1920
Interleukin-1B Polymorphisms and Gastric Cancer
Risk—A Meta-analysis
Farin Kamangar, Cindy Cheng, Christian C. Abnet, and Charles S. Rabkin
Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland
Abstract
Some studies have reported that proinflammatory poly-
morphisms in interleukin-1B (IL-1B) and IL-1 receptor
antagonist (IL-1RN) genes are associated with increased
gastric cancer risk. However, other studies have shown null
or inverse associations. This meta-analysis reviews and
summarizes published evidence for these associations.
Searching the PubMed Database yielded 35 studies that
reported on the association between IL-1B
511 C>T, IL-1B

31 T>C, or IL-1RN variable number tandem repeat
polymorphisms and gastric cancer risk. Q-statistics and
I 2 statistics were calculated to examine heterogeneity.
Summary odds ratios (OR) and 95% confidence intervals
(95% CI) were calculated in the random-effects model using
the DerSimonian-Laird method. For all gastric cancers, the
overall ORs (95% CIs) for IL-1B
511 CT versus CC and TT
versus CC genotypes were 1.07 (0.91-1.25) and 1.16 (0.95-1.42),
respectively. ORs (95% CIs) for the association between
Introduction
Helicobacter pylori infection is the most important identified
risk factor for gastric cancer. However, <3% of individuals
infected with H. pylori are ever diagnosed with gastric cancer
(1). Variations in cancer risk in H. pylori – infected individuals
may, in part, be attributed to genetic predisposition.
A study published in Nature showed for the first time that
polymorphisms in interleukin-1B (IL-1B) and IL-1RN genes
were associated with gastric cancer risk (2). These two genes,
respectively, encode for IL-1h, a strong proinflammatory
cytokine, and IL-1 receptor antagonist, an anti-inflammatory
cytokine that competes with IL-1 in binding to its receptor.
Two linked IL-1B single nucleotide polymorphisms that
increase IL-1h expression (
511 C>T) and (
31 T>C) were
associated with a 2- to 3-fold increased risk of gastric cancer
(2). The IL-1RN gene has a penta-allelic variable number
tandem repeat polymorphism and allele 2 (IL-1RN*2), which
encodes for only two repeats, was associated with a higher risk
of gastric cancer than other alleles, which encode for longer (L)
repeats. Several subsequent studies also found an association
between IL-1B
511 T and
31 C and IL-1RN*2 and increased
gastric cancer risk (3-6). Some of these studies found an
association only with certain anatomic subsites (i.e., noncardia;
ref. 3) or histologic subtypes (i.e., intestinal type; ref. 6) of
gastric cancer. In contrast, several other studies failed to find
an association between these polymorphisms and gastric
cancer or its anatomic and histologic subtypes.
Submitted 3/31/06; revised 7/14/06; accepted 8/9/06.
Grant support: Intramural Research Program of the NIH, National Cancer Institute.
The costs of publication of this article were defrayed in part by the payment of page charges.
This article must therefore be hereby marked advertisement in accordance with 18 U.S.C.
Section 1734 solely to indicate this fact.
Requests for reprints: Farin Kamangar, Division of Cancer Epidemiology and Genetics,
National Cancer Institute, NIH, 6120 Executive Boulevard, Room 3034, Bethesda, MD 20892-
7232. Phone: 301-594-2936; Fax: 301-496-6829. E-mail: kamangaf@mail.nih.gov
Copyright D 2006 American Association for Cancer Research.
doi:10.1158/1055-9965.EPI-06-0267
Cancer Epidemiol Biomarkers Prev 2006;15(10). October 2006
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IL-1B
31 CT versus TT and CC versus TT genotypes were
0.99 (0.83-1.19) and 0.98 (0.78-1.21), respectively. For the
associations between IL-1RN and gastric cancer, ORs
(95% CIs) for *2/L versus LL and *2/*2 versus L/L were 1.15
(0.96-1.38) and 1.23 (0.79-1.92). For each of the examined
associations, there was significant heterogeneity among
studies; P heterogeneity V 0.001 and I 2 ranged from 0.54 to 0.71.
Noncardia cancers showed stronger associations with IL-1B

