Influence of peroxisome proliferator-activated receptor (PPAR)gamma Plo12Ala polymorphism as a shared risk marker for both gastric cancer and impaired fasting glucose (IFG) in Japanese.

Abstract

Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) has been shown to inhibit the proliferation of gastric cancer cells. A common polymorphism at codon 12 of this gene (Pro12Ala) has been shown to confer protection against diabetes and colorectal cancer. We investigated the influence of PPARgamma gene Plo12Ala polymorphism on the risk of gastric cancer and on the severity of Helicobacter pylori-induced gastritis as well as impaired fasting glucose (IFG) in Japanese. About 215 patients with gastric cancer (GC) and 201 patients without GC enrolled in this study. Plo12Ala polymorphism of PPARgamma was investigated by PCR-RFLP in all of the subjects. The gastritis score of noncancerous antral mucosa was calculated by the updated Sydney system. The diagnosis of IFG was based on repeated evidence of serum fasting glucose (SFG) concentration of greater than or equal to 110 mg/dl. The Plo12Ala genotype of PPARgamma showed a significantly higher frequency in GC patients than in controls (OR = 2.43; 95%CI = 1.04-5.67). In contrast, the Plo12Ala genotype held a lower risk of IFG (OR = 0.33; 95%CI = 0.13-0.83). The same genotype was associated with an increased risk of non-cardiac gastric cancer (OR = 2.39; 95%CI = 1.02-5.65), lower third gastric cancer (OR = 3.56; 95%CI = 1.31-9.71), advanced cancer (OR = 2.93; 95%CI = 1.13-7.58), and Lauren's intestinal cancer (OR = 2.94; 95%CI = 1.13-7.66). Among 151 gastric cancer subjects, the atrophy and metaplasia scores of the antral mucosa adjacent to cancer showed a tendency to be higher in those with the 12Ala allele. Our study suggests that the PPARgamma Pro12Ala polymorphism may be a shared risk marker of both IFG and gastric cancer in Japanese.

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ORIGINAL PAPER
Influence of Peroxisome Proliferator-activated Receptor (PPAR)c
Plo12Ala Polymorphism as a Shared Risk Marker for Both
Gastric Cancer and Impaired Fasting Glucose (IFG) in Japanese
Tomomitsu Tahara Æ Æ Tomiyasu Arisawa Æ Æ Tomoyuki Shibata Æ Æ
Masakatsu Nakamura Æ Æ Fangyu Wang Æ Æ Naoko Maruyama Æ Æ Yoshio Kamiya Æ Æ
Masahiko Nakamura Æ Æ Hiroshi Fujita Æ Æ Mitsuo Nagasaka Æ Æ Masami Iwata Æ Æ
Kazuya Takahama Æ Æ Makoto Watanabe Æ Æ Ichiro Hirata Æ Æ Hiroshi Nakano
Received: 11 May 2007/Accepted: 17 July 2007/Published online: 1 September 2007
? Springer Science+Business Media, LLC 2007
Abstract
receptor c (PPARc) has been shown to inhibit the prolif-
eration of gastric cancer cells. A common polymorphism at
codon 12 of this gene (Pro12Ala) has been shown to confer
protection against diabetes and colorectal cancer. We
investigated the influence of PPARc gene Plo12Ala poly-
morphism on the risk of gastric cancer and on the severity
of Helicobacter pylori-induced gastritis as well as impaired
fasting glucose (IFG) in Japanese. About 215 patients with
gastric cancer (GC) and 201 patients without GC enrolled
in this study. Plo12Ala polymorphism of PPARc was
investigated by PCR-RFLP in all of the subjects. The
gastritis score of noncancerous antral mucosa was calcu-
lated by the updated Sydney system. The diagnosis of IFG
was based on repeated evidence of serum fasting glucose
(SFG) concentration of greater than or equal to 110 mg/dl.
