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UNIVERSITI PUTRA MALAYSIA
ASSOCIATION BETWEEN POLYMORPHISMS IN INTERLEUKIN-17A AND
INTERLEUKIN-17F GENES IN COLORECTAL, BREAST AND NASOPHARYNGEAL CANCERS AT A TERTIARY
HOSPITAL IN KUALA LUMPUR, MALAYSIA
GOLNAZ SAMIEI
FPSK(M) 2014 54
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ASSOCIATION BETWEEN POLYMORPHISMS IN INTERLEUKIN-17A AND
INTERLEUKIN-17F GENES IN COLORECTAL, BREAST AND
NASOPHARYNGEAL CANCERS AT A TERTIARY
HOSPITAL IN KUALA LUMPUR, MALAYSIA
By
GOLNAZ SAMIEI
Thesis Submitted to the School of Graduate Studies, Universiti Putra Malaysia, in
Fulfilment of the Requirements for the Degree of Mater of Science
January 2014
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All material contained within the thesis, including without limitation text, logos, icons,
photographs and all other artwork, is copyright material of Universiti Putra Malaysia
unless otherwise stated. Use may be made of any material contained within the thesis for
non-commercial purposes from the copyright holder. Commercial use of material may
only be made with the express, prior, written permission of Universiti Putra Malaysia.
Copyright © Universiti Putra Malaysia
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DEDICATION
Specially dedicated to,
My beloved parents and brothers
For their invaluable love, precious support and encouragement through my study.
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Abstract of thesis presented to the Senate of Universiti Putra Malaysia in fulfillment of
the requirement for the Degree of Master of Science
SOCIATION BETWEEN POLYMORPHISMS IN INTERLEUKIN-17A AND
INTERLEUKIN-17F GENES IN COLORECTAL, BREAST AND
NASOPHARYNGEAL CANCERS AT A TERTIARY
HOSPITAL IN KUALA LUMPUR, MALAYSIA
By
GOLNAZ SAMIEI
January 2014
Chairman : Professor Seow Heng Fong, PhD
Faculty : Medicine and Health Sciences
Interleukin-17 (IL-17) is a CD4+ T cell-drived proinflammatory cytokines. IL-17 plays a
pivotal role in tissue inflammation by inducing the expression of proinflammatory and
neutrophil-mobilizing cytokines. IL-17 also has a critical role in inflammation and
cancer. Polymorphisms of IL-17A and IL-17F has been expected to be associated with
disease.
The purpose of this study was to demonstrate whether there was an association between
two polymorphisms of IL-17A/rs2275913 (G-197A) and IL-17F/rs763780 (A7488G)
genes and risk of sporadic colorectal, breast and nasopharyngeal cancers.
One single-nucleotide polymorphism (SNP) in IL-17A/rs2275913 (G197A) and another
SNP in IL-17F/rs763780 (A7488G) were determined by using genotype-specific
polymerase chain reaction-(PCR) and restriction fragment length polymorphism
(RFLP). DNA Sequencing was conducted to confirm the RFLP results in colorectal,
breast and nasopharyngeal cancer patients and apparently healthy individuals. PCR-
RFLP was carried out on isolated DNA from blood samples from sixty-three breast,
seventy-two nasopharyngeal cancer patients, eighty apparently healthy individuals, and
forty-seven colorectal cancer paraffin-embedded blocks to identify the association
between IL-17A/rs2275913 (G197A) and IL-17F/rs763780 (A7488G) polymorphisms
and risk of colorectal, breast, and nasopharyngeal cancers in Malaysia. This is the first
report on the IL-17 gene polymorphisms in cancer patients in Malaysia.
We compared the alleles and genotypes frequencies of IL-17A/rs2275913 (G197A) and
IL-17F/rs763780 (A7488G) in patients with colorectal, breast, and nasopharyngeal.
Statistical analysis of the results indicated that the homozygous AA genotype and the A
allele of IL-17A/rs2275913 G197A were more frequent in colorectal cancer patients.
