Polymorphisms in PTGS1, PTGS2 and IL-10 do not influence colorectal adenoma recurrence in the context of a randomized aspirin intervention trial.
ABSTRACT Regular use of aspirin and other nonsteroidal antiinflammatory drugs reduces both the development of colorectal neoplasia and recurrence of colorectal adenoma (CRA). Modulation of the effects of aspirin by genetic factors has been reported, potentially allowing targeting of treatment to individuals most likely to gain benefit. Prostaglandin H synthase 1 (PTGS1) and PTGS2 are key enzymes in prostaglandin synthesis and are inhibited by aspirin, whilst interleukin-10 (IL-10) is an important antiinflammatory cytokine. We investigated whether functional genetic polymorphisms in the PTGS1, PTGS2 and IL-10 genes influence CRA recurrence in individuals participating in a randomized aspirin intervention trial. DNA was available for genotyping from 546 patients who received aspirin (300 mg daily) or placebo for a mean 41-months' duration. Homozygote carriers of variant alleles for the PTGS1 50C>T, PTGS2 -765G>C and IL-10 -592C>A polymorphisms did not have a significantly altered risk of CRA recurrence (relative risk [RR]=0.91; 95% confidence interval [CI]: 0.14-6.07, RR=1.32; 95% CI: 0.66-2.62 and RR=1.24; 95% CI: 0.74-2.07, respectively). There were also no significant interactions between aspirin intervention and genotype in determining recurrence risk. These data indicate that these polymorphisms are unlikely to influence CRA recurrence and cannot be used to identify individuals who derive benefit from aspirin intervention.
- [Show abstract] [Hide abstract]
ABSTRACT: The cyclooxygenase (COX) activity of prostaglandin H synthase-2 (PGHS-2) is implicated in colorectal cancer and is targeted by nonsteroidal anti-inflammatory drugs (NSAIDs) and dietary n-3 fatty acids. We used purified, recombinant proteins to evaluate the functional impacts of the R228H, E488G, V511A and G587R PGHS-2 polymorphisms on COX activity, fatty acid selectivity and NSAID actions. Compared to wild-type PGHS-2, COX activity with arachidonate was ∼20% lower in 488G and ∼20% higher in 511A. All variants showed time-dependent inhibition by the COX-2-specific inhibitor (coxib) nimesulide, but 488G and 511A had 30-60% higher residual COX activity; 511A also showed up to 70% higher residual activity with other time-dependent inhibitors. In addition, 488G and 511A differed significantly from wild type in Vmax values with the two fatty acids: 488G showed ∼20% less and 511A showed ∼20% more discrimination against eicosapentaenoic acid. The Vmax value for eicosapentaenoate was not affected in 228H or 587R, nor were the Km values or the COX activation efficiency (with arachidonate) significantly altered in any variant. Thus, the E488G and V511A PGHS-2 polymorphisms may predict who will most likely benefit from interventions with some NSAIDs or n-3 fatty acids.The Pharmacogenomics Journal 10/2011; 11(5):337-47. · 5.13 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Gene discoveries in cancer have the potential for clinical and public health applications. To take advantage of such discoveries, a translational research agenda is needed to take discoveries from the bench to population health impact. To assess the current status of translational research in cancer genetics, we analyzed the extramural grant portfolio of the National Cancer Institute (NCI) from Fiscal Year 2007, as well as the cancer genetic research articles published in 2007. We classified both funded grants and publications as follows: T0 as discovery research; T1 as research to develop a candidate health application (e.g., test or therapy); T2 as research that evaluates a candidate application and develops evidence-based recommendations; T3 as research that assesses how to integrate an evidence-based recommendation into cancer care and prevention; and T4 as research that assesses health outcomes and population impact. We found that 1.8% of the grant portfolio and 0.6% of the published literature was T2 research or beyond. In addition to discovery research in cancer genetics, a translational research infrastructure is urgently needed to methodically evaluate and translate gene discoveries for cancer care and prevention.Public Health Genomics 01/2011; 14(1):1-8. · 2.57 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Abstract The aim of the present work was to perform a meta-analysis to evaluate the association between the interleukin 10 (IL-10) -819C/T (rs1800871) polymorphism and cancer risk. A total of 73 studies, including 