The Plo12Ala genotype of PPARc showed a significantly
higher frequency in GC patients than in controls (OR =
2.43; 95%CI = 1.04–5.67). In contrast, the Plo12Ala
genotype held a lower risk of IFG (OR = 0.33; 95%CI =
0.13–0.83). The same genotype was associated with an
increased risk of non-cardiac gastric cancer (OR = 2.39;
95%CI = 1.02–5.65), lower third gastric cancer (OR =
3.56; 95%CI = 1.31–9.71), advanced cancer (OR = 2.93;
Activation of peroxisome proliferator-activated
95%CI = 1.13–7.58),
(OR = 2.94; 95%CI = 1.13–7.66). Among 151 gastric
cancer subjects, the atrophy and metaplasia scores of the
antral mucosa adjacent to cancer showed a tendency to be
higher in those with the12Ala allele. Our study suggests
that the PPARc Pro12Ala polymorphism may be a shared
risk marker of both IFG and gastric cancer in Japanese.
andLauren’s intestinal cancer
Keywords
Peroxisome proliferator-activated receptor (PPAR)c ?
Polymorphism ? Impaired fasting glucose (IFG)
Gastric cancer ?
Introduction
Gastric cancer remains a significant worldwide health
burden Although the incidence of and mortality due to non-
cardiac gastric cancer have been decreasing over the last
few decades, it still remains second only to lung cancer as
the leading cause of cancer mortality worldwide [1, 2].
Helicobacter pylori infects the human stomach and causes
chronic mucosal inflammation. Although, it has been
classified as a carcinogen [3], there is marked variation in
the extent of gastric inflammation among H. pylori-infec-
ted patients, and only a small percentage of them actually
develop gastric cancer. This suggests that genetic factors
may also play an important role in gastric carcinogenesis.
The peroxisomeproliferator-activated
(PPARs) are ligand-dependent transcription factors that are
members of the nuclear receptor superfamily [4]. At least
three different PPAR subtypes (a, b, and c) have been
described [5]. PPARc is highly expressed in adipocytes and
is responsible for the regulation of adipocyte differentiation
and glucose homeostasis, but it has also been suggested to
act as a regulator of cell proliferation and the inflammatory
receptors
T. Tahara (&) ? T. Arisawa ? T. Shibata ? M. Nakamura ?
F. Wang ? N. Maruyama ? Y. Kamiya ? M. Nakamura ?
H. Fujita ? M. Nagasaka ? M. Iwata ? K. Takahama ?
M. Watanabe ? I. Hirata
Department of Gastroenterology, Fujita Health University
School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho,
Toyoake, Aichi 470-1192, Japan
e-mail: tomomiccyu@yahoo.co.jp
H. Nakano
Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho,
Toyoake, Aichi 470-1192, Japan
123
Dig Dis Sci (2008) 53:614–621
DOI 10.1007/s10620-007-9944-8

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response [6]. When activated by specific ligands, PPARc
forms heterodimers with retinoid X receptor (RXR), which
regulate the expression of target genes by binding to the
peroxisome proliferator-responsive element (PPRE) [7, 8].
Expression of PPARc also has been demonstrated in other
tissues, including the colon, stomach, small intestine, liver,
and pancreas [9]. Recently, it was reported that PPARc
activation had an inhibitory effect on the proliferation of
gastric cancer cells [10]. Furthermore, it has been demon-
strated that PPARc activation can inhibit gastric mucosal
inflammation and apotosis induced by H. pylori [11].
These findings suggest that PPARc may play a significant
role in suppressing gastric mucosal inflammation and tu-
morgenesis by gastric epithelial cells.
Studies on the PPARc gene (PPARG) have identified a
number of polymorphisms, including one that causes an
amino acid substitution, Pro12Ala [12]. This substitution
may significantly alter the conformation of PPARc protein,
and thus may influence its activity. The PPARc Ala allele
has been reported to show decreased binding to the pro-
moter element and demonstrates weaker transactivation of
responsive promoters in vitro [13].
