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Int J Cancer. Author manuscript; available in PMC 2014 February 15.
Published in final edited form as:
Int J Cancer. 2013 February 15; 132(4): 905–915. doi:10.1002/ijc.27660.
Interleukin genes and associations with colon and rectal cancer

risk and overall survival
Kristina L. Bondurant1, Abbie Lundgreen2, Jennifer S. Herrick2, Susan Kadlubar3, Roger K.
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Wolff2, and Martha L. Slattery2

1Department of Environmental and Occupational Health, University of Arkansas for Medical
Sciences, Little Rock, Arkansas, USA

2Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City,
Utah, USA
3Division of Genetics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
Abstract
Interleukins are a group of cytokines that contribute to growth and differentiation, cell migration,
and inflammatory and anti-inflammatory responses by the immune system. In this study we
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examined genetic variation in genes from various anti-inflammatory and pro-inflammatory

interleukins to determine association with colon and rectal cancer risk and overall survival. Data
from two population-based incident studies of colon cancer (1555 cases and 1956 controls) and
rectal cancer (754 cases and 954 controls) were utilized. After controlling for multiple
comparisons, single nucleotide polymorphisms (SNPs) from four genes, IL3, IL6R, IL8, IL15,
were associated with increased colon cancer risk and CXCR1, and CXCR2 were significantly
associated with increased rectal cancer risk. Only SNPs from genes within the IL-8 pathway (IL8,
CXCR1, and CXCR2) showed a significant association with both colon and rectal cancer risk.
Several SNPs interacted significantly with IL8 and IFNG SNPs and with aspirin/NSAID, cigarette
smoking, estrogen use and BMI. For both colon and rectal cancer, increasing numbers of risk
alleles were associated with increased hazard of death from cancer; the estimated hazard of death
for colon cancer for the highest category of risk alleles was 1.74 (95% CI 1.18–2.56) and 1.96
(95% CI 1.28–2.99) for rectal cancer. These data suggest interleukin genes play a role in risk and
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overall survival for colon and rectal cancer.
Keywords
Interleukins; colon cancer; rectal cancer; single nucleotide polymorphisms; inflammatory
Introduction
Interleukins are a type of cytokine that control growth and differentiation, cell migration and
inflammatory and anti-inflammatory responses by the immune system (1). The balance
between inflammatory and anti-inflammatory actions is essential for proper control of the
immune response and protection against underlying tissue damage. However, different
factors such as bacterial or viral infections, diet, individual genetics, and additional
environmental factors may disrupt this balance and lead to a heightened state of
inflammation which may cause tissue damage which may be acute in nature or lead to
Corresponding author: Susan Kadlubar, Ph.D., Division of Medical Genetics, University of Arkansas for Medical Sciences, 4301 W.
Markham, #820, Little Rock, AR 72205, phone: 501-526-7957, sakadlubar@uams.edu.
Bondurant et al. Page 2
chronic conditions (2). Inflammation in the intestinal tract in particular has also been
associated with chronic inflammatory bowels diseases such as Crohn’s disease, ulcerative
colitis, as well as colon and rectal cancers (1–3).
Pro-inflammatory interleukins generally include IL-1, IL-2, IL-6, IL-8, IL-12, IL-15, and
IL-17 while anti-inflammatory interleukins include IL-4 and IL-10. Additionally, IL-3
supports differentiation and proliferation of various immune cells thereby playing a
significant role in immune responses. Genetic polymorphisms in a key pro-inflammatory
interleukin within the gut, IL-6, have been associated with inflammatory bowel disease (4)
as well as colon and rectal cancers (5). Chronic inflammation in the gut is linked to the
activation of macrophages and T cells releasing pro-inflammatory cytokines including
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interleukins such as IL-1beta, IL-6, and IL-8 as well as TNF-alpha and IFN-gamma (4). Of
particular note, signaling by the interleukin IL-8 has been shown to promote malignant
progression of tumors (6) and has been associated with inflammatory pathways and gastric
cancer (7). IL-8 can bind to two different forms of the IL-8 receptor: either IL-8 receptor
alpha also called CXCR1 or IL-8 receptor beta also called CXCR2. Polymorphisms in the
genes coding for IL-1 or the IL-1 receptor antagonist have been associated with chronic
inflammatory diseases including ulcerative colitis (8, 9), Crohn’s disease (10) as well as
survival and recurrence in colorectal cancer (11, 12). IL-17 is also associated with
inflammatory bowel disease (13). Research of chronic inflammation and host defense
indicates that IL-17 works in conjunction with IL-23 to contribute to the pathogenesis
observed in inflammatory diseases (14). Polymorphisms in the human IL-23 receptor have
already been highlighted in the work on inflammatory bowel disease (15–17).
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Improper regulation of anti-inflammatory interleukins is also implicated in cancer and

