Tumor Biol.

DOI 10.1007/s13277-014-3010-x

RESEARCH ARTICLE

An exon variant in insulin receptor gene is associated

with susceptibility to colorectal cancer in women
Touraj Mahmoudi & Keivan Majidzadeh-A &
Khatoon Karimi & Negar Karimi & Hamid Farahani &
Reza Dabiri & Hossein Nobakht &
Hesamodin Dolatmoradi & Maral Arkani &
Mohammad Reza Zali

Received: 27 September 2014 / Accepted: 23 December 2014

# International Society of Oncology and BioMarkers (ISOBM) 2015

Abstract Given the role of insulin resistance in colorectal
cancer (CRC), we explored whether genetic variants in insulin
(INS), insulin receptor (INSR), insulin receptor substrate 1
(IRS1), insulin receptor substrate 2 (IRS2), insulin-like growth
factor 1 (IGF1), and insulin-like growth factor binding protein
3 (IGFBP3) genes were associated with CRC risk. A total of
600 subjects, including 261 cases with CRC and 339 controls,
were enrolled in this case-control study. Six polymorphisms in
INS (rs689), INSR (rs1799817), IRS1 (rs1801278), IRS2
(rs1805097), IGF1 (rs5742612), and IGFBP3 (rs2854744)
genes were genotyped using PCR-RFLP method. No signifi-
cant difference was observed for INS, INSR, IRS1, IRS2,
IGF1, and IGFBP3 genes between the cases and controls.
However, the INSR rs1799817 “TT + CT” genotype and
“CT” genotype compared with “CC” genotype occurred more
frequently in the women with CRC than women controls (P=
0.007; OR=1.93, 95 %CI=1.20–3.11 and P=0.002, OR=
2.15, 95 %CI=1.31–3.53, respectively), and the difference
T. Mahmoudi (*) : K. Karimi : N. Karimi : H. Dolatmoradi :
M. Arkani : M. R. Zali
Department of Cancer, Gastroenterology and Liver Diseases
Research Center, Shahid Beheshti University of Medical Sciences,
Velenjak, Shahid Chamran Highway, Tehran 1985711151, Iran
e-mail: mahmouditouraj@gmail.com
K. Majidzadeh-A
Cancer Genetics Department, Breast Cancer Research Center
(BCRC), ACECR, Tehran, Iran
H. Farahani
Department of Physiology, School of Medicine, Qom University of
Medical Sciences, Qom, Iran
R. Dabiri : H. Nobakht
Internal Medicine Department, Semnan University of Medical
Sciences, Semnan, Iran
remained significant after adjustment for confounding factors
including age, BMI, smoking status, NSAID use, and family
history of CRC (P=0.018; OR=1.86, 95 %CI=1.11-3.10 and
P=0.004, OR=2.18, 95 %CI=1.28–3.71, respectively). In
conclusion, to our knowledge, this study indicated for the first
time that the INSR rs1799817 TT+CT genotype and CT ge-
notype compared with the CC genotype had 1.86-fold and
2.18-fold increased risks for CRC among women, respective-
ly. Furthermore, this finding is in line with previous studies
which found significant associations between other variants of
the INSR gene and CRC risk. Nevertheless, further studies are
required to confirm our findings.
Keywords Colorectal cancer . Insulin . INSR . RFLP . Variant
Introduction
Colorectal cancer (CRC), one of the leading causes of cancer-
related mortality, is the second most commonly diagnosed
cancer across the world [1]. It has been reported that
hyperinsulinemia and insulin resistance (IR) are involved in
the etiology of CRC, and hyperinsulinemia has been proposed
as a putative mechanism that links obesity, an important risk
factor for many human diseases including cancer, with CRC
[2–5]. Furthermore, numerous epidemiologic studies have
shown that individuals with type 2 diabetes mellitus which
is associated with high insulin secretion and IR are at in-
creased risk of CRC [6]. In addition, previous studies have
demonstrated that cases with CRC have higher serum levels of
insulin [4], and insulin therapy may increase the risk of CRC
[7]. Finally, insulin increases cell proliferation and decreases

