAGCTC atctgagca
AACAG GA C
MMP2 -- 1306 T/C TTTCATCTCTGGGCCATT TGAAGTTCTCCCTGTGAC 60 265 TCCCCACCCAGCACT gctgactct
GT AACC
EGF +61 A/G GTCATCCCTGCTTTCCTG CAGAGCAAGGCAAAGGCT 60 266 CCCAATCCAAGGGTTGT cagactgac
TGTG TAGA
PTPN11 (int1) A/G TGGACGAATGGCAAATTG GATCAATCCCACCTGAGA 60 182 TTGTCTCTAAAGGACTG tgagctcat
CAGA TG
NQ01 C609T AACTGCATGGAATTGGTT TGGTGTCTCATCCCAAAT 60 191 GTGGCTTCCAAGTCTTA cgatcgtca
GACTTA ATTCT
STCH rs2242661 AACTCGAATCCTGGACCT CTGGCGTTTATAATCAAA 65 203 GCGGAAAGAGAAAGG gctagtact
GATTAG CCTGTG
STCH rs1882881 CTATGGAAGGCTGCGAGA ACTTCCAGCTACAGGCAA 65 213 GAGGCTTTTTCCATCA gcagtcgtg
AC CATT
STCH rs12479 CTTGAAGGACCGTGTTGA GCAAAGGTCTCGGATAAC 60 312 ATGTTTCAGCACCAT gatagctag
TGT' AAAAA
STCH rs9982492 TCGTGCTTACCTTGTTCA AGTATGAGCCCTGCCATG 60 193 CCACTTGTCCTTTAAGT actcgactc
CATT A CC
SULT1A1 G638A GCCAGATCGCCTCTGAGG TGGGGGACGGTGGTGTA 65 233 CCTGGAGTTTGTGGG tgcgagctc
T GT
ADPRT T2285C GATACCTAAGTCGGGGGC ACAAGCTTTCCAGGAGAT 65 262 TGCTCCTCCAGGCCA cagtctgat
TTTC CCTAAC
HER2 +17ex17 A/G GTCCCTCCCACCCCAAAC CTGCCGTCGCTTGATGAG 65 145 CCCTCTGACGTCCAT gtcagatct
TA
TP53 C215G TCCCAAGCAATGGATGAT AAGCCCAGACGGAAACC 60 230 CAGAGGCTGCTCCCC tgcagtgct
TTGA GTAG
FR-a A1314G AAGTGGAGACTGAGGCCC TGACCCCTCCCCACCAAC 60 183 GTGTGGCCTGCTCAA cgagtacga
AGA
MTHFR C677T ACTGTCATCCCTATTGGC TCGGTGCATGCCTTCACA 60 168 GAAGGTGTCTGCGGG cgagtacga
AGGTTA A

