Genetic Polymorphisms In The Phase I And Phase II Xenobiotic Metabolizing Enzymes In Malaysian Population And Their Influence On Colorectal Cancer Susceptibility

Sporadic Colorectal Cancer (CRC) is a multifactorial disease and factors contributing to its etiopathogenesis include dietary and lifestyle habits on one hand and genetic predisposition on the other hand. Exposure to environmental carcinogens through dietary components and cigarette smoke are associated with an increased risk of CRC. However, the genetic predisposition factors associated with CRC development largely remain undetermined. It was hypothesized that genetic variations in xenobiotic metabolism genes may play a role in how individuals will respond to carcinogenic compounds and hence affect the risk of developing CRC. So, this case-control study which involved 566 study subjects (255 histopathologically confirmed sporadic CRC patients and 311 normal healthy controls) was designed and undertaken at Human Genome Centre, University Sains Malaysia during the period 2009-2011, to investigate the influence of genetic polymorphisms of few xenobiotic metabolizing genes in CRC susceptibility risk. Ten polymorphisms from 6 genes encoding enzymes involved in xenobiotic metabolism (GSTT1, GSTM1, GSTP1 Ile105Val, CYP1A2 G3860A, CYP1A2 T739G, CYP1A2 C729T, NAT1 C1095A, NAT2 G191A, NAT2 A803G, NAT2 G857A) were selected as candidate SNPs to determine their influence, either singly or as combination genotypes, in CRC susceptibility risk and with the ultimate aim of identifying putatively protective and/or at risk genotypes

Risk modification of colorectal cancer susceptibility by interleukin-8 -251T>A polymorphism in Malaysians

AIM: To investigate the allele and genotype frequencies and associated risk of interleukin (IL )-8 -251T>A polymorphism on colorectal cancer (CRC) susceptibility risk. METHODS: Peripheral blood samples of 255 normal controls and 255 clinically and histopathologically confirmed CRC patients were genotyped for IL-8 -251T>A polymorphism employing allele-specific polymerase chain reaction. The relative association of variant allele and genotypes with CRC susceptibility risk was determined by calculating the odds ratios (ORs). Corresponding χ 2 tests on the CRC patients and controls were carried out and 95% confidence intervals (CIs) were determined using Fisher’s exact test. The allele frequencies and its risk association were calculated using FAMHAP, haplotype association analysis software. RESULTS: On comparing the frequencies of genotypes of patients and controls, the homozygous variant AA was significantly higher in CRC patients (P = 0.002) compared to controls. Investigation on the association of the polymorphic genotypes with CRC susceptibility risk, showed that the homozygous variant IL-8 -251AA had a significantly increased risk with OR 3.600 (95% CI: 1.550-8.481, P = 0.001). In the case of allele frequencies, variant allele A of IL-8 -251 showed a significantly increased risk of CRC predisposition with OR 1.32 (95% CI: 1.03-1.69, P = 0.003). CONCLUSION: Variant allele and genotype of IL-8 (-251 T>A) was significantly associated with CRC susceptibility risk and could be considered as a high-risk variant for CRC predisposition

XPC Lys939Gln polymorphism, smoking and risk of sporadic colorectal cancer among Malaysians

AIM: To investigate the risk association of xeroderma pigmentosum group C (XPC ) Lys939Gln polymorphism alone and in combination with cigarette smoking on colorectal cancer (CRC) predisposition. METHODS: Peripheral blood samples of 510 study subjects (255 CRC patients, 255 controls)were collected. DNA was extracted and genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism. The association between polymorphic genotype and CRC predisposition was determined using the OR and 95%CI. RESULTS: The frequency of the homozygous variant (Gln/Gln) genotype was significantly higher in cases compared with controls (16.0% vs 10.2%, P = 0.049). The Gln/Gln genotype of XPC showed a significantly higher association with the risk of CRC (OR = 1.884; 95%CI: 1.082-3.277; P = 0.025). In the case of allele frequencies, variant allele C was associated with a significantly increased risk of CRC (OR = 1.375; 95%CI: 1.050-1.802; P = 0.020). Moreover, the risk was markedly higher for those who were carriers of the Gln/Gln variant genotype and were also cigarette smokers (OR = 3.409; 95%CI: 1.061-10.949; P = 0.032). CONCLUSION: The XPC Gln/Gln genotype alone and in combination with smoking increases the risk of CRC among Malaysians