Some authors have reported that the PPARc Pro12Ala
polymorphism confers protection against diabetes and colo-
rectal cancer [14–18]. Concerning the effect of PPARc
Pro12Ala polymorphism on gastric carcinogenesis, however,
one recent study found that the PPARc 12Ala allele increases
theriskofgastriccancerinChina[19].Inthepresentstudy,we
investigated the influence of PPARc Pro12Ala polymorphism
on the risk of gastric cancer as well as diabetes or impaired
fasting glucose (IFG) in Japanese. We also investigated its
association with various subtypes and clinicopathologic fea-
turesofgastriccancer.Furthermore,weinvestigatedtheeffect
of this polymorphism on the histologic severity of H. pylori-
induced gastritis.
Materials and methods
Study population
We studied 416 patients attending the Gastroenterology
Division of Fujita Health University Hospital (Aichi, Japan)
from January 2005 to January 2006. The 416 patients
contained 215 patients with gastric cancer (GC) who had a
mean age of 64.7 (29–93) years and a male:female (M:F)
ratio of 153:62 and 201 non-cancer patients who had a mean
age of 63.1 (30–90) years and a M:F ratio of 122:79. Non-
cancer patients underwent endoscopic examination for the
complaint of abdominal discomfort and were diagnosed as
having gastric ulcer, duodenal ulcer, gastritis or normal
appearances. Gastric and duodenal ulcer patients were all
selected from H. pylori-positive subjects. Meanwhile, the
diagnosis of gastritis was made by endoscopists when
endoscopic appearances such as erosion and reddish spots
were observed irrespective of H. pylori infection status. GC
was diagnosed histologically and was classified according
to Lauren’s classification [20]. Detailed information was
obtained about the stage, anatomical location, venous and
lymphatic invasion, lymph node metastasis, distant metas-
tasis, and peritoneal dissemination. Patients who had severe
systemic disease and had received non-steroidal anti-
inflammatory drugs were excluded from this study. The
Ethics Committee of Fujita Health University School of
Medicine approved the protocol and written informed
consent was obtained from all of the subjects.
Assessment of diabetes or impaired fasting glucose
(IFG)
The diagnosis of impaired fasting glucose was based on
repeated evidence of serum fasting glucose (SFG) concen-
tration of greater than or equal to 110 mg/dl. Meanwhile,
the patients who had a SFG concentration of \110 mg/dl
were considered as non-IFG.
Histological examination
Biopsy specimens were obtained from the uninvolved
mucosa of the gastric antrum adjacent to cancer for
assessment of gastritis. The extent of neutrophil infiltration,
mononuclear cell infiltration, atropy, and metaplasia was
assessed according to the updated Sydney system [21], with
each factor being scored from 0 (normal) to 3 (marked).
Detection of H. pylori infection
The H. pylori infection status was determined on the basis
of histology, culture, the rapid urease test (RUT), and
antibodies to H. pylori. Infection was diagnosed when at
least one of these four tests was positive.
Genotyping
Genomic DNA was extracted from frozen normal gastric
biopsy tissues or peripheral blood cells using the standard
phenol/chloroform method. Then PPARc Pro12Ala poly-
morphism was determined by the polymerase chain
reaction-restriction fragment length polymorphism tech-
nique, as described previously [22]. The forward primer
was 50-ctgatgtcttgactcatggg-30, and the reverse primer was
50-ggaagacaaactacaagagc-30. PCR was carried out in a
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reaction volume of 25 ll containing 20 lg of genomic
DNA, 1· reaction buffer, 0.125 mmol/l deoxynucleotide
triphosphates, 10 pmol of each primer, and 0.6 units of Taq
polymerase (Toyobo, Osaka, Japan). DNA was denatured
at 95?C for 5 min, followed by 35 cycles of 95?C for 30 s,
53?C for 30 s, and 72?C for 40 s, with final extension at
72?C for 7 min. Then digestion with 5 units of Hga-I (New
England Biolabs, Inc., Bevely, MA) was employed to
analyze PPARc Pro12Ala polymorphism, yielding products
of 295 bp (Pro) and 178 + 117 bp (Ala). Digestion was
performed overnight at 37?C, the products were separated
on a 3% agarose gel, and were stained with ethidium
bromide for visualization. Genotypes were determined by
two independent investigators who were blinded to patient
data.