511 CT or TT and IL1-RN *2/*2 genotypes, but limiting
the analysis to intestinal-type cancers, studies conducted in
Western countries, or studies in which polymorphisms were
in Hardy-Weinberg equilibrium, made no material differ-
ence in the results. The overall associations between IL-1B
or IL-1RN proinflammatory polymorphisms and gastric
cancer were null but several studies showed an association.
The sources of this variation are unclear. (Cancer Epidemiol
Biomarkers Prev 2006;15(10):1920 – 8)
In this meta-analysis, we review studies that have examined
the associations between IL-1B
511, IL-1B
31, and IL-1RN
polymorphisms and gastric cancer risk. Where possible, we
also review these associations by anatomic or histologic
subtypes of gastric cancer.
Materials and Methods
Selection of Studies. We searched the PubMed Database for
all articles that were published by January 19, 2006 on the
association between IL-1B polymorphisms and gastric cancer
risk. The following terms were used in this search: (IL-1B or
IL-1 or interleukin or cytokine) and (gastric cancer or stomach
cancer) and (polymorphism or polymorphisms).
Using these terms, a total of 131 articles were retrieved, of
which 40 (2-41) reported on studies examining the associations
between IL-1B or IL1-RN polymorphisms and gastric
adenocarcinoma. Two articles included data from two geo-
graphic regions (25, 39). We considered each region a separate
study. Therefore, a total of 42 studies were identified. Five
studies (4, 6, 10, 15, 34) were excluded from this analysis
because their results were repeated in subsequent publications
(5, 22, 35, 39). Two more studies (30, 38) were excluded because
complete data on genotypes were not presented in the articles.
Therefore, a total of 35 studies were used for calculating
summary statistics.
Statistical Analysis. All analyses were done using STATA
software, version 8.0 (STATA Corp., College Station, TX).
Throughout the article, two-sided Ps < 0.05 were considered as
statistically significant.
For IL-1B
511, numbers and percentages of CC, CT, and TT
genotypes were extracted by case status, and odds ratios (OR)
and 95% confidence intervals (95% CI) were calculated for CT
and TT (the proinflammatory genotypes) versus CC genotype.
The Q-statistics for homogeneity (using Mantel-Haenszel
weights) and the I 2 statistics (42) were calculated. The
 Cancer Epidemiology, Biomarkers & Prevention 1921

Table 1. Study characteristics

c
First author Study location* Year No. cases/ Source of % IL-1B % IL-1B HWE HWE m2,
b
controls control selection
511 T
31 Cx
511, P k
31, P { P**