inflammatory disease within the gut. IL-10 is an anti-inflammatory interleukin, the absence
of which has been associated with an inflammatory condition and several inflammatory
diseases as well as cancers (1, 3, 18, 19). IL-4 plays a role in anti-inflammatory mechanisms
and researchers have assessed the association of polymorphisms in IL-4 with risk of
developing colorectal cancer in a Korean population (20).
Thus far, few studies have evaluated genetic variation within the pro-inflammatory and anti-
inflammatory interleukins. The interrelated actions and balance between inflammatory and
anti-inflammatory interleukins may influence risk of developing colon and rectal cancer. We
investigated the genetic variation in IL10, IL15, IL1A, IL1B, IL1RN, IL2, IL3, IL4, IL6R,
IL8, CXCR1, CXCR2, and IL17A in relation to the risk of developing colon and rectal
cancer. Environmental influences which may impact responses to inflammatory cytokines
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such as aspirin/NSAID use, cigarette smoking, and estrogen use also were evaluated.
Methods
Data come from two population-based case-control studies of colon cancer (cases n=1,555;
controls n=1,956) and rectal cancer (cases n=754; controls n=959). Colon cancer cases were
identification between October 1, 1991 and September 30, 1994 and included people living
in the Twin Cities Metropolitan Area, Kaiser Permanente Medical Care Program of
Northern California (KPMCP) and a seven-county area of Utah (21). The rectal cancer study
used identical data collection methods as the colon study, except cases came from the entire
state of Utah. Cases also were population-based incident cases of the rectosigmoid junction
or rectum who were diagnosed between May 1997 and May 2001 in Utah and KPMCP (22).
For both studies, cases were between 30 and 79 years old at time of diagnosis with
adenocarcinoma, English speaking, mentally competent to complete the interview, had no
previous history of CRC, and no known familial adenomatous polyposis, ulcerative colitis,
or Crohn’s disease. Controls were matched to cases by sex and by 5-year age groups. At

KPMCP, controls were randomly selected from membership lists; in Utah, controls 65 years
and older were randomly selected from the Health Care Financing Administration lists and
younger controls were randomly selected from driver’s license lists. Controls were selected
from driver’s license and state-identification lists in Minnesota. Details of the study have
been previously reported (21, 22).
Interview Data Collection

Data were collected by trained and certified interviewers using laptop computers. All
interviews were audio-taped and reviewed for quality control purposes (23). The referent
period for the study was two years prior to diagnosis for cases and prior to selection for
controls.
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Tumor Registry Data

Tumor registry data were obtained to determine disease stage at diagnosis and months of
survival after diagnosis. Disease stage was categorized centrally by one pathologist in Utah
using the sixth edition of the American Joint Committee on Cancer (AJCC) staging criteria.
Local tumor registries also provided information on patient follow-up including vital status,
cause of death, and contributing cause of death.
Tumor Marker Data

We have previously evaluated tumors for CpG island methylator phenotype (CIMP),
microsatellite instability (MSI), TP53 mutations, and KRAS2 mutations (24–27) and were
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therefore able to evaluate genes in relation to tumor molecular phenotype. Details for
methods used to evaluate epigenetic and genetic changes have been described (24–27).
Given the rarity of MSI+ rectal tumors (28) we are unable to evaluate that phenotype among
rectal cancers.
TagSNP Selection and Genotyping

TagSNPs were selected using the following parameters: LD blocks were defined using a
Caucasian LD map and an r2=0.8; minor allele frequency (MAF) >0.1; range= −1500 bps
from the initiation codon to +1500 bps from the termination codon; and 1 SNP/LD bin. All
markers were genotyped using a multiplexed bead-array assay format based on GoldenGate
chemistry (Illumina, San Diego, California). A genotyping call rate of 99.85% was attained.
Blinded internal replicates represented 4.4% of the sample set; the duplicate concordance
rate was 100%. Individuals with missing genotype data were not included in the analysis for
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that specific marker. We evaluated associations with candidate genes, including IL1A, IL1B,
IL1RN, IL2, IL3, IL4, IL6R, IL8, CXCR1, CXCR2, IL10, IL15, IL17A. Table 1 contains
information about all SNPs included on the platform.
Statistical Methods
Statistical analyses were performed using SAS® version 9.2 (SAS Institute, Cary, NC). We
report odds ratios (ORs) and 95% confidence intervals (95%CIs) assessed from multiple
logistic regression models adjusting for age, study center, race/ethnicity, and sex. SNPs were
assessed assuming a co-dominant model and based on this initial assessment, those which
appeared to have a dominant or recessive mode of inheritance were evaluated with those
inheritance models in subsequent analysis. Main effect model p values were based on a 1-df
Wald test statistic and interaction p values were determined using a likelihood-ratio test
comparing a full model that included an ordinal interaction term with a reduced model
without an interaction term.