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The genotyping success rate varied from 85-99% for the > 0.05), with the exception of IL10 -819T/C, NQO1 609C/
18 polymorphisms. T and TP53 Arg72Pro. By univariate analysis, the NQO1
609 T allele was the only variant in the overall cohort that
Statistics was significantly associated with IM (OR = 1.82, 95%CI:
Univariate analyses were carried out by Pearson's chi- 1.05-3.15, P = 0.032). In HP- individuals, only the
square or the Fisher's exact test to examine for associations PTPN11 rs2301756 A allele was significantly associated
between genotype distributions, IM status and clinical fac- with IM (OR = 2.51, 95%CI: 1.16-5.40, P = 0.019). Three
tors. As there were more than one polymorphism investi- polymorphisms in HP+ individuals were associated with
gated in IL10 and STCH, the haplotypes were also IM in univariate analysis: the IL-10 819 C allele (OR =
considered in the analyses. Variables found significantly 2.32, 95%CI: 1.21-4.43, P = 0.011), NQO1 609 T allele
associated with IM in the univariate analyses for all cases, (OR = 2.61, 95%CI: 1.18-5.80, P = 0.018) and PTPN11 A
and HP+ and HP- subgroups were entered in respective allele (OR = 0.46, 95%CI: 0.21-0.99, P = 0.048). The hap-
multivariate logistic regression models. The analyses were lotypes in IL10 and STCH were not significantly associ-
based on the assumption of a dominant genetic model. ated with IM in overall cohort, HP-, as well as HP+ groups.
All statistical analyses were performed using SPSS 16.0
(SPSS Inc., Chicago, IL) software at the 5% significance In multivariate analysis that included all cases, HP status
level. The Woolf test was used to test for homogeneity of and age were significantly associated with IM, while the
OR between two strata. As each polymorphism was tested NQO1 T allele showing borderline association (Table 4).
for association with IM independently, it was not neces- In HP- individuals, the PTPN11 A allele was the only fac-
sary to control for the family-wise error rate. Thus, no tor associated with IM. However, in HP+ individuals the
adjustment was made for multiple testing. factors of older age and the NQO1 609 T allele, IL-10 819
C allele and PTPN11 A allele were all significantly associ-
Results ated with IM. These results suggest that HP status is an
The characteristics of 374 subjects evaluated in this study effect modifier of the association between IM and the
are shown in Table 2. A total of 128 were diagnosed with PTPN11 A allele (P = 0.002). As it is possible that IM+/HP-
IM and 246 without IM. No significant differences cases in this study had prior unrecorded HP infection[30],
between IM+ and IM- groups were apparent for sex, family subgroup analysis on cases with a "revised HP+" status
history of GC (including 1st degree and 2nd degree rela- (either HP+/IM-, HP+/IM+ or HP-/IM+) was also per-
tives), alcohol consumption (at least one unit of wine, formed. Age (OR = 2.10, 95%CI: 1.24-3.56, P = 0.006)
beer or liquor per week) or smoking status (at least one and IL-10 -819 C allele (OR = 1.82, 95%CI: 1.07-3.08, P =
cigarette per day for a minimum of one year). IM+ sub- 0.027) were the only significant variables in this sub-
jects showed a significantly higher incidence of HP infec- group.
tion and were also older (P < 0.05).
Discussion
Genotype frequencies for the 18 polymorphisms investi- In this study, 18 polymorphisms that were previously
gated for association with IM are presented in Table 3. All linked to GC were investigated for possible associations
polymorphisms were in Hardy-Weinberg equilibrium (P with IM in a Singapore-Chinese population. The assump-
tion was made that IM represents a precursor lesion for
Table 2: Characteristics of study subjects in relation to the the development of GC and hence should have similar
presence of IM.
genetic risk factors. The cohort evaluated here was consid-
Total (%) IM+ (%) IM- (%) ered to be at elevated risk for GC because of the selection
of individuals aged >50 years[27]. As expected, older indi-
Subjects 374 128 246 viduals and those demonstrating seropositivity for HP
Mean age ± SD (range) 60.5 ± 7.8 62.9 ± 7.8 59.2 ± 7.5 showed a doubling in the frequency of IM (Table 4).
Age 50-59 yrs 190 (51) 48 (38)* 142 (58)*
Age 60-69 yrs 133 (36) 55 (43) 78 (32)
Following univariate analysis, 3 genotypes were found to
Age ≥70 yrs 51 (13) 25 (19) 26 (10)
Male 207 (55) 72 (56) 135 (55) be associated with IM. The NQO1 609 T allele was associ-
Family history of GC 66 (18) 23 (18) 43 (17) ated with IM, particularly in HP+ individuals. The IL-10 -
HP infection 191 (51) 84 (66)* 107 (43)* 819 C allele was also significantly associated with IM in
Drinker 66 (18) 22 (17) 46 (19) HP+ cases. Interestingly, the PTPN11 A allele in intron 3
Smoker 90 (24) 30 (23) 60 (24) (rs2301756) was associated with increased incidence of
Chronic gastritis 290 (78) 115 (90) 175 (71) IM in HP- individuals but a decreased incidence in HP+
Atrophy gastritis 194 (52) 97 (76) 97 (39)
cases. In multivariate analysis, all 3 polymorphisms
Dysplasia 1 (0.3) 1 (0.8) 0
remained significantly associated with IM, with the excep-
* P < 0.05

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Table 3: Distribution of genotype frequencies according to IM and HP infection status