1. El-Omar Poland (W) 2000 366/429 Population based 30 30 0.10 0.07 0.99
2. Kato Japan (E) 2001 127/335 Clinic based 49 0.70
3. He China (E) 2002 50/50 Healthy volunteers 75 0.92
4. Zambon Italy (W) 2002 23/219 Clinic based 34 1.00
5. El-Omar United States (W) 2003 314/210 Population based 27 0.02
6. Lee SG Korea (E) 2003 190/172 Healthy volunteers 51 0.22
7. Machado Portugal (W) 2003 287/306 Healthy volunteers 34 0.27
8. Zeng-Guandong China (E) 2003 84/192 Healthy volunteers 34 90 0.17 0.52 0.001
9. Zeng-Shanxi China (E) 2003 86/169 Healthy volunteers 51 86 0.05 0.02 0.001
10. zur Hausen Netherlands (W) 2003 69/153 Healthy volunteers 34 0.90
11. Chen Taiwan (E) 2004 142/164 Healthy volunteers 51 0.08
12. Gatti Brazil (W) 2004 56/56 Healthy volunteers 57 48 0.001 0.11 0.10
13. Glas Gemany (W) 2004 88/145 Healthy volunteers 35 35 0.14 0.14 1.00
14. Hartland United Kingdom (W) 2004 59/287 Healthy volunteers 41 0.002
15. Kang Korea (E) 2004 242/97 Healthy volunteers 48 51 0.76 0.25 0.69
16. Lee KA Korea (E) 2004 331/433 Clinic based 54 55 0.49 0.79 0.94
17. Wu Taiwan (E) 2004 204/210 Clinic-based 45 45 0.10 0.17 0.98
18. Yang China (E) 2004 280/258 Population based 52 52 0.37 0.73 0.68
19. Alpizar-Alprizar Costa Rica (W) 2005 50/50 Clinic-based 57 59 0.66 0.73 0.96
20. Chang Korea (E) 2005 234/434 Clinic-based 52 52 0.007 0.005 0.99
21. Garza-Gonzalez Mexico (W) 2005 63/215 Clinic based 56 0.60
22. Lu China (E) 2005 250/300 Population based 51 54 0.13 0.99 0.28
23. Muramatsu Japan (E) 2005 89/96 Healthy volunteers 41 0.60
24. Palli Italy (W) 2005 185/546 Population based 34 0.44
25. Perri-North Italy (W) 2005 98/216 Healthy volunteers 36 0.95
26. Perri-South Italy (W) 2005 86/146 Healthy volunteers 32 0.85
27. Rocha Brazil (W) 2005 166/536 Healthy volunteers 45 0.82
28. Ruzzo Italy (W) 2005 138/100 Healthy volunteers 31 37 0.22 0.32 0.45
29. Sakuma Japan (E) 2005 140/103 Healthy volunteers 49 0.37
30. Sicinschi Mexico (W) 2005 158/317 Clinic based 65 0.006
31. Taguchi Japan (E) 2005 373/250 Healthy volunteers 46 0.27
32. Tatemichi Japan (E) 2005 156/176 Healthy volunteers 49 0.99
33. Vilaichione Thailand (E) 2005 39/91 Clinic based 52 0.001
34. Zhang China (E) 2005 154/166 Healthy volunteers 53 43 0.07 0.58 0.05
35. Kamangar Finland (W) 2006 112/207 Healthy cohort subjects 38 39 0.01 0.07 0.81

*W, Western country; E, East-Asian country.

cPublication year.
bPercent IL-1B
511 T allele in controls.
xPercent IL-1B
31 C allele in controls.
kP for HWE for IL-1B
511 polymorphism among controls.
{P for HWE for IL-1B
31 polymorphism among controls.

**P for consistency of the association of IL-1B
511 T and IL-1B
31 C polymorphisms.

Q-statistics were highly significant (P < 0.001) and I 2 (60%)
showed a high degree of heterogeneity. Therefore, we used
random-effects models (DerSimonian-Laird method; ref. 43) to
calculate summary ORs and 95% CIs (44, 45). To estimate the
sensitivity of the summary OR to the choice of model, we also
calculated and report the summary ORs and 95% CI using
fixed effects models (Mantel-Haenszel method). Similar
procedures were used for IL-1B
31 and IL-1RN. For IL-1B

31, ORs and 95% CIs were calculated for CC and CT
(the proinflammatory genotypes) versus TT genotype. For
IL-1RN, *2 was the proinflammatory allele, and ORs and 95%
CIs were calculated for *2/*2 and *2/L versus L/L.
Some of these studies found an association only with
certain anatomic subsites (i.e., noncardia; ref. 3) or histologic
subtypes (i.e., intestinal type; ref. 6) of gastric cancer.
Therefore, we calculated summary ORs and 95% CIs for
noncardia cancer, where genotype data were presented by
anatomic location, and for intestinal type cancer, where data
on histology was available. Seven, nine, and seven studies
reported data on IL-1B
511, IL-1B
31, and IL-1RN
polymorphisms, respectively, and noncardia cancer. Ten,
eight, and seven studies reported data on these same
polymorphisms, respectively, and intestinal-type cancer.
There is also a suggestion that proinflammatory polymor-
phisms in interleukins may be associated with higher risk of
gastric cancer in Western countries but not in East-Asian
countries. Therefore, study populations were classified as
Western (Europe, North, and Central America) versus East-
Asian (China, Japan, Korea, and Taiwan), and subgroup
analyses were done for each group. In all, 17 studies were
from Western and 18 studies were from East-Asian
countries.
We used three strategies to select studies that were less
likely to have had genotyping errors. First, for IL-1B
511 and

