A variant in SIRT2 gene 3'-UTR is associated with susceptibility to colorectal cancer.
ABSTRACT: SIRT2 is a member of sirtuin family and is associated with cell growth in various cancers. In this study, we searched for variants in functional region of SIRT2 gene and identify rs2015 and rs2241703 in the 3'UTR with minor allele frequency >0.05 in Chinese Han Beijing population from 1000 Genomes Project. We then genotyped these two variants in 842 colorectal cancer (CRC) patients and 1,718 healthy controls using Taqman genotyping assay. Association between variants and risk of CRC is calculated using logistic regression adjusted for sex and age. We found that rs2015C was significantly associated with increased risk of CRC. Compared with CC genotype carriers, CA genotype and AA genotype carriers were associated with CRC susceptibility with OR being 0.79 (95% CI: 0.65-0.96, P = 0.019) and 0.73 (95% CI: 0.58-0.92, P = 0.009), respectively. When stratified by sex and age, significant associations were observed only in males (OR = 0.82, 95% CI: 0.71-0.96, P = 0.010) for rs2015, but not females (OR = 0.90, 95% CI: 0.73-1.10, P = 0.287). It is suggested that the sequence including rs2015C allele lies within a binding site for the full seed region of hsa-miR-376a-5p. Through a systematic interrogate of variants in the functional region of SIRT2 gene, we identified rs2015 was significantly associated with CRC susceptibility, providing new insights into the carcinogenesis of CRC.
Project description:Colorectal cancer (CRC) ranks the fifth leading cause of cancer death in China. EZH2 is a member of Polycomb-group (PcG) family and associated with transcriptional repression and cancer development. In this study, we report the association between a missense variant in EZH2 and risk of CRC. Through a systematic selection of variants in EZH2, we identified rs2302427 in the exon region of EZH2 and genotyped this variant in 852 CRC patients and 1,303 healthy controls using Taqman genotyping assay. The association between this variant and CRC risk was calculated using logistic regression with adjustment of sex, age, smoking status and drinking status. The result showed that rs2302427 was significantly associated with CRC susceptibility under an additive model (P=0.0068). Compared with CC genotype carriers, CG genotype and GG genotype carriers were associated with risk of CRC with odds ratio being 0.78 (95% CI: 0.63-0.96, P=0.0198) and 0.54 (95% CI: 0.24-1.18, P=0.1224), respectively. When stratified by sex, age, smoking status or drinking status, significant associations were observed only in younger individuals (OR=0.67, 95% CI: 0.50-0.89, P=0.0067) or smokers (OR=0.65, 95% CI: 0.48-0.88, P=0.0051). This study provides new insights into the personalized prevention of colorectal cancer.
Project description:Colorectal cancer (CRC) is one of the most common types of cancer worldwide and a leading cause of cancer-related mortality. This meta-analysis was conducted to determine the effect of methylenetetrahydrofolate reductase (MTHFR) mutants on the risk of CRC. A literature search was conducted on PubMed, Medline and the China National Knowledge Infrastructure (CNKI) databases. Eligible studies were collected based on rigorous criteria of inclusion. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated by the fixed- or random-effects model. After all the studies were pooled, the OR of CRC for individuals carrying the MTHFR 677TT genotype, compared to the CC genotype, was 0.89 (95% CI: 0.82-0.97). When analyzed by ethnicity, Asians with the MTHFR 1298CC genotype exhibited a decreased risk of CRC (OR=0.69; 95% CI: 0.54-0.89). In a mixed population, a significantly reduced risk of CRC was observed among carriers of the 677TT (OR=0.86; 95% CI: 0.76-0.96) and the 1298CC (OR=0.82; 95% CI: 0.69-0.98) genotypes, compared to the wild-type homozygous genotype. In the subgroup of colon cancer, the OR of 677TT vs. CC+CT was 0.83 (95% CI: 0.72-0.96) and the OR of 1298CC vs. AA+AC was 0.81 (95% CI: 0.69-0.96). In the rectal cancer subgroup, the OR of 677TT vs. CC+CT was 0.86 (95% CI: 0.77-0.97). Therefore, this meta-analysis suggested that the MTHFR 677T and 1298C alleles were associated with a low risk of CRC.