Therefore, our study determined that IL-17A, but not IL-17F, contributes to colorectal
cancer susceptibility. The positive association was found between IL-17F/rs763780
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(A7488G) genotype in colorectal cancer with histological grade (P value< 0.005). No
significant relationship was found between IL-17A/rs2275913 (G197A) and IL-
17F/rs763780 (A7488G) with breast and nasopharyngeal cancer.
The results of this study emphasized the significance of IL-17A/rs2275913 (G197A)
gene polymorphism as the predisposing genetic parameters that confers the genetic
susceptibility for colorectal cancer in Malaysia. It demands expanding the cases and
further investigations to confirm the effect of IL-17A/rs2275913 (G197A)
polymorphism.
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Abstrak tesis dikemukakan kepada Senat Universiti Putra Malaysia sebagai memenuhi
keperluan untuk Ijazah Master Sains
HUBUNGAN ANTARA POLIMORFISMA GEN INTERLEUKIN-17A DAN
INTERLEUKIN-17F DAN RISIKO KANSER KOLOREKTAL, PAYU DARA
DAN NASOFARINKS DALAM HOSPITAL PENGAJIAN TINGGI DI
KUALA LUMPUR, MALAYSIA
Oleh
GOLNAZ SAMIEI
Januari 2014
Pengerusi : Professor Seow Heng Fong, PhD
Fakulti : Perubatan dan Sains Kesihatan
Interleukin IL-17 adalah satu sitokin proinflamasi yang dihasilkan oleh CD4+ T sel. IL-
17 memainkan peranan yang penting dalam inflamasi tisu dengan mendorong
penghasilan sitokin proinflamasi dan pergerakan-neutrofil. IL-17 juga memainkan
peranan yang kritikal dalam inflamasi dan kanser.
Polimorfisma IL-17A dan IL-17F dijangka mempunyai perhubungan dengan penyakit.
Tujuan kajian ini adalah untuk mengenalpasti sama ada terdapat hubungan antara dua
polimorfisma, gen IL-17A (rs2275913, G-197A) and IL-17F (rs763780, 7488 allele
A>G (His161Arg), dengan risiko kanser kolorektal sporadic, payu dara dan nasofarinks.
Satu polimorfisma nucleotide tunggal (SNP), IL-17A rs2275913 (G197A) dan satu lagi
17F rs763780 (A7488G), telah dikenalpasti dengan menggunakan genotype-specific
polymerase chain reaction (PCR) dan restriction fragment length polymorphism (RFLP).
DNA sequencing digunakan untuk mengenalpasti keputusan RFLP dalam pesakit kanser
kolorektal sporadic, payu dara dan nasofarinks dan juga dalam individu yang kelihatan
sihat. PCR-RFLP digunakan ke atas DNA yang dipisahkan daripada sampel darah
daripada enam puluh tiga pesakit payu dara, tujuh puluh dua pesakit kanser nasofarinks,
lapan puluh individu yang kelihatan sihat, dan juga empat puluh tujuh blok tisu paraffin
pesakit kolorektal untuk mengenalpasti hubungan antara polimorfisma IL-17A
rs2275913 (G197A) dan IL-17F rs763780 (A7488G) dengan risiko kanser kolorektal,
payu dara dan nasofarinks di Malaysia. Ini adalah laporan pertama tentang polimorfisma
gen IL-17 pada pesakit kanser di Malaysia.
Frekuensi alel dan genotip IL-17A/rs2275913 (G197A) and IL-17F/rs763780 (A7488G)
dibandingkan antara pesakit kanser kolorektal, payu dara dan nasofarinks. Keputusan
daripada analisasi statistik menunjukkan bahawa terdapat hubungan antara variasi gen
IL-17A/rs2275913( G197A) dengan kanser kolorektal. Oleh itu, kajian ini
mengenalpasti bahawa IL-17A, dan bukan IL-17F, menyumbang kepada kecenderungan
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kanser kolorektal. Perkaitan positif telah ditemui antara genotip IL-17F/rs763780
(A7488G) di kanser kolorektal dengan gred histology (P value< 0.005). Tidak ada
perhubungan yang ketara ditemui antara IL-17A/rs2275913 (G197A) dan IL-
17F/rs763780 (A7488G) dengan kanser payu dara dan nasofarinks.