Statistical analysis
The v2test was used for comparison of PPARc genotype
frequencies between the GC and control groups. The odds
ratio (OR) and 95% confidence interval (CI) were calcu-
lated by logistic regression with adjusment for age, sex,
and H. pylori infection status. For the comparison of of
PPARc genotype frequencies between the IFG and non-
IFG patients, logistic regression with adjusment for age and
sex was performed. Differences of gastritis scores between
the two PPARc genotypes (Ala carriers and Pro/Pro) were
examined by the Mann-Whitney U test. A probability value
of less than 0.05 was considered statistically significant in
all analyses.
Results
Study population
A total of 416 subjects including 215 GC and 201 non-
cancer patients participated in this study. The characteris-
tics of the subjects are summarized in Table 1. There were
no significant differences between the two groups with
respect to the age distribution, but male sex and H. pylori
infection were significantly more common in the GC group.
The main endoscopic diagnoses in the control group were
gastric ulcer in 39 patients (19.4%), duodenal ulcer in 16
patients (8%), gastric + duodenal ulcer in four patients
(2%), and gastritis in 142 patients (70.6%). SFG concen-
tration was measured in 396 of all 416 patients and 164
patients with IFG who had a mean age of 66.5 (33–93) years
and a male:female (M:F) ratio of 112:52, as well as 232
non-IFG patients who had a mean age of 62.4 (29–90) years
and a M:F ratio of 146:86 were identified. There were no
significant differences between IFG patients and non-IFG
patients with respect to sex and occurrence of GC, but age
distribution was significantly higher in the IFG patients
(Table 2).
PPARc genotype
PPARc Pro12Ala polymorphism was investigated in all
416 subjects. The frequency of Pro12Ala polymorphism in
the non-cancer patients did not deviate significantly from
that expected under the Hardy–Weinberg equilibrium and
also did not show any significant difference from the
genotype distribution revealed by other studies performed
in Japanese populations (v2= 0.08, P = 0.77) [23]. There
were no subjects homozygous for the Ala12 allele of the
PPARc gene. First, we compared the prevalence of
Pro12Ala polymorphism between IFG patients and non-
IFG patients by logistic regression analysis and found that
the Pro12Ala genotype held a lower risk of IFG (age and
sex adjusted OR = 0.33; 95%CI = 0.13–0.83) (Table 3). In
contrast, comparison of the genotype frequency between
the GC and control groups showed that the PPARc
Pro12Ala genotype was associated with a significantly
higher risk of gastric cancer (OR = 2.43; 95%CI = 1.04–
5.67) (Table 4). To investigate whether the PPARc Ala12
allele influenced the clinicopathologic features of gastric
cancer, the tumor location, stage, Lauren’s classification,
lymphatic and venous invasion, lymph node metastasis,
peritoneal dissemination, and distant metastasis were
included ina stratifiedanalysis.Amongthese
Table 1 Characteristics of subjects
Gastric cancer
(GC) cases
Patients
without GC
P
Subjects (n)
Sex [male/female (%/%)] 153/62 (71/29) 122/79 (61/39) 0.03a
215201
Mean age ± SD
(years)
64.7 ± 11.963.1 ± 12.6 0.46b
H. pylori infection
positive ratio (%)
85.170.6 0.0005a
av2test,bMann–Whitney U test
Table 2 Characteristics of subjects
IFG casesPatients without
IFG
P
Subjects (n) 164 232
Sex [male/female (%/%)] 112/52 (68/32) 146/86 (63/37) 0.27
0.001b
0.36a
Mean age ± SD (years) 66.5 ± 11.668.9 ± 10.45
GC patients/patients
without GC
89/75115/117
av2test,bMann–Whitney U test
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clinicopathologic features, we found that PPARc Pro12Ala
polymorphism increased the risk of non- cardiac gastric
cancer (OR = 2.39; 95%CI = 1.02–5.65), lower third gas-
tric cancer (OR = 3.56; 95%CI = 1.31–9.71), advanced
cancer (OR = 2.93; 95%CI = 1.13–7.58), and Lauren’s
intestinal cancer (OR = 2.94; 95%CI = 1.13–7.66). We
also found that the Ala12 allele tended to increase the risk
of venous invasion (OR = 3.12; 95%CI = 0.98–9.93) and
lymph node metastasis (OR = 2.38; 95%CI = 0.89–6.40)
(Table 5), but there was no association between this allele
and peritoneal dissemination or distant metastasis. In the
control group, there were no significant genotype differ-
ences among the patients with gastric ulcer, duodenal ulcer,
and gastritis (data not shown).
