Review

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Genetic traits for the persistence of

Helicobacter pylori infection

Helicobacter pylori infection elevates the risk of gastric diseases, including peptic ulcer and gastric cancer.
Persistent infection is the first step to induce H. pylori-induced multistage diseases. Although the roles of
genetic traits on persistent infection have not yet been elucidated, some individuals escape from persistent
infection. Possible favorable conditions for H. pylori seem to be low acid secretion, reduced innate immune
responses, and easier binding to gastric epithelial cells. IL-1b and TNF-a inhibit acid secretion. The genetic
polymorphisms associated with both molecules have the potential to be the genetic traits underlying
persistent infection. Functional polymorphisms associated with innate immune responses could also be
involved with the genetic traits, but no polymorphisms with consistent associations have been identified
so far. The polymorphisms associated with molecules for adhesion to epithelial cells are candidates of
genetic traits, but more research is needed.

KEYWORDS: gastric acid secretion n Helicobacter pylori n innate immunity
n persistent infection n polymorphisms
Helicobacter pylori is a Gram-negative bacterium
colonizing human gastric mucosa that increases
the risk of gastric diseases, including digestive
ulcers and stomach cancer [1] . Although the
colonization does not always induce patho-
logical lesions in the stomach, the incidence of
H. pylori-induced diseases in a certain popula-
tion seems to be proportional to the number of
individuals infected with H. pylori in the popu-
lation, under the assumption that the develop-
ment of H. pylori-induced diseases is constant
among the infected individuals.
H. pylori is transmitted from person to person
through an oral–oral or fecal–oral route, mainly
in childhood [2–4] . The factors directly affect-
ing the transmission routes, such as sewage sys-
tems, are essential components for the infection.
Although the biological background is limited,
lifestyle factors, such as salty food intake [5] , low
intake of fruits [6] and smoking [7–10] , may play
a role to persistent H. pylori infection.
Interacting with a particular lifestyle, genetic
traits could influence persistent H. pylori infec-
tion. A twin study reported that the concordance
of anti-H. pylori antibody status was higher in
monozygotic twin pairs than in dizygotic twin
pairs [11] . This article reviews the genetic poly-
morphisms associated with persistent H. pylori
infection. While the seropositivity for H. pylori
has been used for the definition of persistent
infection, it is better to also classify seronegative
individuals with gastric atrophy into the per-
sistent infection group in the ana­lysis, because
Nobuyuki Hamajima†1
& Asahi Hishida1
1
Department of Preventive Medicine,
Nagoya University Graduate School of
gastric atrophy is a lesion subsequent to a long Medicine, 65 Tsurumai-cho, Showa-ku,
period of persistent H.  pylori infection [12] . Nagoya, 466–8550, Japan
However, in this article, the studies based on †
Author for correspondence:
Tel.: +81 52 744 2133
seropositivity for persistent infection are listed Fax: +81 52 744 2971
and discussed. nhamajim@med.nagoya-u.ac.jp
Factors associated with H. pylori
survival in human stomach
Even in regions where H. pylori infection is very
common, the prevalence rate is not 100% [13] .
Among those exposed to H. pylori, there may be
individuals who escape from persistent H. pylori
infection. Although the mechanisms that cause
H. pylori to fail to colonize in the stomach are
not known, both genetic traits of the host and
their lifestyle could affect the establishment of
persistent infection.
The initial colonization of H. pylori is mainly
restricted in the antrum, which is a less acidic
area than the corpus and has acid-producing
parietal cells. It has been reported that acid-
suppression therapy leaded to the expansion of
the H. pylori colonization to the corpus, result-
ing in atrophic gastritis [14] . Accordingly, the
highly acidic condition could disturb H. pylori
survival in the stomach. The bacterium is able
to grow in vitro between pH 5.0 and 8.0, and
to survive between pH  4.0 and 8.0 in the
absence of urea [15] . In the presence of urea, the
urease of H. pylori produces ammonia, which
is deleter­ious without acid even for H. pylori
[15] . It is not rare that patients with reduced
acidity of the stomach owing to severe atrophy