15,942 cancer cases and 22,336 controls, were identified in this meta-analysis. The odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using the random-effects model. Overall, no significant association was identified between the IL-10 -819C/T polymorphism and cancer risk. In the subgroup analyses, the T allele and TT genotype were associated with a moderately reduced cancer risk in the Asian population (T allele vs. C allele: OR=0.93, 95%CI: 0.87, 0.99; TT vs. CC: OR=0.86, 95%CI: 0.76, 0.98; TT vs. CT/CC: OR=0.90, 95%CI: 0.82, 0.98). Individuals who were homozygous for the T allele (TT) were found to be associated with significantly reduced gastric cancer risk in the Asian population. The heterozygous variant (CT) and the dominant model (TT/CT vs. CC) were associated with an increased risk for cervical and ovarian cancer. However, the IL-10 -819C/T polymorphism was not significantly associated with breast cancer, colorectal cancer, lung cancer, hepatocellular carcinoma, prostate cancer, lymphoma, or melanoma. The depressed cancer risk of the TT genotype occurred in the studies of hospital-based case-control studies and the studies recruited less than 500 subjects, but no statistically significant results were found in the stratified analyses using genotyping method. The results suggest that the IL-10 -819TT genotype may be a protective factor for cancer in Asians, especially gastric cancer. In contrast, the CT genotype and the dominant model could be risk factors for cervical and ovarian cancer. The importance of stratifying by ethnicity, cancer type, study design, and sample size needs to be standardized in future studies, together with considering the association between the IL-10 -819C/T polymorphism and cancer risk. Furthermore, the linkage of -819C/T with other polymorphisms of the IL-10 gene may help explain the variability in findings.Omics: a journal of integrative biology 04/2013; 17(4):200-14. · 2.29 Impact Factor
Polymorphisms in PTGS1, PTGS2 and IL-10 do not influence colorectal
adenoma recurrence in the context of a randomized aspirin intervention trial
Richard A. Hubner1*, Kenneth R. Muir2, Jo-Fen Liu2, Richard F.A. Logan2, Matthew J. Grainge2, Richard S. Houlston1,
and Members of the UKCAP Consortium
1Section of Cancer Genetics, Institute of Cancer Research, Sutton SM2 5NG, United Kingdom
2Division of Epidemiology and Public Health Medical School, University of Nottingham, Queen’s Medical Centre,
Nottingham NG7 2UH, United Kingdom
Regular use of aspirin and other nonsteroidal antiinflammatory
drugs reduces both the development of colorectal neoplasia and
recurrence of colorectal adenoma (CRA). Modulation of the
effects of aspirin by genetic factors has been reported, potentially
allowing targeting of treatment to individuals most likely to gain
benefit. Prostaglandin H synthase 1 (PTGS1) and PTGS2 are key
enzymes in prostaglandin synthesis and are inhibited by aspirin,
whilst interleukin-10 (IL-10) is an important antiinflammatory
cytokine. We investigated whether functional genetic polymor-
phisms in the PTGS1, PTGS2 and IL-10 genes influence CRA
recurrence in individuals participating in a randomized aspirin
intervention trial. DNA was available for genotyping from 546
patients who received aspirin (300 mg daily) or placebo for a
mean 41-months’ duration. Homozygote carriers of variant alleles
for the PTGS1 50C>T, PTGS2 2765G>C and IL-10 2592C>A
polymorphisms did not have a significantly altered risk of CRA re-
currence (relative risk [RR] 5 0.91; 95% confidence interval [CI]:
0.14–6.07, RR 5 1.32; 95%CI: 0.66–2.62 and RR 5 1.24; 95% CI:
0.74–2.07, respectively). There were also no significant interac-
tions between aspirin intervention and genotype in determining
recurrence risk. These data indicate that these polymorphisms are
unlikely to influence CRA recurrence and cannot be used to iden-
tify individuals who derive benefit from aspirin intervention.
' 2007 Wiley-Liss, Inc.
Key words: colorectal adenoma; recurrence; polymorphism; aspirin
Regular use of aspirin or nonsteroidal antiinflammatory drugs
(NSAIDs) has consistently been reported to result in an ?50%
reduction in incidence of colorectal cancer (CRC), and 3 random-
ized intervention trials have demonstrated a reduction in colorectal
adenoma (CRA) recurrence in patients receiving aspirin.1–4A ben-
efit in preventing colorectal neoplasia is not, however, observed in
all patients using aspirin, and it is very likely that other environ-
mental exposures and genetic variation play a part in determining
an individuals’ response.
