Nuclear factor kappa b genetic polymorphisms and association with colorectal cancer susceptibility risk in malaysian population - A molecular epidemiology study
Sporadic colorectal cancer (CRC), the most common gastrointestinal malignancy in Malaysia and one of the most common cause of cancer deaths, is a major public health problem. CRC is a multifactor caused disease resulting from complex interaction between environmental and genetic predisposition fa...
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| Main Author: | |
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| Format: | Thesis |
| Language: | English |
| Published: |
2013
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| Subjects: | |
| Online Access: | http://eprints.usm.my/60859/1/MOHD%20SUZAIRI%20BIN%20MOHD%20SHAFI%27I%20-%20e.pdf |
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| Summary: | Sporadic colorectal cancer (CRC), the most common gastrointestinal malignancy in
Malaysia and one of the most common cause of cancer deaths, is a major public
health problem. CRC is a multifactor caused disease resulting from complex
interaction between environmental and genetic predisposition factors. However, the
genetic predisposition risk of an individual for CRC development remains largely
undetermined. Recently, Nuclear Factor kappa B signalling pathway has been
implicated in colorectal carcinogenesis. Given the important role of NFkB signalling
pathway in CRC development, it was hypothesized that genes and genetic variations
in NFkB signalling pathway could be putative genetic predisposition factors. This
case-control study was designed to test this hypothesis. The objectives were to
investigate the genotype and allele frequencies of three SNPs, namely A to G
variation at 3’ UTR of NFKBIA, -519 C to T of NFKBIA and -94 insertion/deletion
ATTG of NFKB1 gene in Malaysian CRC patients and normal controls and to
determine the risk association of these three SNPs with CRC predisposition. This
case-control study involved 474 study subjects with 237 histophatologically
confirmed CRC patients as cases and 237 normal healthy volunteers as controls. After
getting informed consent, blood samples from study subjects were collected, DNA
extracted and genotyping of the three SNPs was carried out employing Polymerase
Chain Reaction - Restriction Fragment Length Polymorphism (PCR-RFLP)
technique. Genotypes were categorized into homozygous wildtype, heterozygous and
homozygous variant. Risk associations of specific genotypes with CRC susceptibility
were determined by deriving Odds Ratio (OR) with corresponding 95% Confidence
Intervals (C.I) using unconditional logistic regression. The frequencies of
homozygous variant genotype of A to G variation at 3’ UTR of NFKBIA and NFKBI
-94 insertion/deletion ATTG polymorphism were significantly higher in CRC patients
compared to controls. The frequency of homozygous variant genotype of-519 C to T polymorphism of NFKBIA was very low in the cases and nil in the controls. When
analyzed singly, the homozygous variant genotype (GG) of NFKBIA 3’ UTR A to G
SNP showed significantly higher risk association with CRC predisposition, whereas
the -519 C to T variation of NFKBIA did not show any risk association. Similarly, the
homozygous variant genotype (ins/ins) of NFKBI -94 insertion/deletion ATTG SNP
showed significantly higher risk association with CRC predisposition when analyzed
singly. In the two SNP combination analysis, the genotype combinations of NFKBIA -
519 C to T (CC) / A to G variation at 3’ UTR of NFKBIA (AG) genotypes, NFKBIA -
519 C to T (CC) / A to G variation at 3’ UTR of NFKBIA (GG) genotypes, NFKBIA -
519 C to T variation (CC) / NFKBI -94 insertion/deletion ATTG polymorphism
(ins/ins) genotype, A to G variation at 3’ UTR of NFKBIA (AG) / NFKBI -94
insertion/deletion ATTG polymorphism (del/ins), A to G variation at 3’ UTR of
NFKBIA (GG) / NFKBI -94 insertion/deletion ATTG polymorphism (del/del) and A
to G variation at 3’ UTR of NFKBIA (GG) / NFKBI -94 insertion/deletion ATTG
polymorphism (del/ins) emerged as high risk genotype combinations associated with
CRC predisposition. It is presumed that genetic variation in NFKBIA and NFKBI
genes may result in sustained or constitutive activation resulting in incorrect
regulation of the associated proteins and thereby contribute to pathogenesis of CRC.
The genotype and/or genotype combinations which showed high risk association with
CRC could be considered as putative “at risk” predisposition genotypes associated
with CRC susceptibility. |
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