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Review Hamajima & Hishida
are H. pylori seronegative [12] . These findings
indicate that the appropriate levels of acid-
ity are required for H.  pylori survival in the
stomach [16] .
Innate immune responses of the host are also
defensive mechanisms against H. pylori infec-
tion. The responses are a preprogrammed, non-
specific first-line defense responsible for elimi-
nating pathogens at the site of entrance into the
host [17] . H. pylori has a cell wall that contains
lipopoly­saccharide (LPS), which is recognized
by a pattern recognition receptor, CD14, on
the epithelial cell surface. Peptidoglycans from
H.  pylori combine with the receptors in the
surface or the cytosole of host epithelial cells.
The toxins from H. pylori, such as cytotoxin-
associated gene A (cagA), vacuolating cytotoxin
gene A (vacA) and H. pylori neutrophil-acti-
vating protein, cause inflammation [1] , thereby
inducing immune responses [18] .
Adhesion to epithelial cells may be essential
for colonization. Blood group antigen-binding
adhesin (BabA) is an outer membrane protein
of H. pylori that binds to the Lewis B antigen
of human cells [19,20] . Other molecules, such as
H. pylori lectin, were also identified to play roles
in adherence to human epithelial cells [1] . Cell
surface molecules and factors inhibiting binding
may influence persistent H. pylori infection.
Molecules responding to
H. pylori infection
Gram-negative bacteria, including H. pylori, have
a cell wall containing LPS. LPS is recognized
by the innate immune system with CD14 on
the cell surface. CD14 is a glucosylphospatidyl­
inositol-anchored receptor lacking an intra-
cellular domain that binds to LPS with high
affinity. The LPS–CD14 complex then activates
Toll-like receptor (TLR) 4 with an intracellular
domain for signal transduction. TLR4 is stabi-
lized in the form of a homodimer by MD-2. The
signal from LPS is transduced through MyD88,
IRAK, TRAF6 and IKK to NF-kB (Figure 1) [21] .
TLR2 is a cell surface receptor that recognizes
peptidoglycans from H.  pylori. The signal is
transduced through MyD88 to NF-kB. TLR5
is known to be a receptor for the flagellin of
bacterial flagella.
Another signal from H.  pylori to NF-kB
is through a peptidoglycan-derived peptide,
g-d‑glutamyl-meso-diaminopimelic acid, which
is injected through a type IV secretion system
to epithelial cells. g-d-glutamyl-meso-diamino­
pimelic acid is a ligand of NOD1 encoded by
CARD4 [22,23] .
250 Personalized Medicine (2010) 7(3)
NF-kB comprises a group of proteins (NF-
kB/REL proteins) that bind a common sequence
motif known as the kB site [24] . They transcribe
inflammation-related genes, such as IL-1A, IL-1B,
IL-2, IL-6, IL-8, TNF-A, TNF‑B, GM-CSF and
NOS2 [24] . IL-1b, encoded by IL-1B, and TNF-
a, encoded by TNF-A, are proinflammatory
cytokines that activate NF-kB [25] . LPS induces
IL-1b and TNF-a through alternative pathways
to NF-kB [26,27] . IL-1b and TNF-a induce other
cytokines and enzymes for inflammation, as well
as themselves, through the NF-kB pathway [28] .
IL-1 receptor antagonist encoded by IL-1RN dis-
turbs IL-1b binding to IL-1 receptor I (IL-1RI),
resulting in inhibition of IL-1b function.
IL-8 is induced through NF-kB in gastric epi-
thelial cells, as well as in neutrophils [29] . It is
a CXC chemokine that mediates the activation
and migration of neutrophils into tissue from
peripheral blood [1] . The chemokine combines
CXCR-1 (previously known as IL-8RA) and
CXCR-2 (IL-8RB) with similar affinity. IL-10,
a cytokine produced by Th2 cells, inhibits the
production of IL-1b and IL-8 [30,31] . In mice,
cytokine expressions by Helicobacter felis are
modified by a concurrent infection of the enteric
helminth, Heligmosomoides polygyrus, which
drives the immune response through Th2 cells.
The co-infection increases the mRNA of IL-10
in comparison with Helicobacter felis infection
alone, resulting in reduced Helicobacter-associated
gastric atrophy and high Helicobacter coloniza­
tion [32] . These findings suggest that a high level
of IL-10 and a lower level of IL-8 create favorable
conditions for prolonging the H.  pylori infec-
tion in human gastric mucosa. Myeloperoxidase
(MPO) is a lysosomal enzyme in polymorphonu-
clear leukocytes and monocytes. Hypochlorous
acid produced by MPO shows microbicidal activ-
ity against a wide range of organisms [33] , pro-
ducing tissue inflammation. It was reported that
H. pylori water extract activated neutrophils [34]
and enhanced the secretion of MPO [29] .
Another possible pathway of innate immune
response relating to persistent H.  pylori infec-
tion is in polyamine synthesis. H. pylori induces
arginase II and ornithine decarboxylase (ODC),
the enzymes generating polyamines, as well as
inducible nitric oxide synthase (iNOS) (Figure 2) .
Polyamines, especially spermine, restrain immune
response by inhibiting iNOS translation and nitric
oxide production [35] . ODC level is regulated with
antizyme, a polyamine induced protein. NAD(P)
H:quinone oxidoreductase 1 (NQO1) binds and
stabilizes ODC. The regulation of ODC stability
by NQO1 is prominent under oxidative stress [36] .
future science group
 Genetic traits for the persistence of H. pylori infection Review

Helicobacter pylori
PGN
TNF-α

IL-1Ra
IL-1β LPS Type IV
secretion
system Flagellin
TLR4
MD2
TLR2 CD14
TNFAR

TLR5
IL-1RI

iE-DAP

NOD1

NF-κB

DNA

Gastric epithelium
IL-1A IL-1B IL-2

IL-6 IL-8 TNF-A

TNF-B GM-CSF NOS2

Pe Med
Pers. ed. © Futu
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ence
e Gro
oup 2010
0

Figure 1. Signal pathway from Helicobacter pylori to gene expression.

iE-DAP: g- d-glutamyl-meso-diaminopimelic acid; IL-1Ra: IL-1 receptor antagonist; IL-1RI: IL-1 receptor I; LPS: Lipopolysaccharide;
NOD1: Nucleotide-binding oligomerization domain protein 1; PGN: Peptidoglycan; TLR: Toll-like receptor; TNFAR: TNF-a receptor.