The enzymes prostaglandin H synthase 1 (PTGS1, or cyclooxy-
genase1 (COX1)) and PTGS2 (COX2) catalyze prostaglandin syn-
thesis, and play important roles in regulating both constitutive and
reactive inflammation.5Both enzymes are inhibited by aspirin and
other NSAIDs, and this inhibition is thought to mediate at least
part of the protective effect of these drugs in colorectal carcino-
genesis.6Interleukin-10 (IL-10) is an antiinflammatory cytokine
that inhibits synthesis of the proinflammatory cytokines IL-1b, IL-
6, IL-8 and IL-2, and has a crucial role in modulating gastrointesti-
nal tract inflammation which is implicated in colorectal carcino-
genesis.7–9Polymorphisms within the promoter or coding regions
of the PTGS1, PTGS2 and IL-10 genes have been documented to
alter protein expression, and in case–control studies have been
reported to influence risk of developing colorectal neoplasia.10–15
Furthermore, the PTGS1 50C>T (rs3842787), PTGS2 2765G>C
(rs20417) and IL-10 2592C>A (rs 1800872) polymorphisms
have been demonstrated to interact with aspirin or NSAID use in
determining CRC or CRA risk, with the benefits of these drugs
being confined to individuals with certain genotypes.13,15,16
We sought to further investigate the role of these polymor-
phisms in colorectal neoplasia by genotyping patients participating
in a randomized intervention trial of aspirin for the prevention of
Material and methods
The United Kingdom Colorectal Adenoma Prevention (UKCAP)
trial is a recently completed multicenter randomized placebo-con-
trolled intervention trial for the prevention of CRA recurrence.3
Eligible subjects were recruited from 1997 to 2001, had ?1 histo-
logically confirmed CRA, ?0.5 cm in size, detected at full colono-
scopic examination and were not already taking regular aspirin,
nonaspirin NSAID or prescribed folate supplements. Patients were
randomized to aspirin alone (300 mg daily), folate alone (500 lg
daily), both aspirin and folate, or double placebo. The primary
endpoint was histologically confirmed recurrence of CRA or
CRC. Recurrence was ascertained at follow-up colonoscopy
scheduled for 3 years after entry colonoscopy, or performed earlier
if symptoms dictated (mean 41 months). If follow-up colonoscopy
was performed prior to the 3-year time-point and CRA or CRC
was found, then the patient left the trial; if no adenoma was found
then the patient continued on trial medication and underwent fur-
ther colonoscopy at the 3-year time-point. Histopathology was
performed at local hospitals without central review. Suspected
recurrences found at follow-up colonoscopy were reviewed by the
same histopathology department as the original trial entry speci-
men. Compliance with trial medication was assessed at 4-monthly
intervals, and there was ?85% compliance with prescribed tablets
in the aspirin arms of the trial.
Follow-up colonoscopy was performed on 853 patients, and
DNA was available from 546 patients all of whom were of Cauca-
sian ethnicity. Not all patients from the original trial could be
included in this molecular subprotocol as some could not be con-
tacted, and others did not consent to DNA analysis. Informed con-
sent for the study was obtained from all participants and the study
was carried out with ethical review board approval in accordance
with the tenets of the declaration of Helsinki.
PTGS1 50C>T, PTGS2 2765G>C and IL-10 2592C>A
genotypes were generated from germline DNA using Taqman
technology implemented on an ABI 7900HT sequence detection
system (Applied Biosystems, Foster City, USA). Genotyping
assays for each polymorphism were validated using control sam-
ples of known homozygote wild-type, heterozygote and homo-
zygote variant genotype generated by direct sequencing.
Unblinded control samples were included on each sample plate,
and were correctly genotyped on 100% of occasions. Laboratory
personnel employed in genotyping patient DNAs were blinded
to clinical outcome.
Members of the UKCAP Consortium available on request.
*Correspondence to: Section of Cancer Genetics, Institute of Cancer
Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom.
Fax: 144-208722-4359. E-mail: email@example.com
Received 27 February 2007; Accepted after revision 16 May 2007
Published online 19 July 2007 in Wiley InterScience (www.interscience.
Grant sponsors: Cancer Research UK; Bayer Healthcare; Kellogg’s.
