universiti putra malaysiapsasir.upm.edu.my/id/eprint/70444/1/fpsk(m) 2014 54 - ir.pdf ·...

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


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


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



(Member)

Yip Wai Kien, PhD

Associate Professor



(Member)

BUJANG BIN KIM HUAT, PhD

Professor and Dean

School of Graduate Studies


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





4.1.3 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


polymorphisms with breast cancer

40


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





4.1.2.1 Normal blood samples 31




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



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

disease. Inflammatory Bowel Diseases, 15(7), 1090–1100.

Agarwal, S., Misra, R., & Aggarwal, A. (2008). Interleukin 17 levels are increased in

juvenile idiopathic arthritis synovial fluid and induce synovial fibroblasts to

produce proinflammatory cytokines and matrix metalloproteinases. Journal of

Rheumatology, 35(3), 515–519.

Aggarwal, B. B., Shishodia, S., Sandur, S. K., Pandey, M. K., & Sethi, G. (2006).

Inflammation and cancer: how hot is the link? Biochemical Pharmacology,

72(11), 1605–1621.

Arisawa, T., Tahara, T., Shibata, T., Nagasaka, M., Nakamura, M., Kamiya, Y., Fujita,

H., et al. (2007). Genetic polymorphisms of molecules associated with

inflammation and immune response in Japanese. Journal of Molecular

Medicine, 20, 717–723.

Arisawa, T., Tahara, T., Shibata, T., Nagasaka, M., Nakamura, M., Kamiya, Y., Fujita,

H., et al. (2008). The influence of polymorphisms of interleukin-17A and

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