Tumor markers were defined by specific alterations detected; CIMP+, any KRAS2 mutation,
any TP53 mutation, and among colon cases, MSI+ or a combination of CIMP+/MSI+.
Population-based controls were used to assess associations for the population overall when
examining multiple outcomes defined by tumor status. A multinomial generalized estimating
equation (GEE) approach was used to account for correlation introduced by including
subjects multiple times and was implemented in SAS using the GENMOD procedure as
described by Kuss and McLerran (29). We also report 1-df Wald p values from multiple
logistic regression models comparing cases with and without a particular tumor phenotype.
The minimal adjustments were controlled for in all models.
Survival-months were calculated based on month and year of diagnosis and month and year
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of death or date of last contact. Associations between SNPs and risk of dying of colorectal
cancer were evaluated using Cox proportional hazards models to obtain multivariate hazard
rate ratios (HRRs) and 95% confidence intervals. In addition to the minimal adjustments
tumor molecular phenotype, and AJCC stage were also adjusted for when to estimating
HRRs. To summarize risk associated with overall survival for multiple variants across the
pathway we created a summary polygenic score that was based on all at-risk genotypes for
rectal cancer. The score for each SNP was based on the inheritance model and its associated
risk. For the co-dominant or additive model a score of zero, one, or two was assigned which
directly correlates to the number of high-risk alleles. After assigning a score for each SNP
previously identified as being significant after adjustment for multiple testing, the scores
were summed across SNPs to generate an individual polygenic summary score. Individuals
missing SNP data were dropped from the analysis. Trend p values are based on likelihood-
ratio tests comparing full models including ordinal score terms with reduced models without
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score terms; Wald p values are also based on 1-df tests.
Adjusted multiple-comparison p values, taking into account tagSNPs within the gene, were
estimated using the step-down Bonferroni correction (i.e., Holm method) based on the
effective number of independent SNPs as determined using SNPSpD (http://
genepi.qimr.edu.au/general/daleN/SNPSpD/) on the full sample of cases and controls (30,
31).
Results
The population was 55.69% male and 69.66% age 60 and over. The majority of participants
were non-Hispanic white (90.07%), with 4.94% being Hispanic and 3.69% being African
American. We examined 69 SNPs in 13 genes within the cytokine pathway in relation to
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colon and rectal cancer risk (Table 1). Of these, 15 SNPs in nine genes were significantly
associated with either colon or rectal cancer. For colon cancer, one SNP in IL3 (rs181781),
two in IL6R (rs4845623 and rs7549250), one in IL8 (rs4073), one in IL10 (rs3024505) and
two in IL15 (rs13117878 and rs1519551) were significantly associated with cancer risk.
When rectal cancer was examined, one SNP in IL1B (rs1143623), one in IL4 (rs2243263),
two in CXCR1 (rs1008562 and rs1008563), one in CXCR2 (rs1126579), one in IL10
(rs1800871), and two in IL15 (rs12508866 and rs17461269) were significantly associated
with risk. After adjustment for multiple comparisons 6 SNPs in six genes remained
significantly associated with either colon or rectal cancer; IL3 (rs181781), IL6R
(rs4845623), IL8 (rs4073), IL15 (rs13117878), remained significantly associated with
increased colon cancer risk and CXCR1 (rs1008562), and CXCR2 (rs1126579) remained
significantly associated with increased rectal cancer risk (Table 2).
Only SNPs from genes within the IL-8 pathway (IL8, CXCR1, and CXCR2) showed a
significant association with both colon and rectal cancer risk, but different SNPs showed
significance for each cancer type. Several SNPs within the IL8 gene and IL-8 receptor genes

CXCR1 and CXCR2, were associated with increased risk of colon or rectal cancer. For
colon cancer risk, the variant allele for IL8 rs4073 was associated with increased risk (OR
1.21, 95% CI 1.04–1.41; Wald p value 0.0114, Holm p value 0.0149). The CC genotype for
rs1008562 in CXCR1 was associated with increased risk of rectal cancer compared to the
CG or GG genotypes (OR 1.18, 95% CI 0.94–1.49 and OR 1.57, 95% CI 1.20–2.05,
respectively; Wald p value 0.0010, Holm p value 0.0029). The CXCR2 rs1126579 TT
genotype was also associated with increased risk of rectal cancer compared to CC or CT
genotypes (OR 1.18, 95% CI 0.94–1.49 and OR 1.56, 95% CI 1.19–2.05, respectively; Wald
p value 0.0012, Holm p value 0.0014).
Interactions between cytokine SNPs and factors associated with colon and rectal cancer risk
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were examined; those with adjusted p values of <0.05 are shown (Table 3). There were no
significant findings after controlling for multiple testing for interaction with NSAIDS,
smoking, or BMI. However, when recent estrogen use was examined one SNP in IL10
(rs1554286 Holm p value 0.0376), two SNPs in IL1B (rs1143623 Holm p value 0.0375 and
rs1143627 Holm p value 0.0375), and one SNP in CXCR2 (rs1126579 Holm p value
0.0393) interacted significantly for colon cancer whereas one SNP for IL1A (rs3783546
Holm p value 0.0317) and two SNPs for IL8 (rs2227543 Holm p value 0.0407 and rs4073
Holm p value 0.0407) had significant interactions for rectal cancer. There were additional
SNPs from interleukin genes with significant raw p-values for estrogen use but after
controlling for multiple testing they did not remain significant.
IL1A codes for IL-1alpha and IL1B codes IL-1beta both of which are cytokines that bind
specifically to the IL-1 receptor; the IL1RN gene codes for an antagonist which binds to the
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IL-1 receptor, thus we examined interactions between SNPs in these genes. There were no
significant interactions between SNPs within this pathway for colon or rectal cancer after
adjusting for multiple comparisons. IL-8 can bind to two different forms of the IL-8
receptor: either IL-8 receptor alpha also called CXCR1 or IL-8 receptor beta also called
CXCR2. Therefore interactions between SNPs in these genes were examined. For colon
cancer, one IL8 SNP (rs4073) interacted with two CXCR1 SNPs (rs1008563 and rs1008562)
and one CXCR2 SNP (rs1126579) (Table 4). No interactions were detected for rectal cancer
within this pathway. Interferon gamma is a well-known pro-inflammatory cytokine and
interactions between other cytokines or receptors within the pro-inflammatory pathway were
examined. For colon cancer, two SNPs from the IL8 gene (rs4073 and rs2227543) interacted
significantly with one SNP from the IFNG gene (rs2069718) after multiple comparison
adjustment (Table 4). For rectal cancer, similar interactions between SNPs within the pro-
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inflammatory pathways were tested; however there were no significant interactions after
adjusting for multiple comparisons. Anti-inflammatory interleukins were also tested for
interactions and no significant interactions were observed for colon or rectal cancer.
Associations between tumor markers and SNPs from interleukin genes were assessed (Table
5). For colon cancer, four SNPs from IL1RN (rs452204, rs315952, rs4251961, and
rs315949) and one SNP from IL1B (rs1143623) were significantly associated with CIMP+
and/or MSI+ tumor markers when compared to other tumor molecular phenotypes. KRAS2
mutations were associated with one IL17A SNP (rs10484879) for colon cancer and one
IL1B SNP (rs1143633) was associated for both colon and rectal cancer. Also for rectal
cancer, one SNP from IL8 (rs2227543) was associated with TP53 mutations after
adjustments for multiple comparisons.
We also examined whether SNPs in the cytokine pathway were associated with overall
survival rates from colorectal cancer (Table 6). For colon cancer, two SNPs in IL1B were
associated with overall survival. For rectal cancer, SNPs in IL1A, IL3, and CXCR2 were
associated with overall survival. CXCR2 rs1126579 was associated with both risk and