Int. J. Cancer: 121, 2001–2004 (2007)
' 2007 Wiley-Liss, Inc.
Publication of the International Union Against Cancer
Baseline characteristics between the total UKCAP trial popula-
tion and the genotyped subgroup were compared using the v2and
t-tests. Genotype frequencies were tested for departure from
Hardy–Weinberg equilibrium (HWE) using the v2test. The pres-
ence or absence of colorectal neoplasia recurrence was considered
a binary outcome in the cohort study. The relationship between
genotype and risk of colorectal neoplasia recurrence was assessed
by means of relative risks (RRs) and 95% confidence intervals
(CIs) calculated using Poisson regression with robust error var-
iance, adjusting for sex and interval between entry and follow-up
colonoscopy, since these two variables were found to significantly
influence recurrence risk.17,18For each polymorphism, homozy-
gous wild-type patients were compared to heterozygous and
homozygous variant patients separately and combined. The likeli-
hood ratio test was used to explore interactions between genotype
and aspirin treatment with respect to recurrence risk by comparing
models with and without a multiplicative term for the 2 variables.
For the interaction analyses, patients were divided into aspirin-
treated (aspirin alone, and aspirin and folate intervention groups),
and nonaspirin-treated (folate alone, and double-placebo interven-
tion groups) on an intention-to-treat basis. To maximize power in
the interaction analyses, patients with heterozygote and homozy-
gous variant genotypes were combined and compared to homozy-
gous wild-type patients.
Statistical analyses were undertaken using STATA, version 7.0
(Stata Corporation, College Station, TX). All tests were 2-sided,
and a p value less than 0.05 was considered significant.
There were no significant differences in age, sex, intervention
group, interval between entry and follow-up colonoscopy, and out-
comes between the total UKCAP trial population and patients
included in the genotyping analysis (Table I). Of the 546 patients
included in the genotyping analysis, 130 (23.8%) had ?1 CRA
and 7 (1.3%) CRC detected at follow-up colonoscopy. Seventy
patients (12.8%) had advanced colorectal neoplasia, defined as
CRAs with villous or tubulovillous features, size ?1 cm, severe
dysplasia or invasive carcinoma. In the main trial a reduced CRA
recurrence risk was observed in patients who received aspirin
(RR 5 0.81; 95% CI: 0.66–1.02),3and in the genotyped subgroup
a reduced recurrence risk was also seen (RR 5 0.92; 95% CI:
Allele frequencies for the PTGS1 50T, PTGS2 2765C and IL-
10 2592A alleles were 7, 14 and 26%, respectively, consistent
with previous reports in Caucasian populations, and genotype fre-
quencies for all 3 polymorphisms were in HWE.15,16,19When risk
of colorectal neoplasia recurrence was stratified by PTGS1
50C>T, PTGS2 2765G>C or IL-10 2592C>A genotypes, no
statistically significant associations were observed (Table II). Sim-
ilarly, when the analysis was restricted to advanced lesions there
were no significant influences of genotype on recurrence risk
Risks of colorectal neoplasia recurrence following stratification
by both genotype and aspirin intervention are detailed in Table III.
There were no statistically significant interactions between geno-
type and aspirin intervention for any polymorphism. Nor were
there significant interactions when the analysis was restricted to
advanced lesion recurrence (data not shown).
Our study is the first to report on the influence of polymor-
phisms in the PTGS1 and PTGS2 genes and risk of CRA recur-
TABLE I – COMPARISON OF THE TOTAL UKCAP TRIAL POPULATION AND
PATIENTS GENOTYPED IN THIS STUDY
Folate and aspirin
Std. dev. (months)
1Age at entry colonoscopy.–2Values in parentheses indicate percen-
tages.–3Interval between entry and follow-up colonoscopy (mean,
standard deviation, range).–4Follow-up colonoscopy outcome defini-
tions were as follows: adenoma, histologically confirmed colorectal
adenoma; carcinoma, histologically confirmed colorectal carcinoma;
advanced neoplasia, colorectal adenoma ?1 cm diameter, villous or
tubulovillous histology, severe dysplasia or colorectal carcinoma.