H.  pylori attaches to gastric mucosa with
BabA [19,20] . BabA binds both Lewis b and H
type I blood group carbohydrate structure on the
foveolar epithelium of human gastric mucosa.
Type I precursor is converted to H type I anti-
gen by fucosyltransferase 2 (FUT2; the secretor
enzyme), then to Lewis b antigen by fucosyl-
transferase 3 (FUT3; the Lewis enzyme). FUT3
also converts type I precursor to Lewis a antigen.
Genetic polymorphisms of molecules
associated with gastric acid secretion
Gastric acid is secreted from parietal cells and
regulated by histamine, gastrin and acetyl cho-
line. It is known that IL-1b and TNF-a, pro-
inflammatory cytokines, inhibit gastric acid
secretion [37] , and H.  pylori-infected patients
showed a marked increase in IL-1b mRNA in
mucosa [38] . A recent study demonstrated that
IL-1b decreased the gastrin level [39] , elucidat-
ing the mechanism of the acid secretion reduc-
tion due to H. pylori infection. IL-1b induces
TNF‑a, and vice  versa. Although IL-1b and
TNF-a have several roles, polymorphisms con-
nected to both molecules are classified as one
group in this article (Tables 1 & 2) .
„„ IL-1A
IL-1A forms a cluster in chromosome 2q14
with IL-1B and IL-1RN and has two SNPs
of C-889T and G4845T, as well as a 46-bp
variable number of tandem repeats (VNTR)

future science group www.futuremedicine.com 251

Review Hamajima & Hishida
Helicobacter pylori
DNA
Arginase II
ODC
NQO1
stablizes
ODC
Antizyme
Figure 2. Pathway of inducible nitric oxide synthase inhibition due to
Helicobacter pylori infection.
iNOS: Inducible nitric oxide synthase; NO: Nitric oxide; NQO1: NAD(P)H:quinone oxidoreductase 1;
ODC: Ornithine decarboxylase.
polymorphism [40] . It was reported that the
combination of IL-1A -889TT and IL-1B
-511T (-511TT or -511TC) was related to high
plasma levels of IL-1b [41] . The association
with H. pylori infection was examined in only
a Japanese population [42] , providing no asso-
ciation of IL-1A C-889T with H. pylori infec-
tion (Tables 1 & 2) . In the study, the association
with the 46-bp VNTR polymorphism was not
examined, because the polymorphism was not
found among Japanese people [43] . The G4845T
polymorphism was reported to be linked with
the C-889T polymorphism [44] .
„„ IL-1B
Three polymorphisms of IL-1B, T-511C, C-31T
and C3954T, located in chromosome 2q14, have
been studied for many diseases. It is known that
252 Personalized Medicine (2010) 7(3)
iNOS
Arginine Citruline
Ornithine
NO
Putrescine
Spermidine Innate immune
responses
Spermine
Perrs. Med
d. © Futu
ure Science
e Grou
up 2010
-511T and -511C are tightly linked with -31C
and -31T, respectively [42] . An electrophoretic
mobility-shift assay demonstrated that C-31T
was a functional polymorphism [45] , while
C3954T is unlikely to be functional.
We conducted four studies with Japanese peo-
ple and Japanese Brazilians, all of which showed
a similar result: that individuals with -31TT had
a higher risk of H. pylori sero­positivity [42,46,47] .
The risk elevation was marked for smokers
except in one study [46] . Since cigarette smoke
includes approximately 4000 chemicals, many
genes may be upregulated or down­regulated.
A study on the C-31T polymorphism in Brazil
showed a higher seropositive rate for those with
a -31TT genotype, although this was not sig-
nificant [48] . With regards to the T-511C poly-
morphism, no associations were found among
future science group