overall survival for rectal cancer. Summary scores were generated to reflect the combined
effect of risk alleles on overall survival of rectal disease. Increasing numbers of risk alleles
were associated with increased hazard of death from cancer. The estimated hazard of death
for rectal cancer for the highest category of risk alleles was 2.04 (95% CI 1.38–3.00).
Discussion
Chronic inflammatory pathways in the gut have been implicated in the etiology of different
cancer types including colon and rectal cancers (1–3). Our study further supports the roles of
pro-inflammatory and anti-inflammatory cytokines in risk and overall survival for colon and
rectal cancers. Previous studies of colorectal cancer are often not large enough to distinguish
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between colon and rectal cancer. However, recent publications indicate differences in
genetic variations associated with risk and overall survival between colon and rectal cancer
(5, 32–34). The majority of risk alleles for both colon and rectal cancer in this study are
within the pro-inflammatory classification.
Constitutive expression of pro-inflammatory interleukins leads to an inflammatory state

within the gut and is thought to increase risk for the development of colon and rectal cancer
(2). The pro-inflammatory interleukins analyzed in this report included IL-1, IL-2, IL-8,
IL-12, IL-15, and IL-17 while anti-inflammatory interleukins included IL-4 and IL-10. The
IL1RN gene codes for the IL-1 receptor antagonist (IL-1RA) and would be considered anti-
inflammatory. IL-3 was considered separately as it supports differentiation and proliferation
of various immune cells, thereby playing a significant role in immune responses. Of the
interleukins genes tested, we are not aware of any previous reports of associations with
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SNPs from IL2, IL3, IL4, IL15, or IL17 with colon or rectal cancer. There are, however,
reports of genetic associations between IL1A, IL1B, IL1RN, IL2, IL4, IL10, IL17, and
inflammatory bowel disease (35–39). Associations between SNPs in interleukin genes and
risk or survival have been reported with conflicting results. For example, the IL8 rs4073
SNP was significantly associated with reduced risk in one study (40) although two
additional studies indicated no affect on colorectal risk (12, 41). This SNP was significantly
associated with increased colon cancer risk in the current study. A third study indicated that
patients with IL8 rs4073 had an increased time to recurrence of advanced colorectal cancer
(42), but we found no significant associations between this SNP and overall survival for
either colon or rectal cancer. Studies analyzing associations between risk or survival and
SNPs in interleukin genes such as IL1B, IL1RA, IL10 have also reported conflicting results;
some SNPs being associated with increased risk or survival while others associated with a
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lower risk or survival for colorectal cancer (11, 12, 42–44).
The SNP associations for the cytokines examined in this study were not significantly
modified by several of the environmental influences tested, including aspirin/NSAID use or
cigarette smoking. However, there is evidence to suggest that estrogens may influence
inflammation-related mechanisms (45, 46) which is supported by our data. Estrogen use was
associated with increased risk for the TT genotype of one IL10 SNP (rs1554286) in colon.
The variant GC or CC genotypes of IL1B (rs1143623) and TC or CC genotypes of IL1B
(rs1143627) appear to be protective among non-recent estrogen users for colon cancer. One
SNP from the IL-8 interleukin pathway also interacted with recent estrogen use; the CT/TT
genotypes of CXCR2 (rs1126579) were protective for colon cancer among recent users. For
rectal cancer, recent estrogen use interacted with several SNPs from interleukins genes.
Among recent users, a decreased cancer risk was seen for the CC genotype of IL1A
(rs3783546), CT/TT genotype of IL8 (rs2227543) and TA/AA genotypes of IL8 (rs4073).
One SNPs from IL-8 receptor gene CXCR2 (rs1126579), were associated with both risk and
overall survival of rectal cancer. In addition, this SNP also interacted with one SNP from

