Genetic Polymorphisms In The Phase I And Phase II Xenobiotic Metabolizing Enzymes In Malaysian Population And Their Influence On Colorectal Cancer Susceptibility
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Date
2012
Authors
Shahpudin, Siti Nurfatimah Mohd
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Abstract
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. After getting informed consent, peripheral blood of all study subjects were collected, DNA extracted and genotyping carried out using PCR-RFLP and multiplex PCR methods. Genotypes were categorized into homozygous major, heterozygous variant and homozygous variant. The risk of CRC associated with these polymorphisms were estimated by calculating Odds Ratios (ORs) and 95% confidence intervals using unconditional logistic regression. On evaluating the risk associated with the variant genotypes singly, CYP1A2 A3860A, CYP1A2 T739G, GSTP1 val/val genotypes and GSTT1 null showed significant risk association with CRC predisposition. When analyzed in 2 way combinations, remarkably increased risk was observed for carriers of CYP1A2 A3860A/T739T, GSTT1 (-/-)/ GSTM1 (-/-), (GSTT1 (-/-)/ GSTP1 Ile/Ile), (GSTT1 (-/-)/ GSTP1 Ile/Val) genotype combinations. In triple genotype combination analysis, the GSTM1 (-/-)/GSTT1 (-/-)/ GSTP1 Ile/Ile) genotype combination emerged as high risk predisposition genotype associated with CRC susceptibility risk. It is reasonable to suggest that these SNPs studied might be promoting CRC susceptibility through their capability of increased activation of chemical carcinogens and/or decreased ability of cells to detoxify carcinogens. In conclusion, the SNPs of xenobiotic metabolizing genes showing significant risk association with CRC predisposition, either singly or in combination, may be considered as putative high risk predisposition genotypes and as candidate genetic markers of CRC susceptibility.
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Genetic polymorphisms