Keputusan kajian ini menekankan kepentingan polimorfisma gen IL-17A/rs2275913 (
G197A) sebagai satu parameter genetic predisposing yang memberikan kerentanan
genetic terhadap kanser kolorektal di Malaysia. Keputusan ini menuntut agar
menambahkan kes untuk penyiasatan yang lebih lanjut untuk member gambaran kesan
daripada polimorfisma IL-17A/rs2275913 (G197A).
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ACKNOWLEDGEMENTS
I would like to express my gratitude to all those gave me the possibility to complete this
thesis. First, I am thankful to the Almighty God who is the Most Beneficent and Most
Merciful, for all his blessings, without which I wouldn’t be able to achieve this feat.
I would like to express my gratitude to my supervisor, Prof. Dr Seow Heng Fong from
the Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra
Malaysia. Her remarkable level of knowledge and support has led me to work
confidently and her critical comments and suggestions instructed the study in the right
direction.
I am also deeply indebted to my respectable co-supervisors Dr Nurhafizah Mohtaruddin
and Dr Yip Wai Kien for their supportive supervisions and invaluable advice throughout
the entire progress of this project.
I would like to thank my family and friends. My beloved parents who gave me life and
love in the first place; their great trust, dedication and generosity have backed me in my
entire life and I would not have been able to complete this thesis without their support.
Also special regards to my dear brothers, also my respected friends Arezoo Malihi and
Somaye Mohammadnejad for their continuous support and encouragement during my
study.
A special thank also goes to staff at Department of Pathology, Faculty of Medicine and
Health Sciences, Universiti Putra Malaysia. My twin lab mates Chai Boon Lee and Chai
Boon Yean who deserve to be thanked for their helpful collaboration.
There are many more who deserve to be thanked and their priceless help, friendship and
advice will always been appreciated.
A special thank also goes to staff at Department of Pathology, Faculty of Medicine and
Health Sciences, Universiti Putra Malaysia. My twin lab mates Chai Boon Lee and Chai
Boon Yean who deserve to be thanked for their helpful collaboration and discussion.
There are many more who deserve to be thanked whose names I may have forgotten to
mention, but their priceless help, friendship and advice will always been appreciated.
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This thesis was submitted to the Senate of Universiti Putra Malaysia and has been
accepted as fulfilment of the requirement for the degree of Master of Science. The
members of the Supervisory Committee were as follows:
Seow Heng Fong, PhD
Professor
Faculty of Medicine and Health Science
Universiti Putra Malaysia
(Chairman)
Norhafizah Mohtarrudin, PhD
Assiociated Professor
Faculty of Medicine and Health Science
Universiti Putra Malaysia
(Member)
Yip Wai Kien, PhD
Associate Professor
Faculty of Medicine and Health Science
Universiti Putra Malaysia
(Member)
BUJANG BIN KIM HUAT, PhD
Professor and Dean
School of Graduate Studies
Universiti Putra Malaysia
Date:
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Declaration by graduate student
I hereby confirm that
this thesis is my original work;
quotations, illustrations and citations have been duly referenced;
this thesis has not been submitted previously or concurrently for any other degree at
any other institutions;
Intellectual property from the thesis and copyright of thesis are fully-owned by
Universiti Putra Malaysia, as according to the Universiti Putra Malaysia (Research)
Rules 2012;
Written permission must be obtained from supervisor and the office of Deputy Vice-
Chancellor (Research and Innovation) before thesis is published (in the form of
written, printed or in electronic form) including books, journals, modules,
proceedings, popular writings, seminar papers, manuscripts, posters, reports, lecture
notes, learning modules or any other materials as stated in the Universiti Putra
Malaysia (Research ) Rules 2012;
There is no plagiarism or data falsification/fabrication in the thesis, and scholarly
integrity is upheld as according to the Universit Putra Malaysia (Graduate Studies)
Rules 2003 (Revision 2012-2013) and the Universiti Putra Malaysia (Research)
Rules 2012.The thesis has undergone plagiarism detection software.