IL-8, IL8 (rs4073). For CXCR2 (rs1126579), two copies of the variant allele increases colon
cancer risk among those with the TT genotype for IL8 (rs4073). The functional effects of
this SNP is unknown at the present time. However, the SNP is found at the 3’ end of each
respective gene and could potentially alter translation and stability of RNA. No reports of
the functional affect of this SNP is currently available, however, given the results from
multiple previous studies and our own results, it merits further investigation.
The study has many strengths in that it is a large study with the power to evaluate colon and
rectal cancer separately; there is increasing evidence that these represent distinct cancer
sites. The data were collected in a very rigid manner using strict quality control measures.
We used a tagSNP approach to characterize the genetic variation within the candidate genes.
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Our analysis was hypothesis driven, and included evaluation of candidate genes and
interaction of those genes with lifestyle and genetic factors that had a biological basis.
However, we have made numerous comparisons, and although we have adjusted for
multiple comparisons, findings could be spurious. Additionally, we lack information on
functionality of these SNPs. Assessment of functionality of SNPs associated with colon and
rectal cancer is needed.
In summary, genetic variations in multiple interleukin genes were associated with risk for
colon or rectal cancer. Few associations were modified by lifestyle factors such as aspirin/
NSAID use, cigarette smoking, or obesity; however, several associations were modified by
current estrogen use. Genetic variation within interleukins also impacted overall survival
after diagnosis. As a whole, our data suggests that interleukin genes play a role in risk and
overall survival for colon and rectal cancer and future studies to gain further insight into
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specific mechanisms are warranted.
Acknowledgments
This study was funded by NCI grants CA48998. This research also was supported by the Utah Cancer Registry,
which is funded by Contract #N01-PC-67000 from the National Cancer Institute, with additional support from the
State of Utah Department of Health, the Northern California Cancer Registry, and the Sacramento Tumor Registry.
The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the
official view of the National Cancer Institute. We would like to acknowledge the contributions of Dr. Bette Caan,
Donna Schaffer, and Judy Morse at the Kaiser Permanente Medical Care Program in Oakland, California;, Sandra
Edwards, Roger Edwards, and Leslie Palmer at the University of Utah; and Drs. Kristin Anderson and John Potter
at the University of Minnesota for data management and collection.
Abbreviations
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SNPs Single Nucleotide Polymorphisms
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Table 1
Summary of SNPs
Gene Location Coordinate tagSNP Major/Minor MAF FDR

Allele HWE
IL6R 1q21 152648673 rs1386821 A/C 0.19 0.973
Bondurant et al.
152655820 rs4075015 T/A 0.42 0.963

152670960 rs7549250 T/C 0.42 0.683
152682401 rs4845623 A/G 0.42 0.509
152693594 rs8192284 A/C 0.40 0.580
152696716 rs11265618 C/T 0.18 0.895
152703008 rs4509570 C/G 0.23 0.579
152704520 rs2229238 C/T 0.19 0.234
IL10 1q31-q32 205006527 rs3024505 C/T 0.14 0.973

205008152 rs3024498 A/G 0.28 0.997
205008487 rs3024496 T/C 0.48 0.963
205010591 rs3024493 G/T 0.14 0.963
205010856 rs1554286 C/T 0.19 0.997
205011268 rs1518111 G/A 0.21 0.997
205013257 rs1800871 C/T 0.23 0.982
205013520 rs1800896 A/G 0.48 0.954
205015988 rs1800890 T/A 0.39 0.997
IL1A 2q14 113251301 rs3783546 G/C 0.30 0.997

113253694 rs17561 G/T 0.31 0.997
113256443 rs2856838 C/T 0.39 0.997
113260048 rs3783521 C/T 0.30 0.997
113260905 rs1878321 T/C 0.31 0.997
IL1B 113304773 rs1143643 G/A 0.35 0.997

113306861 rs1143634 C/T 0.23 0.997
113306938 rs1143633 G/A 0.35 0.997
113310858 rs1143627 T/C 0.34 0.997
113312300 rs1143623 G/C 0.28 0.997
Page 11

Allele HWE
IL1RN 2q14.2 113590938 rs4251961 T/C 0.38 0.997

113593250 rs2637988 A/G 0.39 0.979
113595768 rs3213448 G/A 0.12 0.020
Bondurant et al.
113597418 rs315936 C/T 0.25 0.997

113603929 rs408392 G/T 0.27 0.997
113605371 rs380092 A/T 0.32 0.997
113605532 rs452204 G/A 0.39 0.952
113606775 rs315952 T/C 0.30 0.901
113607057 rs315951 G/C 0.30 0.920
113607883 rs9005 G/A 0.29 0.997
113608612 rs397211 T/C 0.29 0.997
113608995 rs4252042 G/A 0.11 0.997
113609245 rs315949 C/T 0.41 0.997
CXCR2 2q35 218698831 rs4674258 C/T 0.49 0.901

218708979 rs1126579 C/T 0.47 0.954
CXCR1 218735133 rs1008563 C/T 0.44 0.997

218735217 rs1008562 C/G 0.47 0.901
218737177 rs16858808 C/T 0.03 0.997
218737969 rs1805038 C/T 0
218738088 rs16858811 T/G 0.03 0.948

IL8 4q13-q21 74824888 rs4073 T/A 0.46 0.997
74825533 rs2227307 T/G 0.45 0.997
74826774 rs2227543 C/T 0.42 0.997
IL2 4q26-q27 123591426 rs2069776 T/C 0.27 0.682

123592583 rs2069772 A/G 0.28 0.997
123595585 rs2069778 C/T 0.16 0.874
123597430 rs2069762 T/G 0.30 0.997
IL15 4q31 142785143 rs12508866 T/C 0.23 0.997