Polymorphism Thr241Met of the XRCC3 Gene and Lack of Association with Colorectal Cancer Susceptibility Risk among Malaysian Population: A Preliminary Report

The genesis of colorectal cancer (CRC) involves a series of steps in which environmental and/or endogenous carcinogens interact with genetic factors and induce or promote cancer development. Genetic polymorphisms in DNA repair genes may influence individual variation in DNA repair capacity and may be associated with a high risk of developing cancer. Studies on the association between DNA repair gene polymorphisms and CRC appear to be limited and nil from Malaysia. Objective: To examine the polymorphism at codon 241 of the X-Ray Cross Complementing group 3 (XRCC3) in 118 CRC cases and 118 normal controls and to investigate the associated risk of this polymorphism for CRC susceptibility. Material and Method: Peripheral blood from the study subjects were collected in EDTA tubes, genomic DNA extracted and XRCC3 Thr241Met genotyped by using PCR-RFLP technique using Nla III restriction enzyme. The resulting genotypes were categorized into wildtype homozygous (Thr/Thr), heterozygous (Thr/Met) and homozygous variant (Met/Met). Results and conclusion: The distribution of genotypes (Thr/Thr, Thr/Met and Met/Met) among CRC cases (83%, 16%, 1% respectively) was not significantly different from those among controls (79%, 21%, 0% respectively). On examining the association between the variant genotypes and CRC risk, the variant genotype either single or in combination did not show significant association with CRC susceptibility risk suggesting that the XRCC3 codon 241 polymorphism does not convey moderate increase in susceptibility to CRC in Malaysian population. Lack of association could be attributed to the small sample size, interaction of other polymorphic DNA repair genes and also low frequency of variant allele for the polymorphism studied in this population

Polymorphism in the Tumor Necrosis Factor alpha promoter region and its Influence on Colorectal Cancer Predispositiom risk in Malaysian Population

Objective: A case control study was designed to investigate the TNF-,1 -308 G>A polymorphism allele frequencies and to determine the influence of the polymorphic gcnot.ype on sporadic CRC susceptibility risk in Malaysian population. Material. and Method!: Peripheral blood samples of 164 normal controls and 161 clinically and histopathologically con­firmed CRC patients were genotyped for TNF-u -308 G>A polymorphism employing allele specific PCR. The relative associa­tions of various genotypes with CRC susceptibility risk was determined by calculating Odds Ratios. Corresponding chi-square tests on the CRC patients and controls were carried out and 95% confidence interval (95% CI) were determined using Fisher e,acts tests. Results: On comparing the frequencies of genotypes of patients and controls, the homozygous ,·ariant AA was significantly higher in CRC patients (p = 0.030) compared to controls. On investigating the association of the polymorphic genotypes with CRC susceptibility risk, the homozygous variant TNF-a -308 AA showed significantly increased risk with OR 2.5842. Conclusion: Our results suggest that, pol) morphic genotJpe of inflammation response gene TNF-a is significantly associat­ed with CRC susceptibility risk and could be considered as a high risk variant for CRC predisposition

Risk modification of colorectal cancer susceptibility by interleukin-8 -251T>A polymorphism in Malaysians

AIM: To investigate the allele and genotype frequencies and associated risk of interleukin (IL)-8 -251T>A polymorphism on colorectal cancer (CRC) susceptibility risk

XPC Lys939Gln polymorphism, smoking and risk of sporadic colorectal cancer among Malaysians