Signature: __________________________ Date: ____________________
Name and Matric No: Golnaz Samiei GS29478
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TABLE OF CONTENTS
Page
ABSTRACT i
ABSTRAK iii
ACKNOWLEDGEMENTS v
APPROVAL vi
DECLARATION viii
LIST OF TABLES xiii
LIST OF FIGURES xiv
LIST OF ABBREVIATIONS xv
CHAPTER
I INTRODUCTION 1
II LITERATURE REVIEW 4
2.1 Inflammation and Cancer 4
2.2 Sources and functions of IL-17A 4
2.3 Sources and functions of IL-17F 6
2.4 Association between IL-17A G197A and IL-17F A7488G
Polymorphisms and risk of cancers
7
2.4.1 Colorectal cancer 7
2.4.2 Breast cancer (BC) 9
2.4.3 Nasopharyngeal carcinoma (NPC) 10
2.4.4 Gastric cancer 10
2.4.5 Cervical cancer 10
2.4.6 Bladder cancer 11
2.5 Association between IL-17A/rs2275913 ( G197A) and risk of
other Diseases
11
2.5.1 Behcet's disease (BD) 11
2.5.2 Graft-versus-host disease (GVHD) 11
2.5.3 Periodontitis 11
2.5.4 Chronic Periodontal Disease (CPD) 12
2.5.5 Chronic HBV infection and hepatocellular carcinoma
(HCC)
12
2.6 Association between IL-17F/rs763780 (A7488) and risk of other
Diseases
12
2.6.1 Asthma 12
2.6.2 Immune thrombocytopenia (ITP) 12
2.6.3 Chronic fatigue syndrome (CFS) 13
2.6.4 Vogt–Koyanagi–Harada syndrome (VKH) 13
2.6.5 Neuromyelitis optica (NMO) 13
2.6.6 Hand, foot and mouth disease 13
2.6.7 Extra-pulmonary tuberculosis (EPTB) 14
2.7 Other Diseases that is related to both IL17A/rs2275913 (G197A)
and IL17F/rs763780 (A7488G) Polymorphisms
14
2.7.1 Inflammatory bowl diseases (IBD) 14
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2.7.2 Rheumatoid arthritis (RA) 15
2.7.3 Thyroid disease 15
2.7.4 Ulcerative colitis (UC) 15
2.8 Association between other known SNPs of IL-17 polymorphisms
and diseases
16
2.9 Epidemiology of colorectal, nasopharyngeal, and breast cancers 18
2.10 Single nucleotide polymorphism (SNP) 20
2.10.1 SNP Genotyping Methods 20
2.10.1.1 RFLP 20
2.10.1.2 SSCP 20
III MATERIALS AND METHODOLOGY 21
3.1 Materials 21
3.1.1 Samples 21
3.1.2 DNA Extraction Reagents 21
3.1.3 PCR 21
3.1.4 Gel Electrophoresis Reagents 22
3.1.5 Equipment and Commercial kits 22
3.2 Methods 22
3.2.1 Extraction of DNA 22
3.2.2 Polymerase Chain Reaction (PCR) 22
3.2.3 Gel Electrophoresis 23
3.2.4 PCR-RFLP 23
3.2.5 Statistical Analysis 24
IV RESULTS 25
4.1 Genotyping 25
4.1.1 Genotyping of the IL-17A G197A polymorphism by
PCR-RFLP
25
4.1.1.1 Normal samples 27
4.1.1.2 Colorectal cancer samples 28
4.1.1.3 Breast cancer samples 29
4.1.1.4 Nasopharyngeal carcinoma samples 30
4.1.2 Genotyping of the IL-17F 7488A/G polymorphism
by PCR-RFLP
31
4.1.2.1 Normal samples 31
4.1.2.2 Colorectal cancer samples 32
4.1.2.3 Breast cancer samples 33
4.1.2.4 Nasopharyngeal carcinoma samples 34
4.1.3 DNA sequencing 34
4.2 Association of IL-17F A7488G and IL-17A G197A
polymorphisms with Colorectal cancer susceptibility
37
4.2.1 Association of IL-17F A7488G and IL-17A G197A
polymorphisms with clinicopathological features of
colorectal cancer
38
4.3 Association of IL-17F A7488G and IL-17A G197A
polymorphisms with breast cancer
40
4.4 Association of IL-17F A7488G and IL-17A G197A
polymorphisms with nasopharyngeal cancer
41
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V DISCUSSION 42
5.1 Association between IL-17A G197A(rs2275913)and IL-17F
A7488G (rs763780) polymorphisms and colorectal cancer
42
5.2 Association between IL-17F A7488G (rs763780) and IL-17F
A7488G (rs763780) polymorphisms and breast cancer
42
5.3 Association between IL-17A G197A(rs2275913) and IL-17F
A7488G (rs763780) polymorphisms and nasopharyngeal cancer
43
5.4 Association between IL-17A G197A(rs2275913) and IL-17F
A7488G (rs763780) polymorphisms and other diseases