Page 12

Allele HWE
142789922 rs1519551 A/G 0.45 0.997
142792798 rs17461269 T/A 0.34 0.997
142818672 rs13117878 C/T 0.48 0.979
Bondurant et al.
142822580 rs12498901 G/C 0.14 0.997

142856755 rs6850492 G/A 0.43 0.973
IL3 5q31.1 131423014 rs181781 G/A 0.10 0.682

131424377 rs40401 C/T 0.22 0.963
131424575 rs35482671 A/G <0.01 0.997
IL4 132040624 rs2227284 C/A 0.26 0.997

132041078 rs2227282 C/G 0.26 0.997
132041198 rs2243263 G/C 0.11 0.509
132041862 rs2243268 A/C 0.14 0.997
132046068 rs2243290 C/A 0.14 0.997
IL17A 6p12 52051957 rs10484879 G/T 0.23 0.997
Minor Allele Frequency (MAF) and FDR-adjusted Hardy-Weinberg Equilibrium (FDR HWE) based on white control population.

Page 13
Table 2
Adjusted significant SNPs in candidate interleukin genes
Controls Cases OR (95% CI) Wald P Holm P
Colon Cancer
Bondurant et al.
IL3 rs181781 0.0249 0.0408

GG/GA 1945 1536 1.00
AA 10 19 2.42 (1.12,5.22)
IL6R rs4845623* 0.0046 0.0278
AA/AG 1641 1242 1.00

GG 315 313 1.29 (1.08, 1.53)
IL8 rs4073** 0.0114 0.0149
TT 576 396 1.00

TA/AA 1380 1159 1.21 (1.04, 1.41)
IL15 rs13117878 0.0091 0.0362

CC/CT 1520 1151 1.00
TT 436 402 1.23 (1.05, 1.44)
Rectal Cancer
CXCR1 rs1008562 0.0010 0.0029

CC 283 187 1.00
CG 466 356 1.18 (0.94, 1.49)

GG 206 211 1.57 (1.20, 2.05)
CXCR2 rs1126579*** 0.0012 0.0014
CC 290 192 1.00

CT 470 359 1.18 (0.94, 1.49)
TT 199 201 1.56 (1.19, 2.05)
Odds Ratios (OR) and 95% Confidence Intervals (CI)adjusted for age, sex, study center, and race/ethnicity.
*
Similar associations for IL6R rs8192284 (r2=0.83).
Page 14
**
Similar associations for IL8 rs2227307 (r2=0.94).
***
Associations of similar magnitude (in opposite direction) for IL8RB rs4674258 (r2=0.81).
Bondurant et al.

Page 15
Table 3
Interaction between aspirin/NSAID use, cigarette smoking, estrogen exposure, and BMI and SNPs in candidate interleukin genes.
Controls Cases Controls Cases Interaction P Holm P

N N OR (95% CI) N N OR (95% CI)
Bondurant et al.
No Recent Estrogen Exposure Recent Estrogen Exposure
Colon Cancer
IL10 (rs1554286)* 0.0094 0.0376
CC 318 297 1.00 246 139 0.49 (0.37, 0.67)
CT 173 134 0.83 (0.63, 1.09) 109 73 0.58 (0.40, 0.83)
TT 32 18 0.56 (0.31, 1.04) 6 10 1.40 (0.49, 3.97)
IL1B (rs1143623) 0.017 0.0375

GG 259 259 1.00 196 124 0.50 (0.36, 0.69)
GC 216 167 0.75 (0.58, 0.98) 147 75 0.41 (0.28, 0.58)
CC 48 23 0.47 (0.28, 0.81) 18 22 0.97 (0.50, 1.89)
IL1B (rs1143627) 0.0125 0.0375
TT 197 208 1.00 155 103 0.50 (0.35, 0.71)
TC 249 199 0.73 (0.56, 0.96) 175 86 0.37 (0.26, 0.53)
CC 77 42 0.48 (0.31, 0.74) 31 33 0.77 (0.45, 1.34)
CXCR2 (rs1126579) 0.0331 0.0393
CC 147 107 1 87 66 0.85 (0.55, 1.31)
CT/TT 376 342 1.28 (0.96, 1.72) 274 156 0.65 (0.46, 0.92)

Rectal Cancer
IL1A (rs3783546)** 0.0127 0.0317
GG/GC 156 124 1.00 214 150 0.75 (0.53, 1.07)
CC 13 17 1.63 (0.76, 3.51) 35 11 0.33 (0.16, 0.70)
IL8 (rs2227543) 0.0312 0.0407
CC 71 50 1.00 72 60 1.02 (0.60, 1.71)
CT/TT 98 91 1.36 (0.86, 2.18) 177 101 0.70 (0.44, 1.11)
IL8 (rs4073) 0.0376 0.0407

Page 16
Controls Cases Controls Cases Interaction P Holm P

TT 62 39 1 63 49 1.07 (0.60, 1.89)
TA/AA 107 102 1.54 (0.95, 2.51) 186 112 0.82 (0.50, 1.34)
Odds Ratios (OR) and 95% Confidence Intervals (CI) adjusted for age, sex, study center, and race/ethnicity.
Bondurant et al.
*
Similar associations for IL10 rs1518111 (r2=0.86 with rs1554286).
**
Similar associations for IL1A rs3783521 (r2=0.97).