31, we examined the presence of Hardy-Weinberg equilibri-
um (HWE) and calculated summary ORs and 95% CIs for
studies, in which these alleles were in HWE among controls.
Second, using a m2 test with 2 degrees of freedom, we
examined the consistency of distributions of IL-1B
511 T
and IL-1B
31 C among controls (at a = 0.05) and calculated
summary ORs and 95% CIs for studies in which these two
distributions were consistent. This strategy was adopted
because IL-1B
511 T and IL-1B
31 C alleles are in near-
perfect linkage disequilibrium (46, 47). Third, ORs and 95% CIs
were calculated for studies, which passed both of these criteria
(i.e., alleles were in HWE and distributions of IL-1B
511
T and IL-1B
31 C were consistent).
In addition, we examined whether correcting for deviations
from HWE affected the overall results. Whereas the analyses
discussed in the previous paragraph excluded studies in
which genotypes violated HWE at a = 0.05, HWE correction
enabled all studies to be included. For this analysis, we
calculated expected genotype frequencies under HWE for
controls based on observed allele prevalences. We then
recalculated the ORs using the observed genotype frequencies
in cases and the HWE-expected genotype frequencies in

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1922 IL-1b Polymorphisms and Gastric Cancer

controls (48) and used the Lathrope estimate of variance to We also did cumulative meta-analysis to evaluate the trend
estimate 95% CIs (48). These corrections had negligible effects of summary ORs (95% CIs) by year of publication. Studies
on the results; therefore, the results are not shown in this were added one at a time according to year of publication and
report. the results were summarized as each new study was added.

Figure 1. Forest plot for the

association between IL-1B
511
CT versus CC and TT versus CC
genotypes and gastric cancer
risk, in order of publication year.
A. IL-1B
511 CT versus CC. B.
IL-1B
511 TT versus CC.

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 Cancer Epidemiology, Biomarkers & Prevention 1923

Figure 2. Forest plot for the association

between IL-1B
31 CT versus TT and CC
versus TT genotypes and gastric cancer risk,
in order of publication year. A. IL-1B
31
CT versus TT. B. IL-1B
31 CC versus TT.

Results respective prevalences were 50% and 52% in East-Asian

Overall, 35 studies with a total number of 5,503 cases and 7,865
controls were included in this analysis. Of these, 28, 22, and 26
studies presented data on IL-1B
511, IL-1B
31, and IL-1RN,
respectively. Study characteristics are summarized in Table 1.
Most studies used healthy volunteers or blood donors as
control subjects. The prevalence of IL-1B
511 T and IL-1B
31
C alleles ranged from 27% to 57%, and 30% to 90% in various
studies. Median prevalences of IL-1B
511 T and IL-1B
31 C
were 35% and 39% in Western populations, whereas these
populations.
IL-1B
511. Study-specific ORs (95% CIs) are shown in
Fig. 1. For all gastric cancers, the overall ORs (95% CIs)
associated with CT versus CC and TT versus CC genotypes
were 1.07 (0.91-1.25) and 1.16 (0.95-1.42), respectively. For
noncardia cancers, these ORs (95% CIs) were 1.26 (0.84-1.89)
for CT and 1.78 (0.92-3.47) for TT genotypes. For intestinal-type
gastric cancers, ORs (95% CIs) were 1.25 (0.98-1.59) and 1.35
(0.87-2.10), respectively. When we limited our analysis to