Japanese people [49] and Koreans [50] , while a
Chinese study reported a significant association
with the -511T allele (-511TT and -511TC) [51] ,
which was linked to the -31C allele.
„„ IL-1RI
There are two receptors for IL-1b: IL-1RI
and IL-1RII. The former transduces the sig-
nal, but the latter does not. IL-1RI in 2q12
has reportedly four polymorphisms: C-116T
(RFLP-A), C-90T, T49C and RFLP-B at an
unknown site [52] . There were no reports on
the association between these polymorphisms
and H. pylori seropositivity, except for our study
with C-116T indicating no association [53] .
„„ IL-1RN
IL-1RN has an 86-bp VNTR polymorphism.
Among 241 Japanese people, the allele frequency
was 4.1% for the 2-repeat allele, 0.2% for the
3-repeat allele, 94.6% for the 4-repeat allele and
1.0% for the 5-repeat allele [42] . No significant
differences in H.  pylori soropositivity among
different genotypes of IL-1RN 86-bp VNTR
were observed for Japanese, Korean and Chinese
people [42,50,51] . Since the minor alleles are rare
among the three ethnic groups, the statistical
power of these studies was not high enough.
„„ TNF-A
TNF-A and TNF-B genes are located between
HLA-B and HLA-DR in 6p21.3. In the pro-
moter area of TNF-A, G-238A, G-244A,
G-308A, C-857T, C-863A and T-1031C were
reported [54,55] . Among East Asians, -238A,
-244A and -308A  alleles were rare (2.0, 0.0
and 1.7%, respectively, among Japanese
people [54,55]), and C-863A was tightly linked
with T-1031C [56] . The functions of these alleles
were controversial, but -308A was regarded as a
high-expression allele [57] .
Among the studies reported on the TNF-A
polymorphisms [48,50,58–61] , significant associa-
tions were found for T-1031C and for the com-
bination of T-1031C and A-857T among 1374
Japanese people [58] , as well as for G-308A among
792 Italians [61] . If -1031T and -857T are the
high-expression alleles, the findings of the studies
on TNF-A seemed to rather consistently indicate
that high TNF-a expression favors persistent
H. pylori infection.
„„ TNF-B
The TNF-B A252G polymorphism, whose
G allele is strongly linked with the TNF-A -857C
allele in Japanese people [58] , was not associated
future science group
Genetic traits for the persistence of H. pylori infection Review
with seropositivity, as shown in Tables  1  &  2 .
Another polymorphism, TNF-B Thr26Asn, was
found to link completely with A252G.
Genetic polymorphisms of
molecules associated with innate
immune responses
Innate immune responses have not completely
been understood. The polymorphisms of the
molecules possibly involved in the innate immune
responses are selected in this section (Table 3) .
„„ CD14
CD14, located in chromosome 5q31.1, has
a C-159T polymorphism. Serum-soluble
CD14 levels were reported to be significantly
higher in individuals with -159TT (n  =  42;
median = 4.5 µg/ml) than in those with -159CC
(n = 67; median = 4.1 µg/ml) [62] . Although the
polymorphism seemed functional, no association
was found with H. pylori seropositivity [53] .
„„ CXCR2
CXCR2 in 2q35 was reported to have three
polymophisms; C785T causing a silent codon
change in leucine, and T1208C and G1440A in
the 3´ UTR of exon 3 [63] . These poly­morphisms
are tightly linked, forming a haplotype with
785C, 1208T and 1440G. Accordingly, any
polymorphism of the three may be used for a
pilot association study on disease risk. No signif-
icant difference was observed in the sero­positive
rate among the three genotypes of C785T in
Japanese individuals [53] .
„„ IL-2
T-330G of the IL-2 gene found in chromo-
some 4q26–27 was reported to be a functional
polymorphism; the production was higher with
a -330GG genotype than with the TT geno­
type [64,65] . The -330TT was at a higher risk
of gastric atrophy [66] and less common among
Asians (38% of 29  individuals) than among
Caucasians (51% of 199  individuals) [67] .
While the polymorphism was not associated
with H.  pylori seropositivity among Japanese
people [66] , the -330TT genotype was signifi-
cantly associated with the seropositivity relative
to -330C allele (CC+CT) among Brazilians [48] .
„„ IL-4
IL-4 C-33T in chromosome 5q31.1 was reported
to be functional; IL-4 protein production was
higher in -33TT genotype than in -33CC geno-
type [68] . Our dataset showed no association with
H. pylori seropositivity in Japanese people [66] .
www.futuremedicine.com 253
Review Hamajima & Hishida

Table 1. Genetic polymorphisms of molecules potentially related to gastric acid

secretion, reported associations with Helicobacter pylori infection:
sex–age-adjusted odds ratio or seropositive percentage.
Subjects aOR or HP% Ref.
IL-1A C-889T CC CT/TT
241 Japanese 62% (n = 201) 68% (n = 39)/(n = 1) [42]

IL-1B C-31T CC CT TT
241 Japanese 1 (n = 42) 2.32* (n = 133) 2.46* (n = 66) [42]
55 smokers 1 (n = 16) 6.18* (n = 27) 22.9* (n = 12)
465 Japanese 1 (n = 116) 0.97 (n = 183) 1.73* (n = 163) [47]
80 ever smokers 1 (n = 23) 1.68 (n = 34) 5.29* (n = 22)
547 Japanese 1 (n = 116) 1.32 (n = 237) 1.35 (n = 178) [46]
127 smokers 1 (n = 23) 1.12 (n = 60) 1.01 (n = 41)
963 Japanese Brazilians 1 (n = 226) 1.30 (n = 432) 1.45* (n = 289) [47]
124 smokers 1 (n = ND) 2.45 (n = ND) 3.49* (n = ND)
541 Brazilians 64% (n = 112) 71% (n = 265) 67% (n = 164) [48]

IL-1B T-511C TT TC CC
499 Japanese 52% (n = 113) 54% (n = 243) 53% (n = 143) [49]
474 Koreans 86% (n = 131) 86% (n = 259) 88% (n = 84) [50]
663 Chinese 67% (n = 148) 64% (n = 343) 55%* (n = 172) [51]

IL-1RI C-116T CC CT TT
241 Japanese 65% (n = 93) 58% (n = 114) 72% (n = 32) [53]

IL-1RN VNTR 4rpt/4rpt 2rpt Others

241 Japanese 62% (n = 217) 67% (n = 24) [42]
474 Koreans 80% (n = 60) 87% (n = 414) [50]
663 Chinese 66% (n = 53) 61% (n = 540) [51]
540 Brazilians 67% (n = 378) 70% (n = 162) [48]

TNF-A T-1031C TT TC CC
1374 Japanese 1 (n = 952) 0.92 (n = 385) 0.43* (n = 34) [58]
963 Japanese Brazilians 1.18 (n = 648) 0.96 (n = 269) 1 (n = 31) [59]

TNF-A C-857T CC CT TT
1374 Japanese 1 (n = 931) 1.06 (n = 373) 1.69 (n = 42) [58]
963 Japanese Brazilians 1 (n = 613) 1.17 (n = 301) 1.21 (n = 36) [59]

TNF-A G-308A GG GA AA
393 Germans 52% (n = 277) 56% (n = 89) 56% (n = 18) [60]
792 Italians 54% (n = ND) 61%* (n = ND) – (n = ND) [61]
474 Koreans 86% (n = 400) 89% (n = 59) 89% (n = 2) [50]
539 Brazilians 70% (n = 403) 66% (n = 123) 46% (n = 13) [48]

TNF-B A252G AA AG GG
1374 Japanese 1 (n = 501) 1.05 (n = 656) 1.05 (n = 204) [58]
*Statistically significant (p < 0.05).
aOR: Sex–age-adjusted odds ratio; HP%: Seropositive percentage; ND: Not described; VNTR: Variable number of
tandem repeats.