TABLE II – RISK OF DETECTION OF ANY COLORECTAL NEOPLASIA AND ADVANCED NEOPLASIA AT
FOLLOW-UP COLONOSCOPY STRATIFIED BY GENOTYPE
Any colorectal neoplasiaAdvanced colorectal neoplasia1
1Advanced colorectal neoplasia was defined as colorectal adenomas with villous or tubulovillous fea-
tures, size ?1 cm, severe dysplasia or colorectal carcinoma.–2Relative risk and 95% confidence interval
adjusted for sex and interval between entry and follow-up colonoscopy.–3Values in parentheses indicate
HUBNER ET AL.
rence, and also the first to investigate the IL-10 2592C>A poly-
morphism in this setting. The variant PTGS1 50T allele results in
an amino acid change in the signal peptide of the PTGS1 protein,
and significantly increased inhibition of the PTGS1 enzyme by as-
pirin has been reported in heterozygote carriers of the variant
250T allele.10The PTGS2 2765G>C polymorphism is located
within a putative binding site for stimulatory protein 1, which is
considered to be a positive activator for PTGS2 expression.11Het-
erozygous or homozygous carriers of the variant PTGS2 2765C
allele have been reported to show significantly less PTGS2 expres-
sion in normal gastrointestinal mucosa, and a significantly reduced
increase in PTGS2 expression following surgery.20,21The IL-10
2592C>A polymorphism is in complete linkage disequilibrium
(LD) with a second IL-10 promoter variant, 2819C>T and to-
gether with a third variant 21082G>A forms 3 haplotypes (GCC,
ACC and ATA).15The ATA haplotype has been reported to be
associated with reduced IL-10 expression compared to the GCC
haplotype.12,22Thus there is evidence that all 3 polymorphisms
investigated in this study are functional with significant influences
on protein expression.
Although a case–control study reported no influence of PTGS1
50C>T genotype on risk of developing CRA, homozygote carriers
of the PTGS1 50C allele showed a reduced CRA risk if they
reported regular aspirin or NSAID use, whilst individuals with 1
or 2 PTGS1 50T alleles showed no benefit from NSAID use.13
This finding, however, is seemingly at odds with the in vitro find-
ings of increased aspirin inhibition of the PTGS1 enzyme in
PTGS1 50T carriers. Similarly, in the same group of CRA cases
and control subjects, no direct influence of PTGS2 2765G>C ge-
notype on risk of developing CRA was reported, but a significant
interaction between genotype and aspirin or NSAID use was
noted, with the benefits of NSAIDs being confined to carriers of
PTGS2 2765G alleles.16No such interaction was observed in a
subsequent study of PTGS2 2765G>C genotype and CRA risk,
although this was of smaller sample size.23Two case–control stud-
ies investigating the PTGS2 2765G>C polymorphism in the con-
text of CRC risk also reported no direct influence of genotype, but
no data on the interaction between genotype and aspirin or NSAID
use in determining CRC risk was presented.14,24In a Scottish pop-
ulation the IL-10 2592C>A polymorphism was reported to inter-
act with aspirin use in predicting risk of CRC development, with
the benefits of aspirin being confined to 2592A allele carriers,
although a similar interaction was not observed with nonaspirin
NSAID use.15No direct association of IL-10 2592C>A genotype
and CRC risk was observed.
In our study, no direct influences on risk of CRA recurrence
were conferred by PTGS1 50C>T, PTGS2 2765G>C or IL-10
2592C>A genotypes, and these findings would appear to be con-
sistent with the previous epidemiological studies reporting on the
relationship between genotype and colorectal neoplasia risk. How-
ever, in our study there were also no significant interactions
between aspirin intervention and genotype in determining CRA
recurrence risk, as was reported in some case–control studies.
These differences in results may reflect genuine differences in the
genotype-drug interactions at different stages of colorectal carci-
nogenesis (adenoma development as opposed to adenoma recur-
rence), differences in drug exposures (both dose and duration) or
may be due to sample size or chance. In our study, patients
randomized to aspirin treatment were exposed to a relatively high
dose of aspirin, 300 mg daily, and there was also a high level of
compliance with aspirin treatment. This dose and frequency is
higher than that typically employed in case–control studies to
define individuals as ‘‘aspirin-exposed,’’ and would be expected to
maximize the likelihood of observing any genotype–drug interac-
tion.15,16It is also possible, however, that such interactions require
a longer duration of exposure to exert their influence on colorectal
carcinogenesis than the mean 41-month period in this study.