Gene polymorphism Genotype IM- IM+ HP- HP+

(rs number)

IM- IM+ IM- IM+

ADPRT Val762Ala TT 71 31 33 9 38 22
(rs1136410)
TC 117 60 64 24 53 36
CC 33 16 13 6 20 10

EGF +61A/G AA 22 5 13 1 9 4
(rs4444903)
AG 103 55 54 20 49 35
GG 110 58 50 18 60 40

FR-α 1314A/G GG 164 95 74 30 90 65

(none)
GA 74 31 43 12 31 19
AA 6 1 5 0 1 1

HER2 Ile/Val AA 174 92 87 32 87 60

(rs1801200)
AG 60 30 29 8 31 22
GG 1 1 1 1 0 0

IL1RN 86-bp VNTR 44 212 101 112 33 100 68

(none)
24 28 18 9 4 19 14
34 1 2 0 2 1 0
54 0 1 0 0 0 1
22 2 2 0 1 2 1

IL-1β -511C/T CC 64 35 33 10 31 25
(rs16944)
CT 119 62 63 21 56 41
TT 48 23 20 10 28 13

IL-10 -819T/C TT 131 55 57 21 74* 34

(rs1800871)
TC 78 46 39 15 39 31
CC 22 16 17 3 5 13

IL-10 -1082A/G AA 207 100 98 37 109 63

(rs1800896)
AG 21 14 13 3 8 11
GG 2 0 2 0 0 0

MMP2 -1306C/T CC 178 79 85 28 93 51

(rs243865)
CT 46 22 26 8 20 14
TT 3 2 2 0 1 2

MTHFR 667C/T CC 132 77 64 23 68 54

(rs1801133)
CT 98 42 50 16 48 26
TT 14 7 8 2 6 5

NQO1 609C/T CC 64* 21 27 10 37* 11

(rs1800566)
CT 143 80 78 25 65 55
TT 28 22 13 4 5 18

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Table 3: Distribution of genotype frequencies according to IM and HP infection status (Continued)

TP53 Arg72Pro CC 45 16 22 7 23 9
(rs1042522)
CG 126 78 66 23 60 55
GG 51 26 24 10 27 16

PTPN11 rs2301756 GG 175 85 92* 24 83* 61

(rs2301756)
GA 58 28 26 16 32 12
AA 4 2 0 1 4 1

STCH rs12479 GG 102 58 51 20 51 38

(rs12479)
GA 106 39 52 12 54 27
AA 22 15 10 8 12 7

STCH rs1882881 AA 58 34 24 13 34 21
(rs1882881)
AC 123 58 67 15 56 43
CC 57 31 26 13 31 18

STCH rs2242661 AA 69 31 34 12 35 19
(rs2242661)
AG 106 46 52 13 54 33
GG 44 26 22 13 22 13

STCH rs9982492 CC 85 45 41 15 44 30
(rs9982492)
CT 105 39 53 12 52 27
TT 28 18 14 9 14 9

SULT1A1 638G/A GG 221 108 112 33 109 75

(rs9282861)
GA 16 10 6 6 10 4
AA 1 0 1 0 0 0

* Bold type denotes significant difference in genotype frequencies

tion of the NQO1 609 T allele which was associated with

Table 4: Multivariate logistic regression analysis for associations borderline significance in the overall cohort (P = 0.056).
with IM.