„„ IL-8 are dominant with frequencies of 0.41 and

The IL-8 gene, located in chromosome 4q12‑q21,
was reported to have nine polymorphisms (four
in the 5´ upstream regions, four at introns and
one in the 3´  downstream region). Among
Europeans, two haplotypes, one with -1722delT,
-251A, 396G, 781T, 1633T and 2767T termed
delTAGTTT in the order of those poly­
morphisms, and the other with delTTTCCA,
0.52, respectively. The haplotypes are more
diverse among Africans; delTAGCCA (fre-
quency: 0.36), delTATCCA (frequency: 0.19),
insTATCCA (frequency: 0.18) and delTTTCCA
(frequency:  0.10), respectively [69] , but the
genotyping of T-251A and T396G is sufficient
for classifying the haplotypes, even among
Africans. Among Japanese people, there was

254 Personalized Medicine (2010) 7(3) future science group

 Genetic traits for the persistence of H. pylori infection Review
Table 2. Associations of Helicobacter pylori infection with TNF-A genotype
combinations: sex–age-adjusted odds ratio or seropositive percentage.
Subjects aOR or HP% Ref.
TNF-A -1031 & -857 CC & CC TT & CC TC & CT TT & TT
1374 Japanese 1 (n = 34) 2.37* (n = 595) 2.84* (n = 76) 3.63* (n = 42) [58]
963 Japanese Brazilians 1 (n = 30) 1.08 (n = 377) 1.03 (n = 67) 1.27 (n = 35) [59]
253 ever smokers 1 (n = 11) 2.01 (n = 102) 1.76 (17) 2.30 (n = 5)
*Statistically significant (p < 0.05).
aOR: Sex–age-adjusted odds ratio; HP%: Seropositive percentage; ND: Not described.

strong linkage between the two polymorphisms; „„ IL-13

396TT was found in 90.0% of 110 individu-
als with -251TT, 396TG in 90.5% of 95 indi-
viduals with -251TA, and 396GG in 100% of
22 individuals with -251AA [70] , indicating that
T-251A is a good marker for H. pylori infection
in Japanese people.
However, a study on IL-8 expression found
that the A allele had a higher expression than
the T allele [69] . Plasma IL-8 levels was found to
be higher in A allele carriers among those who
were H. pylori seronegative, but lower among
the seropositives without gastric atrophy [71] .
Although no significant association was found
with the seropositivity, the point estimate of the
adjusted odds ratio was less than unity for the
A allele carriers [70] .
„„ IL-10
IL-10 G-1082A and T-819C polymorphisms
were reported to influence the expression of
IL-10 mapped to 1q31–32; -1082A and -819T
are high-expression alleles [72,73] . There is a
large difference in -1082G allele frequency
among different regions: 0.51 in Belfast (UK),
0.52 in Glasgow (UK) and 0.47 in Strasbourg
(France) [74] , but 0.04 in Japan [75] . We found
that there was no significant association between
T-819C and H. pylori seropositivity.
As previously mentioned, a high level of IL-10
and a lower level of IL-8 create favorable condi-
tions for prolonging the H. pylori infection in
human gastric mucosa. Accordingly, the com-
bination of IL-8 -251TT (the low expression
genotype) and IL-10 -819TT (the high expres-
sion genotype) was expected to be favorable
for persistent H. pylori infection. Among three
studies, one study demonstrated that the other
combinations were at a significantly lower risk of
persistent infection [70] , but another study pro-
duced opposing results [53] . When smokers were
selected, the genotype combinations other than
IL-8 -251TT and IL-10 -819TT were at a lower
risk in the three studies, although these were not
significant for both of the studies (Table 3) .
IL-13 encodes for a Th2 cytokine, whose gene
is located in 5q31. The closely linked poly­
morphisms, A-1512C, C-1111T and Arg130Gln,
have been examined for disease risk [76] .
Although the association between gastric atro-
phy development and C-1111T was observed [66] ,
there was no association with the seropositivity.
„„ Myeloperoxidase
Myeloperoxidase is a lysosomal enzyme in poly-
morphonuclear leukocytes and monocytes. It
produces hypochlorous acid to kill a wide range
of organisms. While the mutations Arg569Trp,
Val173Cys or Met251Thr of MPO located in
17q23.1 cause fatal diseases, such as chronic
granulomatous disease owing to severe enzyme
activity deficiency [77] , MPO G-463A does not
cause those diseases, but the transcription level of
A allele was reported to be 4% of the G allele [78] .
Two studies demonstrated that A-allele carriers
were at a lower risk of the seropositivity, although
this was not significant [79,80] . Intuitively, low
enzyme activity seemed to provide a favorable
situation, but the results were opposite.
„„ NF-KB2
NF-KB2, coding NF-kB2 (p100), has a ins/del
polymorphism at -10G (or 1867GG/G), as
well as two polymorphisms with a rare minor
allele [81] . Although the function of ins/del -10G
has not been demonstrated, no association was
found with H. pylori seropositivity [53] .
„„ NOS2
Nitric oxide synthase has three isozymes; neu-
ronal constitutive NOS encoded by NOS1,
iNOS encoded by NOS2 and endothelial con-
stitutive NOS encoded by NOS3. There were
several polymorphisms reported for NOS2 in
chromosome 17cen-q11.2, such as C-1173T,
G-954C, (TAAA)n and (CCTTT)n. A C150T
(Ser608Leu) polymorphism at exon 16 was
reported to have an association with Type I dia-
betes [82] , but the association with H. pylori was