Page 17
Table 4
Associations between candidate interleukin genes in colon cancer
Colon
Controls Cases Controls Cases Controls Cases Interaction P Holm P

Bondurant et al.
N N OR (95% CI) N N OR (95% CI) N N OR (95% CI)
IL8 (rs4073)*
TT TA AA
CXCR1(rs1008563) CC 185 152 1 290 254 1.06 (0.81,1.39) 149 118 0.92 (0.67,1.28)
CT 286 185 0.77 (0.58,1.02) 486 389 0.96 (0.75,1.24) 208 182 1.03 (0.77,1.39)
TT 104 59 0.68 (0.46,1.00) 181 136 0.9 (0.66,1.23) 66 76 1.34 (0.90,1.99) 0.0067 0.0233
CXCR1(rs1008562) CC 153 100 1 262 195 1.14 (0.83,1.56) 112 118 1.55 (1.08,2.24)
CG 292 182 0.95 (0.69,1.30) 498 418 1.29 (0.97,1.71) 215 186 1.31 (0.95,1.81)
GG 130 114 1.36 (0.95,1.95) 195 167 1.34 (0.96,1.85) 96 70 1.11 (0.74,1.65) 0.0233 0.0447
CXCR2(rs1126579)** CC 158 98 1 266 200 1.21 (0.88,1.65) 112 119 1.63 (1.13,2.35)
CT 289 187 1.04 (0.76,1.42) 500 420 1.36 (1.02,1.80) 220 187 1.36 (0.99,1.87)
TT 129 111 1.41 (0.99,2.02) 191 163 1.41 (1.02,1.96) 91 70 1.23 (0.82,1.84) 0.0265 0.0265
IFNG (rs2069718)
IL8 (rs4073)*** TT 187 148 1 272 180 0.83 (0.62,1.11) 117 68 0.71 (0.49,1.03)
TA 297 282 1.2 (0.91,1.57) 474 364 0.97 (0.75,1.25) 186 137 0.9 (0.66,1.23)
AA 157 116 0.91 (0.66,1.25) 186 180 1.19 (0.88,1.61) 80 80 1.19 (0.81,1.75) 0.0204 0.0357
IL8(rs2227543)*** CC 219 184 1 327 236 0.85 (0.66,1.11) 152 95 0.69 (0.50,0.96)

CT 291 266 1.11 (0.86,1.44) 448 345 0.93 (0.73,1.19) 182 139 0.9 (0.67,1.21)
TT 131 96 0.88 (0.63,1.22) 157 143 1.09 (0.81,1.47) 49 51 1.22 (0.78,1.89) 0.0207 0.0357
Odds Ratios (OR) and 95% Confidence Intervals (CI) adjusted for age, sex, study center, and race/ethnicity.
*
Similar associations for IL8 rs2227307 (r2=0.94)
**
Associations of similar magnitude (in opposite direction) for IL8RB rs4674258 (r2=0.81).
***
Similar associations for IL8 rs2227307 (r2=0.94 with rs4073 and r2=0.84 with rs2227543).
Page 18
Table 5
Associations between candidate interleukin genes and tumor markers
Heterogeneity P
Values
Bondurant et al.
Colon CIMP+ and/or MSI+
IL1RN (rs452204)1
GG/GA 1668 314 1 0.0005 0.0024
AA 288 35 0.63 (0.44,0.89)
IL1RN (rs315952)2
TT/TC 1767 327 1 0.0464 0.0478
CC 189 22 0.62 (0.40, 0.95)
IL1RN (rs4251961)
TT 776 116 1 0.0004 0.0022
TC/CC 1180 233 1.4 (1.12, 1.75)
IL1RN (rs315949)
CC 702 109 1 0.0015 0.0062
CT 930 163 1.17 (0.92, 1.50)
TT 324 77 1.6 (1.19, 2.14)
IL1B (rs1143623)
GG/GC 1811 337 1 0.0012 0.0037
CC 145 12 0.45 (0.26, 0.79)

KRAS2 Mutations
IL17A (rs10484879)
GG 1201 239 1.00 0.0111 0.0111
GT/TT 772 114 0.76 (0.61, 0.95)
IL1B (rs1143633)3
GG 819 123 1.00 0.0072 0.0217
GA/AA 1137 224 1.30 (1.04, 1.62)
Rectal
IL1B (rs1143633)3
Page 19
Heterogeneity P
Values
GG 428 88 1.00 0.0054 0.0151
GA 398 73 0.89 (0.65, 1.21)
Bondurant et al.
AA 133 12 0.44 (0.24, 0.79)
TP53 Mutations
IL8 (rs2227543)
CC 330 113 1.00 0.0016 0.0021
CT 474 134 0.82 (0.63, 1.06)
TT 155 30 0.58 (0.38, 0.88)
Models are adjusted for age, study center, race/ethnicity, and sex.
Odds Ratios (OR) and 95% Confidence Intervals (CI) compare cases with tumor molecular phenotype to controls.
Heterogeneity p values based on comparison of cases with tumor molecular phenotype to cases without.
1
Similar associations for IL1RN rs2637988 (r2=0.88).
2
Similar associations for IL1RN rs315951 (r2=0.99).
3
Similar associations for IL1B rs1143643 (r2=0.99).