AIM: To investigate the risk association of xeroderma pigmentosum group C (XPC) Lys939Gln polymorphism alone and in combination with cigarette smoking on colorectal cancer (CRC) predisposition. METHODS: Peripheral blood samples of 510 study subjects (255 CRC patients, 255 controls)were collected. DNA was extracted and genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism. The association between polymorphic genotype and CRC predisposition was determined using the OR and 95%CI. RESULTS: The frequency of the homozygous variant (Gln/Gln) genotype was significantly higher in cases compared with controls (16.0% vs 10.2%, P = 0.049). The Gln/Gln genotype of XPC showed a significantly higher association with the risk of CRC (OR = 1.884; 95%CI: 1.082-3.277; P = 0.025). In the case of allele frequencies, variant allele C was associated with a significantly increased risk of CRC (OR = 1.375; 95%CI: 1.050-1.802; P = 0.020). Moreover, the risk was markedly higher for those who were carriers of the Gln/Gln variant genotype and were also cigarette smokers (OR = 3.409; 95%CI: 1.061-10.949; P = 0.032). CONCLUSION: The XPC Gln/Gln genotype alone and in combination with smoking increases the risk of CRC among Malaysians

The functional −94 insertion/deletion ATTG polymorphism in the promoter region of NFKB1 gene increases the risk of sporadic colorectal cancer

Objective: To investigate the allele and genotype frequencies of NFKB1 −94 ins/del ATTG (rs28720239) polymorphism and to evaluate the association between the polymorphism and colorectal cancer (CRC) risk in Malaysian population. Methods: Genomic DNA was extracted from the peripheral blood samples of 474 study subjects, which consisted of 237 histopathologically confirmed CRC patients and an equal number of cancer-free controls. The NFKB1 −94 ins/del ATTG (rs28720239) polymorphism was genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and confirmed by DNA sequencing. The association between the polymorphic genotypes and CRC risk was evaluated by deriving odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression analysis. Results: The frequencies of wildtype (del/del), heterozygous (del/ins) and variant (ins/ins) genotypes in CRC patients were 31.7%, 53.6% and 14.8%, respectively, while those in cancer-free controls were 35.0%, 58.2% and 6.8%, respectively. The frequency of the variant genotype was significantly higher in cases compared to controls (P < 0.01). Evaluation of the risk association of the polymorphic genotypes revealed that the variant genotype could contribute to a significantly increased risk of CRC (OR = 2.42, 95% CI = 1.24–4.73, P < 0.01). Conclusions: The variant allele of NFKB1 −94 ins/del ATTG (rs28362491) polymorphism is associated with higher risk of sporadic CRC in Malaysian population

Awards of Best Poster Presentation entitled Lack of association of single nucleotie polymorphisms IL-6-174G> and PPARyPro12Ala with sporadic colorectal cancer predisposition risk in Malaysian population , June 2011

16th National Conference on Medical and Health Sciences. 22-23rd June 2011. 3rd Place for Best Poster Presentation in Basic Science

The functional -94 insertion/deletion ATTG polymorphism in the promoter region of NFKB1 gene increases the risk of sporadic colorectal cancer

Objective: To investigate the allele and genotype frequencies of NFKB1 94 ins/del ATTG (rs28720239) polymorphism and to evaluate the association between the polymorphism and colorectal cancer (CRC) risk in Malaysian population. Methods: Genomic DNA was extracted from the peripheral blood samples of 474 study subjects, which consisted of 237 histopathologically confirmed CRC patients and an equal number of cancer-free controls. The NFKB1 94 ins/del ATTG (rs28720239) polymorphism was genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and confirmed by DNA sequencing. The association between the polymorphic genotypes and CRC risk was evaluated by deriving odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression analysis. Results: The frequencies of wildtype (del/del), heterozygous (del/ins) and variant (ins/ins) genotypes in CRC patients were 31.7%, 53.6% and 14.8%, respectively, while those in cancer-free controls were 35.0%, 58.2% and 6.8%, respectively. The frequency of the variant genotype was significantly higher in cases compared to controls (P < 0.01). Evaluation of the risk association of the polymorphic genotypes revealed that the variant genotype could contribute to a significantly increased risk of CRC (OR = 2.42, 95% CI = 1.24–4.73, P < 0.01). Conclusions: The variant allele of NFKB1 94 ins/del ATTG (rs28362491) polymorphism is associated with higher risk of sporadic CRC in Malaysian population