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1924 IL-1b Polymorphisms and Gastric Cancer
studies from Western countries, ORs (95% CIs) were 1.03
(0.76-1.39) and 1.32 (0.86-2.02), respectively. For East-Asian
studies, the corresponding numbers were 1.05 (0.90-1.23) and
1.03 (0.87-1.21), respectively.
IL-1B
31. Figure 2 summarizes the ORs and 95% CIs for
the associations between IL-1B
31 genotypes and gastric
cancer risk. For all gastric cancers, the overall ORs (95% CIs)
associated with CT versus TT and CC genotypes versus TT
genotypes were 0.99 (0.83-1.19) and 0.98 (0.78-1.21), respec-
tively. For noncardia cancers, ORs (95% CIs) were 0.96
(0.67-1.36) for CT and 0.91 (0.71-1.16) for CC genotypes.
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Limiting the results to intestinal-type cancers, these ORs
(95% CIs) were 1.05 (0.80-1.38) and 0.97 (0.62-1.51), respective-
ly. For studies from Western countries, summary ORs (95% CI)
were 1.13 (0.87-1.48) for CT and 1.21 (0.88-1.65) for CC
genotypes. For East-Asian studies, the corresponding figures
were 0.88 (0.70-1.10) and 0.82 (0.63-1.06), respectively.
IL-RN. As shown in Fig. 3, ORs (95% CIs) for the association
between IL-1RN L/*2 versus LL and *2/*2 versus L/L were
1.15 (0.96-1.38) and 1.23 (0.79-1.92), respectively. For noncardia
cancers, the ORs (95% CIs) were 1.08 (0.69-1.70) and 1.99
(0.69-5.81), respectively. For intestinal-type cancers, these ORs
Figure 3. Forest plot for the association
between IL-1RN L/*2 versus LL and *2/*2
versus L/L genotypes and gastric cancer risk,
in order of publication year. A. IL-1RN L/*2
versus LL. B. IL-1RN *2/*2 versus LL.
 Cancer Epidemiology, Biomarkers & Prevention 1925

Figure 4. Cumulative meta-analysis graph for IL-1B
511 CT versus CC and TT versus CC genotypes and risk of gastric cancer. A. IL-1B

511 CT versus CC. B. IL-1B
511 TT versus CC. Horizontal line, the summary of all results as each study is added rather than the results of a
single study.

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1926 IL-1b Polymorphisms and Gastric Cancer

(95% CIs) were 1.13 (0.63-2.01) for L/*2 and 1.53 (0.55-4.25) for
*2/*2. Among studies conducted in Western countries, these
ORs (95% CIs) were 1.14 (0.93-1.41) and 1.37 (0.84-2.23), re-
spectively. For studies conducted in East-Asian countries,
these ORs (95% CIs) were 1.21 (0.85-1.72) and 0.84 (0.29-2.44),
respectively.
Effect of HWE and Consistency of IL-1B
511 T and
31 C
on the Results. With a cut point of P = 0.05, IL-1B
511 and

31 were in HWE among controls in 23 of the 28 (82%) and 20
of the 22 (91%) studies that reported on these polymorphisms.
In these studies, the summary ORs (95% CIs) were 1.09
(0.92-1.30) for IL-1B
511 CT, 1.17 (0.97-1.42) for IL-1B
511
TT, 1.03 (0.85-1.25) for IL-1B
31 CT, and 0.98 (0.76-1.27) for
IL-1B
31 CC.
In 12 of the 15 (80%) studies that reported on both IL-1B

511 and IL-1B
31, the distribution of IL-1B
511 T was
consistent with that of IL-1B
31 C. In these studies, the
summary ORs (95% CIs) were 1.00 (0.80-1.25) for IL-1B
511
CT, 1.07 (0.78-1.46) for IL-1B
511 TT, 0.99 (0.79-1.23) for IL-1B

31 CT, and 1.01 (0.76-1.34) for IL-1B
31 CC.
When analysis was limited to the nine studies, in which the
polymorphisms were in HWE and the distribution of IL-1B