43
VI CONCLUSION AND FUTURE RECOMMENDATION 45
6.1 Limitation of Study 45
REFERENCES 46
APPENDICES 59
BIODATA OF STUDENT 71
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LIST OF TABLES
Table Page
2.1 The association between other IL-17A with diseases 17
2.2 The association between other IL-17F SNPs and diseases 18
2.3 Colorectal, nasopharyngeal and breast cancer cases in the major ethic
groups in Malaysia
19
3.1 PCR thermal cycling conditions 23
3.2 Polymerase chain reaction (PCR) primers, restriction enzymes, and
fragment sizes
24
4.1 The distribution of genotype and allele frequencies of IL-17A G197A
and IL-17F A7488G polymorphisms among colorectal, breast and
nasopharyngeal cancers patients and normal controls
37
4.2 Association between of IL-17A G197A and IL-17F A7488G
polymorphisms and clinicopathological features of colorectal cancer
39
4.3 Association between IL-17A/rs2275913 (G197A) and IL-
17F/rs763780 (A7488G) polymorphism and demographic data of
breast cancer subjects
40
4.4 Association between IL-17A 197 and IL-17F 7488 polymorphism and
demographic data of nasopharyngeal cancer subjects
41
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LIST OF FIGURES
Figure
Page
2.1 Ten most frequent cancers, all residence, Malaysia 19
4.1 Gene loci of IL-17A and IL-17F SNPs on chromosome 6 and digest
position of Restriction Enzymes
26
4.1.1.1 Normal samples 27
4.1.1.2 Colorectal cancer samples 28
4.1.1.3 Breast cancer samples 29
4.1.1.4 Nasopharyngeal carcinoma samples 30
4.1.2.1 Normal blood samples 31
4.1.2.2 Colorectal cancer samples 32
4.1.2.3 Breast cancer samples 33
4.1.2.4 Nasopharyngeal carcinoma samples 34
4.1.3.1 Sequencing analysis for genotypes of the IL-17A G197A
polymorphisms
35
4.1.3.2 Sequencing analysis for genotypes of IL-17F/rs763780 (A7488G)
polymorphisms
36
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LIST OF ABBREVIATIONS
AITD Autoimmune thyroid disease
BC Breast cancer
BD Behcet`s disease
CAD Coronary artery disease
CD Crohn`s disease
CRC Colorectal cancer
CPD Chronic periodontal disease
CFS Chronic fatigue syndrome
CD4+ Cluster of differentiation 4
CD8+ Cluster of differentiation 8
CD45+ Cluster of differentiation 45
CTLA-8 Cytotoxic T-lymphocyte Antigen 8
EPS Epigastric pain syndrome
EPTB Extra-pulmonary tuberculosis
EV71 Enterovirus71
GD Graves disease
GVHD Graft-versus-host disease
HCC Hepatocellular carcioma
HFMD Hand, foot, and mouth disease
HT Hashimoto`s thyroiditis
IL-1 Interleukin-1
IL-23 Interleukin-23
IL-17A Interleukin-17A
IL-17F Interleukin-17F
IL-17R Interleukin-17 receptor
IBD Inflammation bowel disease
ITP Immune thrombocytopenia
NFAT Nuclear factor of activated T-cells
NK Natural killer
NKT Natural killer T
NMO Neuromyelitis optica
NPC Nasopharyngeal carcinoma
PTB Pulmonary tuberculosis
RA Rheumatoid arthiritis
rs2275913 Rearrangement sequence 2275913
rs763780 Rearrangement sequence 763780
SNP Single nucleotide polymorphism
Th T helper
Th17 T helper 17
TNF-α Tumor necrosis factor-alpha
TGF-β Transforming growth factor beta
UC Ulcerative colitis
VKHS Vogt-Koyanagi-Harada syndrome
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CHAPTER I
INTRODUCTION
Interlukin-17 is a proinflammatory cytokine expressed by a Th cell lineage, named
―Th17‖. The IL-17 cytokine family has six members and includes IL-17 (also called
IL-17A), IL-17B, IL-17C, IL-17D, IL-17E (also termed as IL-25) and IL-17F and
also at least five receptors (IL-17RA to IL-17RE). Although they are of similar
molecular weight of 20-30 kDa and have overlapping activities but their biological
functions are not identical (Moseley et al., 2003).