future science group www.futuremedicine.com 255

Review Hamajima & Hishida

Table 3. Genetic polymorphisms of molecules potentially involved in innate immune responses, reported
associations with Helicobacter pylori infection: sex–age-adjusted odds ratio or seropositive percentage.
Subjects aOR or HP% Ref.
CD14 T-159C TT TC CC
1374 Japanese 1 (n = 413) 0.94 (n = 678) 1.16 (n = 413) [53]

CXCR2 C785T CC CT TT
241 Japanese 65% (n = 110) 63% (n = 100) 56% (n = 25) [53]

IL-2 T-330G GG GT TT
454 Japanese 1 (n = 45) 1.10 (n = 196) 1.15 (n = 202) [66]
541 Brazilians 70% (n = 27) 63% (n = 221) 72%* (n = 293) [48]

IL-4 C-33T CC CT TT
454 Japanese 1 (n = 42) 1.43 (n = 183) 1.25 (n = 227) [66]

IL-8 T-251A TT TA AA
454 Japanese 1 (n = 234) 0.86 (n = 177) 0.70 (n = 37) [70]

IL-10 T-819C TT TC CC
454 Japanese 1 (n = 220) 0.67 (n = 177) 0.82 (n = 37) [70]

IL-8 & IL-10 TT&TT Others

454 Japanese 1 (n = 115) 0.62* (n = 327) [70]
65 smokers 1 (n = ND) 0.13* (n = ND)
241 Japanese 1 (n = 57) 1.04 (n = 178) [53]
55 smokers 1 (n = ND) 0.45 (n = ND)
679 Japanese 1 (n = 164) 1.49* (n = 507) [53]
158 smokers 1 (n = ND) 0.89 (n = ND)
IL-13 C-1111T CC CT TT
454 Japanese 1 (n = 310) 0.73 (n = 127) 1.09 (n = 11) [66]

MPO G-463A GG GA/AA

241 Japanese 1 (n = 192) 0.69 (n = 47)/(n = 2) [79]
454 Japanese 1 (n = 354) 0.84 (n = 77)/(n = 6) [80]

NF-kB2 -10G InsIns InsDel DelDel

1374 Japanese 1 (n = 513) 1.03 (n = 648) 1.15 (n = 199) [53]

NOS2 C150T (Ser608Leu) CC CT TT

454 Japanese No association [83]

NQO1 C609T (Pro187Ser) TT TC CC

241 Japanese 1 (n = 48) 1.13 (n = 107) 2.42* (n = 86) [86]
454 Japanese 1 (n = 83) 1.57 (n = 210) 1.70 (n = 153) [86]

ODC A317G AA AG GG
465 Japanese 1 (n = 167) 1.09 (n = 229) 1.02 (n = 69) [89]

TLR2 Arg753Gln ArgArg ArgGln GlnGln

541 Brazilians 68% (n = 531) 70% (n = 10) – (n = 0) [48]

TLR4 Asp299Gly AspAsp AspGly GlyGly

541 Brazilians 68% (n = 490) 71% (n = 51) – (n = 0) [48]

TLR4 G3725C GG GC CC
1592 Japanese 1 (n = 827) 0.95 (n = 474) 0.72 (n = 90) [94]

TLR5 Arg392Ter ArgArg ArgTer TerTer

541 Brazilians 68% (n = 504) 71% (n = 34) 67% (n = 3) [48]
*Statistically significant (p < 0.05)
aOR: Sex–age-adjusted odds ratio; HP%: Seropositive percentage; ND: Not described.