apoptosis [3, 6]. Insulin also increases the expression [8] and
bioavailability [3] of insulin-like growth factor 1 (IGF1) via
decreases of the synthesis of insulin-like growth factor bind-
ing proteins (IGFBPs), especially IGFBP3. The pleiotropic
biological actions of insulin are mediated by its receptor, in-
sulin receptor (INSR), through its ability to modulate the ex-
pression of target genes. It has also been demonstrated that
colonic cancer cells overexpress INSR in comparison to nor-
mal mucosae [9].
Insulin receptor substrates (IRSs) are the other important
proteins involved in insulin signaling pathway [10]. IRS1 and
IRS2 are cytoplasmic proteins which express in almost all
cells and mediate the major metabolic, proliferative, and
antiapoptotic functions of the INSR and IGF1 [11, 12]. While
IRS1 plays a key role in insulin action and cell proliferation,
IRS2 plays a central role in glucose metabolism, tumor pro-
gression, and metastasis [11, 13].
The other factors influencing IR are IGF1 and IGFBP3. In
fact, the insulin axis and IGF axis are biologically interrelated.
IGF1 regulates cell proliferation and differentiation, prevents
apoptosis [14], and increases metastasis [15] and could there-
fore contribute to the development of cancer. On the other
hand, IGFBP3 regulates the bioavailability of IGF1 to the
target tissues, and the action of IGF1 is partly regulated by
IGFBP3. Furthermore, IGFBP3 reduces the growth of exper-
imental colon tumors [16] and independent of IGF1, and
IGFBP3 has its own apoptotic effects [17].
Accordingly, this information support the hypothesis that
the gene variants related to IR including INS (rs689), INSR
(rs1799817), IRS1 (rs1801278), IRS2 (rs1805097), IGF1
(rs5742612), and IGFBP3 (rs2854744) might have a role in
the pathogenesis of CRC. Selection criteria for these variants
were based on their use in previous genetic epidemiology
studies, functional importance, and somewhat degree of
heterozygosity.
Materials and methods
Participants
A hospital-based case-control study of 261 cases with CRC
(age range, 22–84 years) and 339 controls (age range, 19–
85 years) was performed between March 2008 and June
2012 in Tehran, Iran. Both cases and controls were recruited
from individuals who were undergoing colonoscopy for vari-
ous gastrointestinal complaints such as change of bowel
habits, unexplained weight loss, long-term pain in the abdo-
men, rectal bleeding, chronic diarrhea, or constipation. How-
ever, the case group consisted of all eligible colonoscopy pa-
tients with positive pathologic report for CRC, while only
subjects whose colonoscopic results were negative for malig-
nancy, adenomatous polyps, or other polyps were chosen as
Tumor Biol.
controls. All subjects were Iranian and genetically unrelated,
and they were informed about the aims of the study. Informa-
tion on demographic, anthropometric, and clinical character-
istics of the cases and controls was recorded using self-
administered questionnaire before diagnosis of CRC. Study
protocol was approved by the Ethical Review Boards of the
Institution, and it was in accordance with the principles of the
Helsinki Declaration. Body mass index (BMI) was calculated
by weight (kg)/height (m2) formula.
Genotype analysis
Genomic DNA was extracted from 5 ml EDTA-
anticoagulated whole blood using standard methods, and
genotyping was done by PCR-RFLP method. Furthermore,
genotyping process was performed by investigators who
were blinded to the subjects’ clinical data. Details of the
studied gene variants and PCR and RFLP conditions are
shown in Table 1. All the PCR products were digested
overnight by corresponding restriction enzymes
(Fermentas, Leon-Rot, Germany) and then electrophoresed
on 2 to 3 % agarose gels. The PCR and RFLP bands in
gels stained with ethidium bromide for visualization under
UV light. INS, INSR, IRS1, IRS2, IGF1, and IGFBP3 ge-
notypes of each subject were identified according to the
digestion pattern and the presence or absence of the
Alw26I, PmlI, MvaI, HhaI, BselI, and NsbI sites, respec-
tively. To check for genotyping error rate, we repeated the
genotyping analysis of approximately 20 % of the randomly
selected samples. The genotyping was also confirmed by
the DNA sequencing of approximately 3 % of the samples
with different genotypes, and all the results were
concordant.
Statistical methods
We calculated differences in demographic or anthropo-
metric factors using t test or chi-square (χ2) test when
appropriate. Consistency of genotype frequencies with
the Hardy-Weinberg equilibrium (HWE) for each SNP
among cases and controls was tested using χ2 test. χ2
test was also used to calculate the differences in the
allele frequencies between the groups. Logistic regres-
sion was used to compare the distribution of the geno-
type frequencies between the different groups. To adjust
confounding factors including age, BMI, sex, smoking
status, and family history of CRC, logistic regression
analysis was also used. The odds ratios (ORs) were
the measure of associations and for all ORs; 95 % con-
fidence intervals (95 % CI) were calculated. For statis-
tical analyses, we used SPSS software, version 15.0
(SPSS Inc. Chicago, IL, USA). Significance was as-
sumed for P<0.05.
Tumor Biol.