Both IL-17A and IL-17F coding genes are located on the same chromosome (6p),
and are adjacent to each other. Both genes are in a tail-to-tail orientation and
approximately 50 kb telometric to the IL-17A gene (Kawaguchi et al., 2001). IL-
17A and IL-17F have the strongest amino acid homology (Akimzhanov et al., 2007).
Interleukin-17 (IL-17) is produced following signals from TGFβ, IL-6, and IL-23
(Weaver et al., 2006).
Although the relationship between IL-17 and cancer has been demonstrated, but its
activity in the context of tumors is still controversial (Zhou et al., 2012).
Interleukin-17A (IL17A) has an indispensable role in host defense against infection
and progression of inflammatory diseases (Nakada et al., 2011; Cho et al., 2010;
Hamada et al., 2008). The binding of the IL-17A to IL-17RA and IL-17RC, induces
the release of proinflammatory cytokines, chemokines, growth factors and cell
adhesion molecules (Kawaguchi et al., 2004). It is essential in reducing exclusively
extracellular pathogens and responses of IL-17A leading to inflammation in tissue,
elevating graft versus host disease and autoimmune diseases (Kolls & Lindén, 2004;
Park et al., 2005) such as inflammatory bowel disease, rheumatoid arthritis and
multiple sclerosis (Korn et al., 2009).
Expression of IL-17A in tumor cells has been determined to slow or suppress tumor
progression and strong tumor-specific cytotoxic responases ( Hirahara et al., 2001;
Wilke et al., 2011). Some researchers have shown that the IL-17A-positive cells
numbers are associated with tumor progression and prognosis of patient (Kawaguchi
et al., 2004). An increased frequency of IL-17-positive cells in tumors were found in
ovarian cancer, prostate cancer and hepatocellular cancer (Dong, 2008; Sfanos et al.,
2008). IL-17A-overexpression in cervical cancer (Tartour et al., 1999), NSCLC
(non-small cell lung cancer) , and fibrosarcoma (Numasaki et al., 2003)
preferentially increases oncogenic growth (Numasaki et al., 2005).
IL-17F is known to play a principal role in inflammatory diseases (Pappu et al.,
2010). IL-17F was demonstrated to stimulate various cytokines, chemokines, and
adhesion molecules in airway epithelial cells, fibroblasts, and vein endothelial cells
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(Hizawa et al., 2006). The IL-17F gene is a remarkable candidate gene for chronic
inflammatory disease including inflammatory bowel disease (Seiderer et al., 2008),
ulcerative colitis (UC) (Arisawa et al., 2008), asthma (Kawaguchi et al., 2006), and
Behcet’s disease (Jang et al., 2008).
Since gene polymorphisms can influence the expression of molecules in controlling
the response of immune system, therefore, gene polymorphisms have a significant
impact on the mechanisms involved in development of disease (Dutra et al., 2009).