256 Personalized Medicine (2010) 7(3) future science group


not observed among Japanese people [83] . There
were no studies with the other polymorphisms
of NOS2.
„„ NQO1
NQO1 is an obligate two-electron reductase,
whose gene is located in chromosome 16q22 [84] .
The gene has a functional polymorphism C609T
(Pro187Ser); the T allele has no enzyme activ-
ity [85] . The CC genotype was found to favor
persistent H. pylori infection among Japanese
people [86] .
„„ ODC
The ODC gene in chromosome 2p25, encoding
ornitine decarboxylase, has a functional poly-
morphism G317A in intron 1; the expression is
higher in the A allele than in the G allele [87] .
Aspirin chemoprevention of colorectal adenoma
recurrence was reported to be more effective
among patients with 317AA than those with
the other genotypes. Occurrence of the 317AA
genotype was 5–7% in Europe and the USA [88] ,
while it was 36% in Japan [89] . The association
with H. pylori seropositivity was not observed
among Japanese people [89] .
„„ TLR2
Arg677Trp, Arg753Gln and ins/del at -196 to
-174 were reported as polymorphisms of TLR2
on chromosome 4q32 [48,90] . Although the minor
allele was rare, the association with Arg753Gln
was examined among Brazilians. They found no
association with the polymorphism [48] .
„„ TLR4
In TLR4 on chromosome 9q32–33, two polymor-
phisms, Asp299Gly and Thr399Ile, have been
reported. The 299Gly/399Ile allele is less sensitive
to LPS than 299Asp/399Thr allele, resulting in
Table 4. Genetic polymorphisms of molecules related to epithelial cell adhesion,
reported association with Helicobacter pylori infection: sex–age-adjusted odds
ratio or seropositive percentage.
Subjects
FUT2 SeSe
241 Japanese 1 (n = 61)
679 Japanese 1 (n = 170)
464 Japanese 1 (n = 139)
FUT3 LeLe
241 Japanese 1 (n = 124)
679 Japanese 1 (n = 353)
424 Japanese 1 (n = 235)
*Statistically significant (p < 0.05).
aOR: Sex–age-adjusted odds ratio; HP%: Seropositive percentage.
future science group
Genetic traits for the persistence of H. pylori infection Review
lower NF-kB activity [91] . The LPS-hyposensitive
allele was found to be 5.9% among 879 blood
donors in England [92] , but was not found among
275 Japanese people [93] . For Japanese people,
G3725C in 3´UTR was reported to have an
association with perio­dontitis. We found that
the polymorphism had an association with severe
gastric atrophy, but not with persistent H. pylori
infection [94] .
„„ TLR5
The Arg392Ter polymorphism on the TLR5 gene
in chromosome 1q41–42 was examined for associ-
ation with H. pylori infection among Brazilans [48] .
There was no significant association in the study.
Genetic polymorphisms of molecules
associated with adhesion to
epithelial cells
Blood group antigen-binding adhesin of H. pylori
binds to H type I and Lewis b antigen carbo-
hydrate structure on human epithelial cells.
H type I is synthesized from Type I precursor
with its secretor enzyme encoded by FUT2,
and it is further metabolized to Lewis b by the
Lewis enzyme, which is encoded by FUT3. Both
enzymes are fucosyltransferases (Table 4) .
„„ FUT2 (secretor gene)
Although many polymorphisms were reported,
the main alleles of FUT2 located in 19q13.3
are Se1 (357C, 385A, 571C and 628C), Se2
(357T, 385A, 571C and 628C), sej (357T, 385T,
571C and 628C), se3 (357C, 385A, 571T and
628C), se4 (357C, 385A, 571C and 628T) and
se5 (combined with a pseudogene). Se1 and Se2
exhibit full enzyme activity, sej shows very low
activity, and se3, se4 and se5 reveal no activity.
Accordingly, Se1 and Se2 are denoted by Se, and
the others by se. Among Caucasians, se3 and se4
aOR Ref.
Sese sese
0.79 (n = 127) 0.35* (n = 51) [96]
1.51* (n = 328) 1.50 (n = 181) [97]
1.57 (n = 218) 1.29 (n = 107) [97]
Lele lele
1.95* (n = 98) 2.80 (n = 17) [96]
0.98 (n = 251) 1.31 (n = 59) [97]
1.06 (n = 155) 1.40 (n = 33) [97]
www.futuremedicine.com 257
Review Hamajima & Hishida
are common se alleles; in East Asians, se5 and
sej are the main se alleles [95] . Since individuals
with sese genotype cannot synthesize H type I
nor Lewis b, they were expected to have the lower
seropositive rate. Our first study was in line with
this expectation [96] , but it was not confirmed in
the second and third datasets [97] . Those with
the sese genotype were reported to be resistant to
Norwalk virus infection [98] .
„„ FUT3 (Lewis gene)
The FUT3 gene has three polymorphisms;
T59G, G508A and T1067A. A Le allele is defined
as one with 59T, 508G and 1067T, a le1 allele
with 59G, 508A and 1067T, a le2 allele with
59G, 508G and 1067A, and a le3 allele with 59G,
508G and 1067T. The le1 and le2, denoted by le,
lack enzyme activity. Since le3 shows almost full
enzyme activity, it is grouped into Le [95] . The
LeLe genotype, which may disturb the synthesis
of H type I by FUT2 through sharing the same
substrate (type I precursor), showed the lower
seropositivity in the first dataset, while the find-
ing was not reproduced by the second and third
datasets [97] .
Difficulties with the studies on the
associations of H. pylori infection
& genotype
The higher the proportion of those without
H. pylori exposure among the study subjects,
the weaker any associations with genetic poly-
morphisms become. For example, the follow-
ing conditions are assumed in a cross-sectional
study (Table 5) :
ƒƒ
A total of 50% of the study subjects are
exposed to H. pylori infection;
ƒƒ
A total of 80% of the exposed subjects have
persistent infection;
ƒƒ
In total, 80% (64 out of 80) of patients with
persistent infection and 20% (four out of 20)
of patients without persistent infection have a
genotype susceptible for persistent infection.
Table 5. A hypothetical example for a cross-sectional study between persistent
Helicobacter pylori infection and the susceptibility genotype.
Genotype Exposed (%)
Infected Uninfected
Yes 64 4 68
No 16 16
Total 80 20
Odds ratios of susceptible genotype is 16 (64 out of 16 vs 4 out of 16) among 100 exposed and 2.7 (64 out of 16 vs 72 out
of 48) among 100 exposed plus 100 unexposed.
258 Personalized Medicine (2010) 7(3)
Since there is no association between the expo-
sure and genotype, the genotype frequency among
the unexposed is the same as among the exposed;
68% in Table 5. The odds ratio of the susceptible
genotype among the exposed subjects is 16; the
odds of susceptible genotype versus unsusceptible
genotypes is 64 out of 16 for those with persistent
infection, and four out of 16 for those without
persistent infection. When 100 unexposed sub-
jects are added into 100 exposed subjects in the
study, the odds ratio become 2.7 (64 out of 16
and 72 out of 48, respectively), demonstrating
the reduced odds ratio of susceptible genotypes
for persistent H. pylori infection. It indicates that
studies on associations of persistent H.  pylori
infection with genotypes could be conducted suc-
cessfully only among populations highly exposed
to H. pylori. This may be the reason that a lim-
ited number of studies have been reported from
developed countries other than Japan. This is one
limitation of the present overview.
Another limitation is that patients who have
previously suffered persistent H. pylori were classi-
fied into the uninfected group, because persistent
infection was examined using the sero­positivity
in those cross-sectional studies. Patients with
spontaneous disappearance after severe gastric
atrophy, as well as those treated for H. pylori infec-
tion, also become seronegative. However, they
have the same genetic traits as the sero­positives
as a group. If data on gastric atrophy and his-
tory of eradication treatment had been available,
misclassification would have been reduced.
Conclusion
The associations were rather consistent for IL-1B
and TNF-A, at least in Japanese people, both
of which encode cytokines that inhibit gastric
acid secretion. The finding that acid inhibition
by medication established favorable conditions
for H. pylori to form colonies provides bio­logical
plausibility for the polymorphisms of both
cytokines. Another pathway to influence per-
sistent H. pylori infection may exist in relation
to innate immune responses, but this remains to
Unexposed (%)
Total Uninfected
68
32 32
100 100
future science group