Table 1 Information for the studied markers in insulin (INS), insulin receptor (INSR), insulin receptor substrate-1 (IRS1), insulin receptor substrate-2 (IRS2), insulin-like growth factor-1 (IGF1), and

Allele A: 156+107

Allele T: 234+176
Allele T: 230+211

Allele G: 221+70
Allele C: 274+43

Allele C: 166+80
Results

Alleles: RFLP

Allele A: 441

Allele A: 246
Allele G: 263

Allele A: 291

Allele C: 410
Allele T: 317
Clinicopathological analysis
fragments
size (bp)
Table 2 summarizes the selected characteristics of the cases
with CRC and controls. There were no statistically significant
Alw26I, 37 °C differences between the two groups regarded to their BMI,
gender, smoking status, and family history of CRC. However,
Eco72I, 37 °C

MvaI, 37 °C

BselI, 55 °C
HhaI, 37 °C

NsbI, 37 °C
temperature

the cases compared with the controls were older and less likely
Restriction

incubation
enzyme,

to use NSAIDs.

INS, INSR, IRS1, IRS2, IGF1, and IGFBP3 gene variant

analyses
fragment
size (bp)

Table 3 shows the genotype and allele distributions for INS

PCR

410
317
441

263

291

246
(rs689), INSR (rs1799817), IRS1 (rs1801278), IRS2
(rs1805097), IGF1 (rs5742612), and IGFBP3 (rs2854744)
gene variants in the cases with CRC and the controls. No
93 °C 45 s, 67 °C
93 °C 45 s, 57 °C

93 °C 45 s, 60 °C

93 °C 45 s, 64 °C

94 °C 45 s, 59 °C

95 °C 40 s, 55 °C

significant deviations from HWE were found for INSR,

40 s, 72 °C 45 s

35 s, 72 °C 45 s
40 s, 72 °C 45 s
30s, 72 °C 45 s

30s, 72 °C 45 s

30s, 72 °C 45 s

IRS1, IRS2, and IGFBP3 genes in both cases and controls,

(35 cycles)

suggesting that the alleles are in equilibrium (P>0.05). How-

program

ever, the genotype frequencies of the IGF1 gene rs5742612

PCR

variant were consist with HWE among the controls, but were
out of HWE in the cases (P<0.05). Furthermore, significant
deviations from HWE was observed for the INS gene rs689
5′-GACAGTGACAGGCAGCCTAGTAGAAG-3′

variant in both case and control populations. As shown in

Table 3, we observed no significant difference in genotype
5′-CCAAGGATGCTGTGTAGATAAG-3′