Although aspirin treatment reduced CRA recurrence in the main
UKCAP trial, in the genotyped subgroup, the protective effect was
more limited. This will have reduced the power of our study to
detect an interaction between aspirin and genotype, and could also
account for the absence of such interactions in our study. While
our study had 80% power to detect the main effect of genotype on
recurrence risk (assuming a variant allele frequency of 0.3 and RR
of recurrence of 0.5 associated with presence of the variant allele
in a dominant model), power to detect interactions between geno-
type and aspirin treatment in determining recurrence risk was lim-
ited (32% assuming a RR of recurrence of 0.92 associated with
aspirin treatment as observed in this study).
A previous study has reported on IL-10 2819C>T and
21082G>A polymorphism genotype and CRA recurrence risk in
participants in a dietary intervention trial.25In this study, neither
variant influenced recurrence risk directly, and there was no sig-
nificant interaction between the IL-10 2819C>T and NSAID use
in determining recurrence risk. Since the IL-10 2819C>T and
2592C>A variants are in strong LD, these results corroborate the
findings of our study. A significant interaction between IL-10
21082G>A genotype and NSAID use was reported in the study
by Sansbury et al.,25which was not observed in the case–control
study by Macarthur et al.,15highlighting the differences in geno-
type–drug interactions that may occur at different stages of color-
In summary, our results indicate that the PTGS1 50C>T,
PTGS2 2765G>C and IL-10 2592C>A polymorphism geno-
types are unlikely to influence CRA recurrence, or interact with
aspirin in determining CRA recurrence risk. As such in patients
diagnosed with CRA, these polymorphisms are unlikely to be clin-
ically useful in identifying those who will gain differential benefit
from aspirin intervention in preventing recurrence.
R.A.H. is in receipt of a Cancer Research UK Clinical Research
TABLE III – RISK OF DETECTION OF COLORECTAL NEOPLASIA STRATIFIED BY GENOTYPE AND INTERVENTION
Placebo treated (n 5 280)Aspirin treated (n 5 266)
p interaction 5 0.91
p interaction 5 0.73
p interaction 5 0.74
1Relative risk and 95% confidence interval adjusted for sex and interval between entry and follow-up
colonoscopy.–2Values in parentheses indicate 95% CIs.
PTGS1, PTGS2 AND IL-10 SNPs AND CRA RECURRENCE
1.Baron JA, Cole BF, Sandler RS, Haile RW, Ahnen D, Bresalier R,
McKeown-Eyssen G, Summers RW, Rothstein R, Burke CA, Snover
DC, Church TR, et al. A randomized trial of aspirin to prevent color-
ectal adenomas. N Engl J Med 2003;348:891–9.
Sandler RS, Halabi S, Baron JA, Budinger S, Paskett E, Keresztes R,
Petrelli N, Pipas JM, Karp DD, Loprinzi CL, Steinbach G, Schilsky
R. A randomized trial of aspirin to prevent colorectal adenomas in
patients with previous colorectal cancer. N Engl J Med 2003;348:
Logan RFA, Muir KR, Grainge MJ, Shepherd VC on behalf of the
UKCAP Trial Group. Aspirin for the prevention of recurrent colorec-
tal adenomas—results of the UKCAP trial. Gut 2006;55(Suppl 2):
Baron JA, Sandler RS. Nonsteroidal anti-inflammatory drugs and can-
cer prevention. Ann Rev Med 2000;51:511–23.
Brown JR, DuBois RN. COX-2: a molecular target for colorectal can-
cer prevention. J Clin Oncol 2005;23:2840–55.
Chan TA. Nonsteroidal anti-inflammatory drugs, apoptosis, and
colon-cancer chemoprevention. Lancet Oncol 2002;3:166–74.
Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A. Interleu-
kin-10 and the interleukin-10 receptor. Ann Rev Immunol 2001;
Yilmaz V, Yentur SP, Saruhan-Direskeneli G. IL-12 and IL-10 poly-
morphisms and their effects on cytokine production. Cytokine 2005;
Clevers H. At the crossroads of inflammation and cancer. Cell
10. Halushka MK, Walker LP, Halushka PV. Genetic variation in cyclo-
oxygenase 1: effects on response to aspirin. Clin Pharmacol Ther
11. Papafili A, Hill MR, Brull DJ, McAnulty RJ, Marshall RP, Humphries
SE, Laurent GJ. Common promoter variant in cyclooxygenase-2
represses gene expression: evidence of role in acute-phase inflamma-
tory response. Arterioscler Thromb Vasc Biol 2002;22:1631–6.