be investigated. Research on further associations
with the polymorphisms of adhesion molecules
is further limited.
There are many studies reporting the asso-
ciations between genotypes and gastric cancer
risk [99–101] . In the areas where H. pylori-related
gastric cancer is dominant, the obtained odds ratios
seems to be the product of the following steps:
ƒƒ Persistent H. pylori infection among
exposed individuals;
ƒƒ
Gastric atrophy development among
infected individuals;
ƒƒ Gastric cancer development among patients
with gastric atrophy.
Since carcinogenesis is a complicated process,
including many mutually related molecules,
some genetic traits could affect all the steps.
The roles of IL-1B and TNF-A polymorphisms,
for example, are not excluded from the develop-
ment of gastric atrophy and cancer. However,
epi­demiologic studies on each step will produce
useful information directly applicable for gastric
cancer prevention. The high-risk genotypes iden-
tified with case–control studies, without taking
the steps into account, may be not only relevant
to gastric cancer risk but also to risk of persistent
infection and/or gastric atrophy develop­ment.
In addition, the attribution to each step may be
different among different ethnic groups.
Future perspective
Since some individuals do not become infected
with H.  pylori after exposure to the bacte-
rium; therefore, genetic traits against H. pylori
Genetic traits for the persistence of H. pylori infection Review
colonization in the stomach may exist. Although
the definite genotypes against H. pylori infection
have not been identified so far, several polymor-
phisms potentially playing a role in creating
high-risk conditions for H. pylori colonization
were introduced in this article. Further studies,
including genome-wide association studies, could
detect the more influential genotypes.
Elucidation of genetic traits against H. pylori
colonization will provide data on the mecha-
nisms underlying persistent H. pylori infection.
These data could be useful for identifying the
types of lifestyles that have the same effects
as the genotypes. Treatments for eradication,
other than antibiotics, might be discovered.
Although blockage of the infection routes
is the most effective method of avoiding dis-
ease for uninfected individuals, a personalized
approach to interrupting the persistence of
H. pylori infection based on genetic traits will
contribute to the reduction of H. pylori-related
diseases. In addition, knowledge of the relevant
genetic traits will be useful for personalized
medication for H. pylori eradication treatments.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial
involvement with any organization or entity with a finan-
cial interest in or financial conflict with the subject matter
or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or
options, expert testimony, grants or patents received or
pending, or royalties.
No writing assistance was utilized in the production of
this manuscript.

Executive summary
ƒƒ The favorable conditions for Helicobacter pylori survival in the human stomach may be influenced by gastric acid secretion, innate
immune responses and adhesion of the bacterium to gastric epithelial cells.
ƒƒ Molecules responding to lipopolysaccharide, peptidoglycans, g-d-glutamyl-meso-diaminopimelic acid and blood group antigen-binding
adhesin from H. pylori have been identified in the signal-transduction-causing host responses.
ƒƒ Functional polymorphisms of IL-1B and TNF-A were associated with seropositivity, possibly through the mechanisms of gastric acid
secretion inhibition.
ƒƒ Although several genetic polymorphisms involved in innate immune responses and H. pylori adhesion have been examined, consistently
significant associations with persistent infection were not found.
ƒƒ The association with H. pylori infection could only be successfully examined among populations that are highly exposed to H. pylori.

2 Banatvala N, Mayo K, Megraud F, Jennings R, 5 Tsugane S, Tei Y, Takahashi T,

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