or allele frequencies between the cases and controls for all

5′-TCAGGAAAGCCAGCCCATGTC-3′

5′-CCGAGAGCGGAAGGGGTAAG-3′
5′-TCCAGGACAGGCTGCATCAG-3′
5′-AGCAATGGGCGGTTGGCTCA-3′

5′-TGGCGAGGTGTCCACGTAGC-3′

5′-GGCCACACCAAAAGCCATCT-3′

5′-CCCGTGCTTCGCCCTGAGCA-3′
5′-AGCTCCCCCAAGTCTCCTAA-3′

six genes either before or after adjustment for confounding

5′-CTTCTGTCAGGTGTCCATCC-3′

5′-CTGGGCATGAACACAAACG-3′

factors including age, BMI, sex, smoking status, NSAID

use, and family history of CRC.
Interestingly, when we stratified the analyses by gender, we
observed a significant difference between the cases and con-
trols for the INSR gene rs1799817 variant in female subjects.
The INSR rs1799817 “TT+CT” genotype compared with
Forward primer
Reverse primer

“CC” genotype occurred more frequently in the women with

CRC than women controls (P=0.007, OR=1.93, 95 %CI=
insulin-like growth factor binding protein-3 (IGFBP3) genes

1.20–3.11), and the difference remained significant after ad-

justment for confounding factors including age, BMI,
smoking status, NSAID use, and family history of CRC (P=
0.018; OR=1.86, 95 %CI=1.11–3.10). Furthermore, carriers
Promoter (C/A)
Promoter (T/A)

Promoter (C/T)
Exon 17 (T/C)

of INSR “CT” genotype compared with CC genotype occurred

Exon 1 (G/A)

Exon 1 (G/A)
(base change)

more frequently in the female cases with CRC than female

Location

controls (P=0.002, OR=2.15, 95 %CI=1.31–3.53), and the

difference remained significant after adjustment for confound-
ing factors (P=0.004, OR=2.18, 95 %CI=1.28–3.71).
IGFBP3 (rs2854744)
IGF1 (rs5742612)
INSR (rs1799817)

IRS1 (rs1801278)

IRS2 (rs1805097)

Discussion
INS (rs689)
(SNP ID)

With regard to the role of IR in the pathogenesis of CRC, our

Gene

case-control study was design to clarify whether there was an

 Tumor Biol.