Effect of PPARc polymorphism on the severity of
gastritis in noncancerous gastric mucosa adjacent to
cancer
Among all 21 subjects with 12Ala allele and randomly
selected age, sex matched 130 subjects with homozygous
for the Plo12 allele, the atrophy and metaplasia scores of
the antral mucosa showed a tendency to be higher in those
prossessing the 12Ala allele (Table 6), but the neutrophil
infiltration and mononuclear cell infiltration scores did not
show any correlation between the 12 Ala carriers and
subjects homozygous for the Plo12 allele.
Discussion
In two Japanese populations, the frequency of the common
polymorphism of PPARc Ala12 allele was shown to be
significantly lower in individuals with type 2 diabetes than
in normal subjects [14, 15]. In addition, the same genotype
was also associated with reduced risk of colorectal cancer
[17, 18], suggesting that this allele may confer protection
against diabetes and colorectal cancer. In our study, we
have also shown the frequency of Ala12 allele was signi-
fiantly lower among IFG patients. This indicates that the
Ala12 allele may be associated with lower risk of both
diabetes and IFG. Meanwhile, in agreement with a recent
study performed in China [19], we found that the Ala12
allele is associated with the risk of gastric cancer in a
Japanese population. The Ala12 allele frequency was sig-
nificantly higher in patients with gastric cancer than in
controls. In 1998, Deeb et al. reported that Pro12Ala
polymorphism of PPARc was associated with reduced
transactivation activity [13]. Activation of PPARc has been
shown to inhibit cell growth and to induce the apoptosis of
gastric cancer cells [10]. Although we did not investigate
the effect of PPARc polymorphism on PPARc activity in
human gastric epithelial cells, it is possible that the poly-
morphism might have altered the activity of PPARc. Thus,
it seems reasonable for the 12Ala allele to be a risk factor
for gastric cancer.
PPARc 12Ala allele has been shown to be associated
with reduced risk of colorectal cancer and diabetes [14–
18]. Presence of the Pro12Ala variant polymorphism is
reported to be associated with lower body mass index
(BMI), improved insulin sensitivity, and a reduced risk for
type 2 diabetes [14–16]. Therefore, it is possible that
PPARc is associated with risk for colorectal cancers
through insulin-related mechanisms.
However, in the stomach, experimental studies have
actually demonstrated that activation of PPAR gamma
inhibited the growth of gastric cancer cells and suppressed
the gastric mucosal inflammation [10, 11, 33]. Considering
the function of PPAR gamma in the stomach, our result of
PPAR gamma 12Ala allele, which is associated with
reduced promoter activity, of increasing the risk of gastric
cancer and gastric atrophy may suggest that gastiric car-
cinogenesis may have different genetic background to
colorectal carcinogenesis in some measure.
Next, we investigated the effect of PPARc Pro12Ala
polymorphism on the characteristics of gastric cancer by
stratified analysis, and found that the Ala12 allele was
associated with a higher risk of non-cardiac, or lower third
cancer and intestinal cancer. These results may be explained
by both the anti-tumor effect [10, 24] and the anti-inflam-
matory effect [11, 25–27] of PPARc. Correa et al. reported
Table 3 Association between PPARc polymorphism and risk of IFG
Variables (n)Genotype Pro/Pro vs. Pro/Ala
Pro/ProPro/AlaOR (95%CI)
P
Patients without
IFG (201)
20923Reference
IFG (215) 1586 0.33 (0.13–0.83) 0.02
Data are adjusted for sex and age
Table 4 Association between
PPARc polymorphism and risk
of gastric cancer
Data are adjusted for sex, age,
and H. pylori infection status
Variables (n) GenotypePro/Pro vs. Pro/Ala
Pro/Pro Pro/AlaOR (95%CI)
P
Patients without GC (201)1938Reference
Overall GC (215)19421 2.43 (1.04–5.67) 0.04
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that gastric atrophy and metaplasia following severe
inflammation are an especially strong risk factor for
developing the intestinal type of gastric cancer [28, 29].