OR for IM P Previous data lends support to our observations. NQO1

(95% CI) (NAD(P)H: quinine oxidoreductase 1) codes for a
cytosolic enzyme that protects cells from oxidative dam-
All cases age by preventing the generation of semiquinone free rad-
HP (positive vs negative) 2.16 (1.35 - 3.45) 0.001
icals and reactive oxygen species[31]. The C to T
Age (>60 vs <60 yrs) 2.21 (1.40 - 3.49) 0.001
NQO1 (CT/TT vs CC) 1.74 (0.99 - 3.06) 0.056 substitution at nucleotide 609 in exon 6 results in a
change of amino acid from Pro to Ser at codon 187[32].
HP- cases Whereas the CC homozygous wildtype genotype (Pro/
Age (>60 vs <60 yrs) 1.92 (0.92 - 4.00) 0.082 Pro) has full enzymatic activity, the TT genotype (Ser/Ser)
PTPN11 (GA/AA vs GG) 2.51 (1.16 - 5.40) 0.019 completely lacks activity. The NQO1 609 TT genotype has
been associated with an increased risk for various tumour
HP+ cases
types including gastrointestinal and urological cancers
Age (≥60 vs <60 yrs) 2.19 (1.15 - 4.17) 0.017
NQO1 (CT/TT vs CC) 2.61 (1.18 - 5.80) 0.018 [33-36]. An increased risk of GC in patients with a family
IL-10 -819 (TC/CC vs TT) 2.32 (1.21 - 4.43) 0.011 history of upper gastrointestinal cancers was also reported
PTPN11 (GA/AA vs GG) 0.46 (0.21 - 0.99) 0.048 for the NQO1 609 TT genotype in a study on Chinese sub-
jects[22]. Our observation of increased prevalence of IM
in carriers of the NQO1 609 T allele concurs with earlier
reports on its association with various cancers and can be
explained by a decreased activity for the detoxification of
environmental and dietary carcinogens.

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The NQO1 C609T polymorphism was previously associ- Conclusion

ated with seropositivity to HP in a Japanese study[37], In summary, we found 3 polymorphisms associated with
thus raising the possibility that it is an indirect risk factor IM in a Singapore-Chinese population that was at high
for IM via association with HP infection. However, we risk for GC because of older age and seropositivity for HP.
found no association between the NQO1 C609T poly- The value of these SNPs in facilitating more cost-effective
morphism and HP infection in the present cohort (results surveillance programs awaits further validation in large,
not shown). independent cohorts.

Carriers of the IL-10 -819 C allele express higher mucosal Competing interests
levels of IL-10 (interleukin 10) mRNA and experience col- The authors declare that they have no competing interests.
onization with more virulent HP strains[38]. Similar to
NQO1 C609T, no association was observed here between Authors' contributions
the IL-10 T-819C polymorphism and HP infection. The FZ participated in the design of the study and its coordi-
current result showing the IL-10 -819 C allele is associated nation, performed the statistical analysis and drafted the
with IM is at odds with an Italian study that reported the manuscript. ML performed the literature review/statistical
TT genotype was associated with increased risk of IM[29] analysis and drafted the manuscript. JH, KWL, MST and
However, two studies in Chinese and German popula- KGY provided clinical and biological insights for the
tions found no associations between IL-10 T-819C and study. SL and KXK carried out the genotyping of the sam-
IM[38,39]. ples. BI drafted the manuscript. RS participated in its
design and coordination, supervised the study and drafted
Other common polymorphisms in the IL-1β and TNF-α the manuscript. All authors read and approved the final
cytokine genes have been proposed to influence the host manuscript.
response to HP and therefore the risk of developing
GC[13,29,38-42]. The IL-1β C-511T and IL-10 A-1082G Acknowledgements
polymorphisms were investigated in this cohort, but no This work was funded in part by the National Medical Research Council of
significant associations were found with seropositivity to Singapore (NMRC/TCR/001-NUS/2007), Biomedical Research Council of
HP or with the presence of IM (Table 3). Previous studies Singapore (BMRC 04/1/21/19/312) and the Singapore Cancer Syndicate
(SCS#BU51, SCS#GN015). The authors would like to thank contributors
reported the IL-1β -511 T allele increased the risk of IM in
from the Singapore Gastric Cancer Consortium that include Khek Yu HO,
some[38,39], but not all populations[12]. One study Yoshiaki ITO, Christopher JL KHOR, Andrea RAJNAKOVA, Kwong Ming
found an association between the IL-10 A-1082G poly- FOCK, Choon Jin OOI, Chung King CHIA, Wee Chian LIM, Wai Keong
morphism and IM[12,43], but 3 other studies did WONG, Andrew WONG, Ming TEH, Nilesh SHAH, Robert HEWITT,
not[12,29,39]. Bow HO, Kee Seng CHIA, Yoon Pin LIM, Jimmy JB SO, Lynette PHAY.

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