Table 2 Study population characteristics Table 3 Association between genotypes and alleles of insulin (INS),
insulin receptor (INSR), insulin receptor substrate-1 (IRS1), insulin
Variables Controls (n=339) Cases (n=261) P value receptor substrate-2 (IRS2), insulin-like growth factor-1 (IGF1), and
insulin-like growth factor binding protein-3 (IGFBP3) gene variants
Age (years) 44.3 (16.3) 56.1 (12.6) <0.001 and risk of colorectal cancer
BMI (kg/m2) 25.2 (4.2) 25.6 (4.9) 0.261
Gene (variant) Controls Cases OR (95 % CI) P valuea
Sex (n=339) (n=261)
Male 164 (48.4) 146 (55.9)
Female 175 (51.6) 115 (44.1) 0.066 INS (rs689)
Smoking status Genotype-wise comparison
Never smoker 290 (85.5) 214 (82.0) AA 212 (62.6) 162 (62.1) 1.0 (reference)
Former smoker 39 (11.5) 32 (12.3) AT 75 (22.1) 66 (25.3) 1.24 (0.82–1.89) 0.314
Current smoker 10 (3.0) 15 (5.7) 0.261 TT 52 (15.3) 33 (12.6) 0.81 (0.48–1.36) 0.419
Regular NSAID use AT and TT 127 (37.4) 99 (37.9) 1.06 (0.74–1.52) 0.756
No 270 (79.6) 248 (95.0) TT versus others 52 (15.3) 33 (12.6) 0.76 (0.46–1.26) 0.290
Yes 69 (20.4) 13 (5.0) <0.001 Allele-wise comparison
Family history of colorectal cancer A 499 (73.6) 390 (74.7) 1.0 (reference)
No 303 (89.4) 229 (87.7) T 179 (26.4) 132 (25.3) 0.94 (0.73–1.23) 0.662
Yes 36 (10.6) 32 (12.3) 0.530 INSR (rs1799817)
Tumor location Genotype-wise comparison
Colon – 167 (63.9) CC 193 (56.9) 136 (52.1) 1.0 (reference)
Rectum – 94 (36.1) – CT 122 (36.0) 109 (41.7) 0.67 (0.33–1.37) 0.272
Metastasis TT 24 (7.1) 16 (6.1) 1.33 (0.92–1.93) 0.128
No – 176 (89.3) CT and TT 146 (43.1) 125 (36.9) 1.20 (0.84–1.71) 0.309
Yes – 21 (10.7) – TT versus others 24 (7.1) 16 (6.1) 0.59 (0.29–1.20) 0.147
Allele-wise comparison
Continuous variables presented as mean (SD); categorical variables as C 508 (74.9) 381 (73.0) 1.0 (reference)
number (%)
T 170 (25.1) 141 (27.0) 1.11 (0.85–1.43) 0.448
IRS1 (rs1801278)
association between insulin resistance-related gene variants
Genotype-wise comparison
and susceptibility to CRC risk in the Iranian population. The
GG 300 (88.5) 236 (90.4) 1.0 (reference)
results of this study showed no significant differences in allele
GA 38 (11.2) 24 (9.2) 0.92 (0.51–1.64) 0.767
and genotype frequencies of INS, INSR, IRS1, IRS2, IGF1,
AA 1 (0.3) 1 (0.4) 1.09 (0.05–23.70) 0.955
and IGFBP3 gene variants between the cases with CRC and
controls. However, when the subjects were subdivided by GA and AA 39 (11.5) 25 (9.6) 0.92 (0.52–1.64) 0.778
gender and after adjustment for confounding factors, the INSR AA versus others 1 (0.3) 1 (0.4) 1.10 (0.05–23.95) 0.950
rs1799817 TT+CT genotype and CT genotype compared Allele-wise comparison
with CC genotype had 1.86-fold and 2.18-fold increased risks G 638 (94.1) 496 (95.0) 1.0 (reference)
for CRC among women, respectively. A 40 (5.9) 26 (5.0) 1.20 (0.72–1.99) 0.489
IRS2 (rs1805097)
Genotype-wise comparison
INS gene rs689 variant
GG 139 (41.0) 109 (41.8) 1.0 (reference)
GA 153 (45.1) 118 (45.1) 1.04 (0.71–1.51) 0.854
To identify the majority of genes involved in complex multi-
AA 47 (13.9) 34 (13.1) 0.97 (0.56–1.66) 0.898
factorial diseases such as CRC may be difficult due to their
GA and AA 200 (59.0) 152 (58.2) 1.02 (0.72–1.51) 0.854
modest individual effects and complex interactions [18]. Pre-
vious epidemiologic studies, however, have suggested that the AA versus others 47 (13.9) 34 (13.1) 0.95 (0.57–1.57) 0.835
genes involved in insulin signaling pathway are candidate Allele-wise comparison
genes for CRC because as mentioned, the clinical and meta- G 431 (63.6) 336 (64.4) 1.0 (reference)
bolic features of cases with CRC include the increased risk of A 247 (36.4) 186 (35.6) 0.97 (0.76–1.22) 0.775
IR and obesity. To our knowledge, only one study [19] has IGF1 (rs5742612)
examined the association between INS gene variants and CRC Genotype-wise comparison
risk, which did not find any association. Furthermore, another TT 322 (95.0) 249 (95.4) 1.0 (reference)
previous study has reported that there was no association be- TC 16 (4.7) 11 (4.2) 0.92 (0.39–2.17) 0.850
tween the gene variants and advanced colorectal adenoma CC 1 (0.3) 1 (0.4) 0.62 (0.03–11.10) 0.742
Tumor Biol.