12. Eskdale J, Gallagher G, Verweij CL, Keijsers V, Westendorp RG,
Huizinga TW. Interleukin 10 secretion in relation to human IL-10
locus haplotypes. Proc Natl Acad Sci USA 1998;95:9465–70.
13. Ulrich CM, Bigler J, Sparks R, Whitton J, Sibert JG, Goode EL, Yasui
Y, Potter JD. Polymorphisms in PTGS1 (5COX-1) and risk of colo-
rectal polyps. Cancer Epidemiol Biomarkers Prev 2004;13:889–93.
14. Cox DG, Pontes C, Guino E, Navarro M, Osorio A, Canzian F, Mor-
eno V. Polymorphisms in prostaglandin synthase 2/cyclooxygenase 2
(PTGS2/COX2) and risk of colorectal cancer. Br J Cancer 2004;
15. Macarthur M, Sharp L, Hold GL, Little J, El-Omar EM. The role of
cytokine gene polymorphisms in colorectal cancer and their interac-
tion with aspirin use in the northeast of Scotland. Cancer Epidemiol
Biomarkers Prev 2005;14:1613–18.
16. Ulrich CM, Whitton J, Yu JH, Sibert J, Sparks R, Potter JD, Bigler J.
PTGS2 (COX-2) 2765G > C promoter variant reduces risk of color-
ectal adenoma among nonusers of nonsteroidal anti-inflammatory
drugs. Cancer Epidemiol Biomarkers Prev 2005;14:616–19.
17. McNutt LA, Wu C, Xue X, Hafner JP. Estimating the relative risk in
cohort studies and clinical trials of common outcomes. Am J Epide-
18. Zou G. A modified Poisson regression approach to prospective studies
with binary data. Am J Epidemiol 2004;159:702–6.
19. Ulrich CM, Bigler J, Sibert J, Greene EA, Sparks R, Carlson CS, Pot-
ter JD. Cyclooxygenase 1 (COX1) polymorphisms in African-Ameri-
can and Caucasian populations. Hum Mutat 2002;20:409–10.
20. Brosens LA, Iacobuzio-Donahue CA, Keller JJ, Hustinx SR, Carvalho
R, Morsink FH, Hylind LM, Offerhaus GJ, Giardiello FM, Goggins
M. Increased cyclooxygenase-2 expression in duodenal compared
with colonic tissues in familial adenomatous polyposis and relation-
ship to the 2765G -> C COX-2 polymorphism. Clin Cancer Res
21. Lee YS, Kim H, Wu TX, Wang XM, Dionne RA. Genetically medi-
ated interindividual variation in analgesic responses to cyclooxygen-
ase inhibitory drugs. Clin Pharmacol Ther 2006;79:407–18.
22. Crawley E, Kay R, Sillibourne J, Patel P, Hutchinson I, Woo P. Poly-
morphic haplotypes of the interleukin-10 50flanking region determine
variable interleukin-10 transcription and are associated with particular
phenotypes of juvenile rheumatoid arthritis. Arthritis Rheum 1999;
23. Gunter MJ, Canzian F, Landi S, Chanock SJ, Sinha R, Rothman N.
Inflammation-related gene polymorphisms and colorectal adenoma.
Cancer Epidemiol Biomarkers Prev 2006;15:1126–31.
24. Koh WP, Yuan JM, van den Berg D, Lee HP, Yu MC. Interaction
between cyclooxygenase-2 gene polymorphism and dietary n-6 poly-
unsaturated fatty acids on colon cancer risk: the Singapore Chinese
Health Study. Br J Cancer 2004;90:1760–4.
25. Sansbury LB, Bergen AW, Wanke KL, Yu B, Caporaso NE, Chatter-
jee N, Ratnasinghe L, Schatzkin A, Lehman TA, Kalidindi A, Modali
R, Lanza E. Inflammatory cytokine gene polymorphisms, nonsteroidal
anti-inflammatory drug use, and risk of adenoma polyp recurrence in
the polyp prevention trial. Cancer Epidemiol Biomarkers Prev 2006;
HUBNER ET AL.