Uemura et al. also reported that severe gastric atrophy,
corpus-predominant gastritis, and intestinal metaplasia are
strong risk factors for the development of intestinal-type
gastric cancer [30]. PPARc Pro12Ala polymorphism may
influence both the anti-tumor and anti-inflammatory actions
of PPARc and thus may modify the risk of developing
intestinal gastric cancer, which frequently arises from a
background of severe atrophic gastritis in the non-cardiac
and lower third regions.
We have also showed that the Ala12 allele is associated
with the risk of more advanced stage. Similarly, Ala12
allele also tended to be associated with a higher risk of
venous invasion and lymph node metastasis, possibly due
to anti-angiogenetic and anti-metaplastic effects of PPARc.
For example, PPARc ligands suppress angiogenesis by
induction of apoptosis in endothelial cells [31, 32]. Acti-
vation of PPARc has also been shown to inhibit peritoneal
metastasis by gastrointestinal cancer cells [33], while a
decrease of PPARc activity has been found in some cancers
with metastasis [34, 35]. Thus, PPARc may play a key role
in suppressing the progression and metastasis of gastric
Table 5 Association between
PPARc polymorphism and
clinicopathologic features of
gastric cancer
All data are adjusted for sex,
age, and H. pylori infection
status
Variables (n)Genotype Pro/Pro vs. Pro/Ala
Pro/Pro Pro/AlaOR (95%CI)
P
Patients without GC (201)1938 Reference
Tumor location
Cardia (6)514.97 (0.48–51.40)0.18
Non-cardia (209)190 192.39 (1.02–5.65) 0.049
Upper third (17)1612.50 (0.27–23.11) 0.42
Middle third (101) 929 2.04 (0.74–5.65)0.17
Lower third (87) 779 3.56 (1.31–9.71)0.01
Staging
Early (105)9692.03 (0.74–5.54) 0.17
Advanced (91) 80112.93 (1.13–7.58)0.03
Lauren’s classification
Intestinal type (124) 111 132.94 (1.13–7.66)0.03
Diffuse type (90) 827 2.21(0.79–6.21)0.14
Lymphatic invasion
Positive (97) 889 2.21(0.80–6.08) 0.13
Negative (74)677 2.39 (0.82–7.02)0.11
Venous invasion
Positive (50) 44 63.12 (0.98–9.93) 0.053
Negative (121)111 101.93 (0.72–5.14)0.19
Lymph node metastasis
Positive (101) 89122.38 (0.89–6.40) 0.08
Negative (114) 10681.96 (0.72–5.34)0.19
Peritoneal dissemination
Positive (33) 294 3.19 (0.88–11.58) 0.08
Negative (182)166 162.31(0.96–5.58) 0.06
Distant metastasis
Positive (19)17 22.86 (0.55–14.82)0.21
Negative (196)177 192.36 (0.99–5.63) 0.053
Table 6 Association between
genotypes and histologic scores
in noncancerous gastric antral
mucosa adjacent to cancer
Scores shown are mean ± SD.
Mann–Whitney U test
Genotype (n)Pro/Pro(130) Pro/Ala(21)
P
Neutrophil infiltration 0.85 ± 0.461.00 ± 0.32 0.14
Mononuclear cell infiltration1.65 ± 0.620.9 ± 0.640.1
Atrophy1.09 ± 0.761.4 ± 0.820.09
Intestinal metaplasia1.42 ± 1.031.85 ± 0.460.08
618Dig Dis Sci (2008) 53:614–621
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cancer, so that PPARc Pro12Ala polymorphism may also
influence these complications. With regard to the associa-
tion betweenPPARc
polymorphism
dissemination or distant metastasis, we expected that the
12Ala allele would be associated with the risk of these
complications. However, no correlation was observed
between the 12Ala allele and the risk of such complica-
tions, possibly because the number of patients with
peritoneal dissemination and distant metastasis in this
study was small, suggesting that further investigation is
needed in a larger population.