Table 3 (continued) association of the INSR gene rs1799817 variant with CRC
Gene (variant) Controls Cases OR (95 % CI) P value a risk. In previous studies, other INSR gene variants
(n=339) (n=261) (rs1051690 and rs1864010) were found to be associated with
CRC risk. Since the rs1799817 variant at exon 17 is a “syn-
TC and CC 17 (5.0) 12 (4.6) 0.89 (0.39–2.04) 0.787 onymous” polymorphism (His1085His), meaning that it does
CC versus others 1 (0.3) 1 (0.4) 0.62 (0.03–11.14) 0.743 not alter the amino acid sequence of the INSR, the exact mo-
Allele-wise comparison lecular mechanism responsible for the biological effects of the
T 660 (97.3) 509 (97.5) 1.0 (reference) variation is largely undetermined at present. However, the
C 18 (2.7) 13 (2.5) 1.07 (0.52–2.20) 0.859 INSR gene contains 22 exons, and exon 17 of the gene is
IGFBP3 (rs2854744) critical for the function of INSR because it encodes the partial
Genotype-wise comparison region of the tyrosine kinase domain. For this reason, it is
CC 124 (36.6) 92 (35.2) 1.0 (reference) critical for the function of the receptor [24], and it is important
CA 154 (45.4) 126 (48.3) 1.24 (0.84–1.83) 0.272 to study the association between genetic variants of this region
AA 61 (18.0) 43 (16.5) 1.22 (0.73–2.05) 0.444 and risk of diseases related to insulin signaling, including
CA and AA 215 (63.4) 169 (64.8) 1.24 (0.86–1.78) 0.253 CRC. Furthermore, previous studies have also shown a sig-
AA versus others 61 (18.0) 43 (16.5) 1.08 (0.68–1.72) 0.745 nificant association between the INSR gene variants and IR
Allele-wise comparison [25], type 2 diabetes [26], and BMI [20]. Any defects in num-
C 402 (59.3) 310 (59.4) 1.0 (reference) ber or function of INSR might impair the biological response
A 276 (40.7) 212 (40.6) 0.99 (0.79–1.26) 0.974 to insulin and lead to IR which is involved in the etiology of
CRC [2–5]. Therefore, our finding raises the possibility that
Variables presented as number (%) INSR gene may contribute to CRC development. However,
a
Adjusted for age, BMI, sex, smoking status, NSAID use, and family further studies with increased numbers of CRC patients are
history of colorectal cancer in genotype-wise comparisons
required to confirm our findings.