511 T was consistent with that of IL-1B
31 C, the summary
ORs (95% CIs) were 1.05 (0.82-1.34) for IL-1B
511 CT, 1.16
(0.79-1.71) for IL-1B
511 TT, 1.01 (0.80-1.28) for IL-1B
31 CT,
and 1.04 (0.76-1.41) for IL-1B
31 CC.
Cumulative Meta-analysis. In cumulative meta-analysis, for
each polymorphic site, the associations were initially strong,
but they tended toward null associations with accumulation of
more data over time. As one example, the cumulative meta-
analysis graph for the association between IL-1B
511 CT
versus CC and TT versus CC genotypes is shown in Fig. 4.
Sensitivity of the Results to the Choice of Model. Table 2
shows the Q-statistics and I 2 statistics for the overall analyses
and compares the results of random effects with fixed effects
models. The Q-statistics were highly significant (V0.001) and
I 2 showed a moderate to strong variation in all meta-analyses.
Because of the high degree of variation, 95% CIs were
narrower using the fixed effects method. However, using the
fixed effects method had little effect on the ORs, except for IL1-
RN *2/*2, which showed a significant association with gastric
cancer (OR, 1.70; 95% CI, 1.14-2.02).
Discussion
Inflammation in the form of chronic superficial gastritis is
thought to be one of the early phases in the development of
intestinal-type gastric cancer (49), the predominant histologic
type of gastric cancer. Therefore, a stronger inflammatory
response by the host could theoretically modify gastric cancer
risk. The first published epidemiologic study examining such
associations found that proinflammatory polymorphisms in
IL-1B and IL-1RN were strongly associated with both gastric
cancer and chronic atrophic gastritis (2), a precursor of gastric
cancer. Further evidence came from a subsequent study that
showed >20-fold increased risk of gastric cancer associated
with the presence of three or more proinflammatory poly-
morphisms in IL-1B, IL-1RN, IL-10, and TNF-A (3). However,
as shown in this systematic review, subsequent studies found
mostly null results, and cumulative meta-analysis showed a
trend toward a null association.
Because this systematic review did not find a statistically
significant association between proinflammatory polymor-
phisms in IL-1B
31, IL-1B
511, or IL-1RN with gastric
cancer risk, one might argue that the initial findings were due
to chance. The pattern observed with these polymorphisms is
similar to associations between many other polymorphisms
that have been studied in relation to cancer. Polymorphisms
in other inflammation-related genes (e.g., IL-10 and TNF-A)
have shown variable associations with gastric cancer (16).
More broadly, there is no single polymorphism that has been
consistently associated with gastric cancer (50), and recent
large multicenter studies investigating the associations be-
tween promising polymorphisms with risks of other cancers
have yielded null results (51). Cumulative meta-analyses of
several gene-disease associations have shown that initially
promising associations often gravitate toward null over time
(52). Indeed, Ioannidis (53) has commented recently that
journals should be cautious about publishing positive results
on the associations between genetic polymorphisms and
cancer.
One may alternatively argue that some of the studies that
found positive associations were well designed and had large
sample sizes and narrow 95% CIs, and their findings are
unlikely to have been due to chance. The finding of significant
heterogeneity among results in the current meta-analysis, as
shown by the Q-statistics and I 2, may indicate true heteroge-
neity and is consistent with this view. Large Q and I 2 may
alternatively indicate bias in the design of some of the
published studies or certain forms of publication bias (54).
Studies that find strong positive or inverse associations are
more likely to be published and contribute to overall
heterogeneity. However, for the association between IL-1B
and IL-1RN polymorphisms and gastric cancer, the first
published studies had valid designs and large sample sizes.
Therefore, their positive findings do not seem to imply
publication bias. We investigated several possible sources of
heterogeneity, including tumor location, histology, geography,
and genotyping error, but were not able to find a clear reason
for this variation.

Table 2. Comparing summary statistics using random and fixed models

c b
Q-statistic (degrees of freedom)* P I2 Random effects, OR (95% CI) Fixed effects, OR (95% CI)

IL-1B
511
C/C — — — Baseline Baseline
C/T 70.76 (27) <0.001 0.62 1.07 (0.91-1.25) 1.12 (1.02-1.23)
T/T 68.11 (27) <0.001 0.60 1.16 (0.95-1.42) 1.17 (1.04-1.32)
IL-1B
31
T/T — — — Baseline Baseline
T/C 48.07 (21) 0.001 0.56 0.99 (0.83-1.19) 1.05 (0.94-1.17)
C/C 46.14 (21) 0.001 0.54 0.98 (0.78-1.21) 0.99 (0.87-1.14)
IL-1RN
L/L — — — Baseline Baseline
L/*2 61.62 (25) <0.001 0.59 1.15 (0.96-1.38) 1.14 (1.03-1.27)
*2/*2 87.40 (25) <0.001 0.71 1.23 (0.79-1.92) 1.70 (1.14-2.02)

*m2 Q-statistic for homogeneity.

cP for the Q-statistic.
bHiggins I 2 statistic for heterogeneity.