We also showed that the PPARc 12Ala allele is asso-
ciated with the severity of gastric mucosal atrophy and
intestinal metaplasia. Among 151 gastric cancer subjects,
the atrophy and metaplasia scores of the antral mucosa
showed a tendency to be higher in those prossessing the
12Ala allele. Gastric mucosal atrophy and intestinal
metaplasia are caused by chronic exposure to inflammation
induced by H. pylori infection. PPARc has an anti-
inflammatory effect by regulating the expression of various
genes associated with inflammation, and such an effect also
occurs in persons with H. pylori-related gastritis. Solimi-
any et al. reported that PPARc activation by administration
of ciglitazone led to a dose-dependent reduction in the
severity of mucosal inflammatory elicited by H. pylori LPS
[27]. Rajnish et al. also reported that two PPARc ligands
(15dPGJ2 and BRL-49653) significantly attenuated H.
pylori-induced apoptosis, while co-treatment with PPARc
agonists blocked the ability of H. pylori to activate nuclear
factor (NF)-jB and increase the level of IL-8, a target of
(NF)-jB [11]. Because of the important role that PPARc
plays with respect to the inflammatory response in H.
pylori-induced gastritis, PPARc Pro12Ala polymorphism,
associated with PPARc activity, may also be important for
determining the severity of gastric mucosal atrophy.
However, we did not find any association between PPARc
Pro12Ala polymorphism and acute or chronic inflamma-
tion. Progression of atrophic gastritis is terminated by the
development of extensive intestinal metaplasia, so patients
with severe atrophic gastritis and intestinal metaplasia
often have mild, but not severe inflammation. However, it
should be noted that they had had long-term prior exposure
to severe mucosal inflammation.
Regarding the histological differences in gastritis, it has
been suggested that patients with gastric ulcer have more
severe gastric mucosal atrophy and have increased risk of
gastric cancer compared to those with duodenal ulcer [29,
36, 37].
But in this study, frequencies of PPARc genotypes were
not significantly different among patients with gastric
ulcer, duodenal ulcer, and gastritis. In addition, when
patients with peptic ulcer were included in non-cancer
patients, the frequency of PPARc 12Ala polymorphism
andperitoneal
over all non-cancer patients did not deviate from the fre-
quency of healthy controls reported in previous studies. So
we considered the group of patients was appropriate as
control subjects in this study.
Although we showed that the PPARc 12Ala allele held a
higher risk of gastric mucosal atrophy, which supports the
result of suppressive effect of PPARc against H. pylori-
induced gastric inflammation in vitro, previous studies have
also demonstrated the direct suppressive effect of PPARc
against gastric cancer cells and their metastasis. Our data
suggest that PPAR gamma polymorphism may be an
important factor, which determines the risk of developing
gastric cancer by diverse mechanisms, not only by increasing
the more severe gastric mucosal atrophy. In this study, we
assessed the histological severity of gastric mucosal atrophy
and intestinal metaplasia only in the antrum. It is well known
that the serum peptinogen (PG) I/II ratio also reflects the
severity of gastric mucosal atrophy [38]; future study will be
needed to confirm the association of PPARc genotype and
gastric mucosal atrophy using such markers.
In conclusion, the present study demonstrated that
PPARc Pro12Ala polymorphism was associated with
reduced risk of IFG, but in contrast, the same genotype was
also associated with more severe gastric mucosal atrophy,
with intestinal metaplasia, and with an increased risk of
gastric cancer, especially the intestinal type, non-cardiac
cancer, lower third cancer, and advanced cancer, venous
invasion, and lymph node metastasis, suggesting that the
PPARc Pro12Ala polymorphism may be a shared risk
factor for both IFG and gastric cancer. However, we only
investigated PPARc polymorphism in a limited region of
Japan. Since the PPARc gene polymorphism shows varia-
tions in different ethnic groups [39], further studies will be
needed in a larger and ethnically diverse population to
confirm the influence of this gene on gastric carcinogenesis
as well as developing IFG.
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