The influence of cytokine SNPs on the inflammatory response, innate and adaptive
immunity may result in differences in susceptibility to diseases. While
polymorphisms that impact the production of a cytokine are correlated with
susceptibility in one population, the identical polymorphisms may act differently in
individuals of different ethnic back grounds (Dutra et al., 2009).
As inflammatory diseases may share the same gene susceptibility, we chose the
SNPs of IL-17, which were demonstrated to be related to other diseases as
candidates (Metzger et al., 2008; Nordang et al., 2009; Shibata et al., 2009). The
rs2275913, also known as G-197A, is a SNP in the IL-17A gene. The rs2275913 of
IL-17A which was investigated in our study has been associated with risk of breast
cancer (Wang et al., 2012), gastric carcinogenesis (Shibata et al., 2009), rheumatoid
arthritis (Hen et al., 2010), graft-versus-host disease (GVHD) ( Espinoza et al.,
2011), ulcerative colitis (Arisawa et al., 2008), Behcet ’s disease (BD ) (Jang et al.,
2008), coronary artery disease (Xiaolin Zhang et al., 2011), chronic HBV infection,
hepatocellular carcinoma (HCC) (Hejr et al., 2013), chronic periodontal disease
(CPD) (Correa et al., 2012), and cervical cancer (Quan et al., 2012).
The rs763780, known as A7488G in the IL-17F gene which can antagonize wild type
IL-17F was also investigated in this study. The IL-17F/rs763780 (A7488G) SNP
causes a substitution from histidine (CAT) to arginine (CGT) (A7488G) at the level
of amino acid, due to a substitution of adenine to guanine. This SNP was selected
because it has been identified as the unique gene variant which has an effect on
susceptibility to human disease. It has been defined that the IL-17F/rs763780
(A7488G) is the most frequent of the IL-17F variants (Kawaguchi et al., 2006).
IL-17F /rs763780 (A7488G) polymorphism has been correlated to numerous
infections and immune-related diseases such as asthma (Kawaguchi et al., 2006;
Qian et al., 2012), Immune thrombocytopenia (ITP) (Saitoh et al., 2011), Vogt–
Koyanagi–Harada syndrome (VKH) (Shu et al., 2010), graves' disease (Hayashi,
Tahara, Shiroeda, Matsue, et al., 2012), chronic fatigue syndrome (CFS) (Metzger et
al., 2008), Behcet`s disease (jang et al., 2008), IBD (Chen et al., 2009), gastric
cancer (Wu et al., 2010), tuberculosis (Peng et al., 2013), Enterovirus 71 (EV71)
(Tiegang et al., 2013), and neuromyelitis optica (NMO) (Wang et al., 2012). A
significant relation between the IL-17F/rs763780 (7488A/G) polymorphism and
ulcerative colitis (UC) was observed in both Chinese and Japanese populations
(Arisawa et al., 2008; Chen et al., 2009). An inverse association between the IL-
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17F/rs763780 SNP and psoriasis vulgaris or atopic dermatitis was demonstrated in a
Japanese population (Shibata et al., 2009). There is no association between IL-17F
His161Arg and Behcet’s disease (BD), in Chinese and Korean populations (Jang et
al., 2008; Shu et al., 2010).
The reason for selection of cancer type was because of colorectal, breast, and
nasopharyngeal cancer were top five most common cancer in Malaysia. As the
significance of IL-17A and -17F in the pathogenesis of the colorectal, breast, and
nasopharyngeal disorders still remains unknown, the general objective of this study
was to test the hypothesis that both IL-17A and 17F gene polymorphisms
(rs2275913 and rs763780, respectively) may be associated with risk of colorectal
breast, and nasopharyngeal. The specific objectives of this project were to determine
the frequencies of single nucleotide polymorphisms in the IL-17A gene which is
localized in intron 1 at position 197 and IL-17F gene at position 7488 in exon 3 in
colorectal, breast, and nasopharyngeal carcinoma and compared to normal controls
from apparently healthy individuals and to determine the association with IL-17A
gene polymorphisms and risk of colorectal, breast, and nasopharyngeal cancer.
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REFERENCES
Abraham, C., & Cho, J. (2009). Interleukin23/Th17 pathways and inflammatory bowel
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