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Results of a previous study showed that these polymor-
phisms were more strongly associated with cancers arising
from the noncardiac region of the stomach (3). The majority of
gastric cancers worldwide (especially in East-Asian countries)
are noncardia cancers. Therefore, the overall results of this
study, which are mostly null, are probably applicable to
noncardia cancers. However, when we limited our analysis to
a few studies that included only noncardia cancer cases or
reported data by tumor location, the associations became
stronger for IL-1B
511 CT and CC and for IL-1RN *2/*2 but
not for other polymorphisms. IL-1B
511 T and IL-1B
31 C
are strongly linked. The differences observed between IL-1B

511 and IL-1B
31 in this latter analysis mainly reflect
interstudy variation; of 11 studies that reported on these
polymorphisms and noncardia cancer, only five reported on
both, and six others reported on only IL-1B
511 or IL-1B
31.
Other studies have found an association only with intestinal-
type, but not with-diffuse type, gastric cancer (6). Our analysis
of intestinal-type cancers found an overall null association.
The subgroup analyses according to anatomic subsite and
histologic subtype were limited by selective availability of data
from only some of the studies. Because significant subgroup
results may be preferentially reported in individual studies,
any significant subgroup results reported in meta-analyses
need to be interpreted with caution.
An analysis of results from Western versus East-Asian
studies also did not find a significant difference. Indeed,
few gene-disease associations have shown heterogeneity in
genetic effects (in terms of ORs) among races (55). Finally, we
restricted our analysis to studies in HWE and/or with
consistent distributions of IL-1B
511 T and IL-1B
31 C
polymorphisms to reduce the likelihood of genotyping error.
When the analysis was limited to these studies, the results
remained largely unchanged.
Biological evidence for and against the above-mentioned
associations are also mixed. El-Omar (56) has given a
comprehensive review of the biological effects of IL-1h. On
the one hand, proinflammatory polymorphisms in IL-1B and
IL-1RN may reduce gastric cancer risk by mounting a
stronger inflammatory reaction against H. pylori, reducing
gastric injury in response to a wide variety of noxious stimuli,
and increasing apoptosis of gastric epithelial cells. On the
other hand, stronger inflammatory reaction may increase
cancer risk by causing genomic damage to gastric cells,
mucosal atrophy, and secondary hypochlorhydria and bacte-
rial overgrowth (56).
Strengths of this meta-analysis include the large number of
studies included, the large number of cases and controls
examined, presentation of data on several aspects of the
listed studies, and subgroup analyses according to prede-
fined criteria. This meta-analysis also has limitations.
Combining studies with various qualities of design is not
always optimal, and summary ORs and 95% CIs should be
interpreted with caution. Nevertheless, most of the studies
included in this meta-analysis have used healthy volunteers
donating blood as control subjects, and interleukin poly-
morphisms are unlikely to be associated with their partici-
pation. Furthermore, the patterns shown in the graphs,
rather than just the summary estimates, convey valuable
information.
In summary, this systematic review did not find an overall
association of IL-1B
511 T, IL-1B
31 C, or IL-1RN *2 alleles
with risk of gastric cancer, but there was significant heteroge-
neity among study results. Few studies reported data by
anatomic subsite (cardia versus noncardia). Analysis of other
study subgroups (intestinal versus diffuse histology), Western
versus East-Asian studies, and studies that passed certain
quality criteria also found no consistent association. Thus, the
heterogeneity of these associations among published studies
remains unexplained.
Cancer Epidemiol Biomarkers Prev 2006;15(10). October 2006
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Cancer Epidemiology, Biomarkers & Prevention 1927
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Interleukin-1B Polymorphisms and Gastric Cancer Risk−−A
Meta-analysis
Farin Kamangar, Cindy Cheng, Christian C. Abnet, et al.

Cancer Epidemiol Biomarkers Prev 2006;15:1920-1928.

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