Page 20
Table 6
Colorectal Overall Survival
Death/
Person Years HRR (95% CI) Trend P Wald P Holm P
Colon Cancer
Bondurant et al.
IL1B rs1143623
GG 162 / 4625 1.00 0.0073 0.0220
GC/CC 147 / 3518 1.37 (1.09, 1.72)
rs1143627
TT 126 / 3682 1.00 0.0232 0.0465
TC/CC 183 / 4466 1.31 (1.04, 1.65)
Rectal Cancer
IL1A rs3783546*
GG 73 / 2099 1.00 0.0204 0.0191 0.0478
GC 72 / 1831 1.08 (0.77, 1.52)
CC 26 / 359 2.07 (1.28, 3.36)
IL3 rs181781
GG 128 / 3475 1.00 0.0253 0.0196 0.0321
GA 36 / 761 1.31 (0.90, 1.92)
AA 7 / 53 2.47 (1.11, 5.53)
IL8RB rs1126579**
CC 38 / 1109 1.00 0.0228 0.0233 0.0277
CT 75 / 2077 1.14 (0.76, 1.71)

TT 58 / 1087 1.61 (1.05, 2.46)
Summary Score***
(0–1) 54/1833 1.00 0.0003
(2–2) 54/1405 1.36 (0.92, 2.00)
(3–6) 63/1051 2.04 (1.38, 3.00)
Hazard Rate Ratios (HRR) and 95% Confidence Intervals (CI) adjusted for age, study center, race/ethnicity, sex, AJCC stage, and tumor molecular phenotype.
*
Similar associations for IL1A rs3783521 (r2=0.97).
**
Similar associations for IL8RB rs4674258 (r2=0.81).
Page 21

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Interleukin genes and associations with colon and rectal cancer

Wolff2, and Martha L. Slattery2

Sciences, Little Rock, Arkansas, USA

examined genetic variation in genes from various anti-inflammatory and pro-inflammatory

overall survival for colon and rectal cancer.

Improper regulation of anti-inflammatory interleukins is also implicated in cancer and

Int J Cancer. Author manuscript; available in PMC 2014 February 15.

Interview Data Collection

Tumor Registry Data

Tumor Marker Data

TagSNP Selection and Genotyping

Int J Cancer. Author manuscript; available in PMC 2014 February 15.

score terms; Wald p values are also based on 1-df tests.

Int J Cancer. Author manuscript; available in PMC 2014 February 15.

Int J Cancer. Author manuscript; available in PMC 2014 February 15.

Constitutive expression of pro-inflammatory interleukins leads to an inflammatory state

lower risk or survival for colorectal cancer (11, 12, 42–44).

Int J Cancer. Author manuscript; available in PMC 2014 February 15.

specific mechanisms are warranted.

SNPs Single Nucleotide Polymorphisms

Int J Cancer. Author manuscript; available in PMC 2014 February 15.

16. Oliver J, Rueda B, Lopez-Nevot MA, Gomez-Garcia M, Martin J. Replication of an association

2010; 12:1208–1212. [PubMed: 19863607]

Int J Cancer. Author manuscript; available in PMC 2014 February 15.

responses: an introduction to generalized estimating equations and multi-level mixed modelling.

Gastroenterol. 2011; 45:531–535. [PubMed: 20975573]

Int J Cancer. Author manuscript; available in PMC 2014 February 15.

Int J Cancer. Author manuscript; available in PMC 2014 February 15.

Gene Location Coordinate tagSNP Major/Minor MAF FDR

152655820 rs4075015 T/A 0.42 0.963

IL10 1q31-q32 205006527 rs3024505 C/T 0.14 0.973

IL1A 2q14 113251301 rs3783546 G/C 0.30 0.997

Int J Cancer. Author manuscript; available in PMC 2014 February 15.

IL1B 113304773 rs1143643 G/A 0.35 0.997

Gene Location Coordinate tagSNP Major/Minor MAF FDR

IL1RN 2q14.2 113590938 rs4251961 T/C 0.38 0.997

113597418 rs315936 C/T 0.25 0.997

CXCR2 2q35 218698831 rs4674258 C/T 0.49 0.901

CXCR1 218735133 rs1008563 C/T 0.44 0.997

Int J Cancer. Author manuscript; available in PMC 2014 February 15.

IL2 4q26-q27 123591426 rs2069776 T/C 0.27 0.682

IL15 4q31 142785143 rs12508866 T/C 0.23 0.997

Gene Location Coordinate tagSNP Major/Minor MAF FDR

142822580 rs12498901 G/C 0.14 0.997

IL3 5q31.1 131423014 rs181781 G/A 0.10 0.682

IL4 132040624 rs2227284 C/A 0.26 0.997

IL17A 6p12 52051957 rs10484879 G/T 0.23 0.997

Int J Cancer. Author manuscript; available in PMC 2014 February 15.

Controls Cases OR (95% CI) Wald P Holm P

IL3 rs181781 0.0249 0.0408

IL6R rs4845623* 0.0046 0.0278

AA/AG 1641 1242 1.00

IL8 rs4073** 0.0114 0.0149

TT 576 396 1.00

IL15 rs13117878 0.0091 0.0362

CXCR1 rs1008562 0.0010 0.0029

Int J Cancer. Author manuscript; available in PMC 2014 February 15.

CXCR2 rs1126579*** 0.0012 0.0014

CC 290 192 1.00

Int J Cancer. Author manuscript; available in PMC 2014 February 15.

Controls Cases Controls Cases Interaction P Holm P

No Recent Estrogen Exposure Recent Estrogen Exposure

IL10 (rs1554286)* 0.0094 0.0376