IRS1 rs1801278 and IRS2 rs1805097 gene variants

[20]. In accordance with these studies, we also found no sig-
nificant association between the INS gene rs689 variant and
CRC risk. The rs689 variant is located in the promoter of the
INS gene, and alterations in promoter sequence may influence
protein expression. In our study, significant deviations from
HWE were observed for the variant in both case and control
populations. Deviations from HWE may be due to different
reasons including small sample size, population stratification,
genotyping error, or inbreeding. Therefore, we suggest that
INS is not a predisposing gene for CRC in the Iranian popu-
lation, but we have to keep in mind that the deviation from
HWE can affect the interpretation of the association between
the INS gene rs689 variant and CRC risk. Accordingly, to
conclude that the gene is not involved in the pathogenesis of
CRC, other INS gene variants should also be investigated in
larger studies.
INSR gene rs1799817 variant
We also analyzed the association between the His 1085 C/T
variant in the exon 17 of INSR gene and CRC risk. Our find-
ings are in line with other studies [19, 21, 22] showing signif-
icant associations between the INSR gene variants and CRC
risk; nevertheless, null associations have also been observed
[23]. In our study, the INSR rs1799817 TT+CT genotype and
CT genotype compared with the CC genotype had 1.86-fold
and 2.18-fold increased risks for CRC among women, respec-
tively. To our knowledge, this is the first study reporting the
The other two genes studied here, IRS1 and IRS2, interact with
signaling pathways that modulate glucose metabolism and cell
growth. The rs1801278 (Gly972Arg) variant of the IRS1 gene
has been shown to be associated with IR and type 2 diabetes
[27], and a significant association between IRS2 gene
rs1805097 (Gly1057Asp) variant and obesity has been found
[28]. Nevertheless, studies of the effects of IRS1 and IRS2
gene variants on CRC risk have been inconclusive [19,
29–32]. In this study, we did not observe a significant associ-
ation between IRS1 gene rs1801278 variant and CRC risk,
which is in line with a previous report [19]. Furthermore,
consistent with our findings, most previous studies have found
no association between IRS2 gene rs1805097 variant and
CRC [19, 31, 32]. Significant associations, however, have
been found between CRC risk and both the rs1801278 [29,
30] and rs1805097 variants [29]. These inconsistent results
may be due to false-positive results, differences in genetic
makeup, nutritional factors, genotyped markers, statistical
methods, or disease definition. Alternatively, the rs1801278
and rs1805097 variants may be in linkage disequilibrium with
other unknown functional variants of the IRS1 and IRS2 genes
that explain the discrepancy observed.
IGF1 rs5742612 and IGFBP3 rs2854744 gene variants
In the present study, we also investigated the association be-
tween the IGF1 rs5742612 and IGFBP3 rs2854744 gene

variants and CRC risk. These two polymorphisms are located
in the promoter region, and alterations in promoter sequence
may influence protein expression. Furthermore, previous epi-
demiologic studies have indicated higher serum levels of
IGF1 and lower serum levels of IGFBP3 in the cases with
CRC than controls [3, 33]. In addition, significant associations
have been found between the IGF1 gene variants and serum
levels of IGF1 and between IGFBP3 gene variants and
IGFBP3 levels [34]. Nevertheless, our findings are in concor-
dance with those studies that show no associations between
CRC risk and IGF1 [23, 29, 35, 36] and IGFBP3 [23, 29, 35,
36] gene variants. In contrast, significant associations have
also been reported between IGF1 [37] and IGFBP3 [38] gene
variants and CRC risk. Accordingly, despite the fact that there
is no simple explanation for these discrepancies, our findings
do not support the hypothesis that the IGF1 rs5742612 and
IGFBP3 rs2854744 gene variants might play a role in patho-
genesis of CRC in the Iranian population.
Study limitations
Although well designed, our study has several limitations and
we should consider them in interpreting our results. One lim-
itation is the modest sample size that precludes drawing strong
conclusions and doing detailed analyses. Another limitation is
that by genotyping only one variant in each gene, the coverage
of the genes was incomplete. The other potential limitation is
our lack of information on serum levels of insulin, IGF1, and
IGFBP3, which could modify the effects observed here. How-
ever, this study provides interesting information and the pos-
sibility of true finding should not be excluded. In particular,
our findings are in line with previous studies.
Conclusions
In summary, in accordance with a previous study, our findings
indicated that the INSR rs1799817 TT+CT genotype and CT
genotype compared with CC genotype had a 1.86-fold and
2.18-fold increased risk for CRC among women, respectively.
Furthermore, this study does not support a role for effect of
the INS, IRS1, IRS2, IGF1, and IGFBP3 gene variants inves-
tigated and CRC risk in Iranian population. However, further
studies in other populations with increased numbers of CRC
patients are needed to confirm these findings.
Acknowledgments The authors are grateful to all the subjects for par-
ticipating. This work was supported by a grant from Gastroenterology
and Liver Diseases Research Center, Shahid Beheshti University of Med-
ical Sciences.
Conflicts of interest None
Tumor Biol.
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