Project description:Introduction:Colorectal cancer (CRC) remains a major public health concern worldwide. However, the detailed molecular mechanisms of CRC remain poorly understood. Methods:In the current study, we evaluated associations of four genetic variants located in the promoter and gene region of long noncoding RNAs metastasis-associated lung adenocarcinoma transcript 1 (lncRNA MALAT1) with CRC susceptibility among a Chinese population with 966 CRC cases and 988 healthy controls, using a two-stage, case-control study design (400 CRC cases and 400 controls in stage 1, and 566 CRC cases and 588 controls in stage 2). Results:We found that the minor alleles of rs619586 (OR=0.73; 95% CI=0.60-0.88; P=0.001) and rs1194338 (OR=0.80; 95% CI=0.70-0.92; P=0.001) were significantly associated with decreased CRC susceptibility. Compared with those with rs619586 -AA genotype, the risk of CRC was significantly lower in individuals with AG genotype (OR=0.76; 95% CI=0.61-0.95) and GG genotype (OR=0.46; 95% CI=0.23-0.90). Compared with those with rs1194338 -CC genotype, the risk of CRC was significantly lower in individuals with AC genotype (OR=0.79; 95% CI=0.65-0.95) and AA genotype (OR=0.68; 95% CI=0.51-0.89). Conclusion:Taken together, our findings provided strong evidence for the hypothesis that genetic variants in lncRNA MALAT1 might contribute to the carcinogenesis of CRC.
Project description:Sirtuins (SIRT1-7) are NAD⁺-dependent protein deacetylases/ADP ribosyltransferases with important roles in chromatin silencing, cell cycle regulation, cellular differentiation, cellular stress response, metabolism and aging. Sirtuins are components of the epigenetic machinery, which is disturbed in Alzheimer's disease (AD), contributing to AD pathogenesis. There is an association between the SIRT2-C/T genotype (rs10410544) (50.92%) and AD susceptibility in the APOEε4-negative population (SIRT2-C/C, 34.72%; SIRT2-T/T 14.36%). The integration of SIRT2 and APOE variants in bigenic clusters yields 18 haplotypes. The 5 most frequent bigenic genotypes in AD are 33CT (27.81%), 33CC (21.36%), 34CT (15.29%), 34CC (9.76%) and 33TT (7.18%). There is an accumulation of APOE-3/4 and APOE-4/4 carriers in SIRT2-T/T > SIRT2-C/T > SIRT2-C/C carriers, and also of SIRT2-T/T and SIRT2-C/T carriers in patients who harbor the APOE-4/4 genotype. SIRT2 variants influence biochemical, hematological, metabolic and cardiovascular phenotypes, and modestly affect the pharmacoepigenetic outcome in AD. SIRT2-C/T carriers are the best responders, SIRT2-T/T carriers show an intermediate pattern, and SIRT2-C/C carriers are the worst responders to a multifactorial treatment. In APOE-SIRT2 bigenic clusters, 33CC carriers respond better than 33TT and 34CT carriers, whereas 24CC and 44CC carriers behave as the worst responders. CYP2D6 extensive metabolizers (EM) are the best responders, poor metabolizers (PM) are the worst responders, and ultra-rapid metabolizers (UM) tend to be better responders that intermediate metabolizers (IM). In association with CYP2D6 genophenotypes, SIRT2-C/T-EMs are the best responders. Some Sirtuin modulators might be potential candidates for AD treatment.
Project description:defective DNA repair has a causal role in hereditary colorectal cancer (CRC). Defects in the base excision repair gene MUTYH are responsible for MUTYH-associated polyposis and CRC predisposition as an autosomal recessive trait. Numerous reports have suggested MUTYH mono-allelic variants to be low penetrance risk alleles. We report a large collaborative meta-analysis to assess and refine CRC risk estimates associated with bi-allelic and mono-allelic MUTYH variants and investigate age and sex influence on risk.MUTYH genotype data were included from 20?565 cases and 15?524 controls. Three logistic regression models were tested: a crude model; adjusted for age and sex; adjusted for age, sex and study.all three models produced very similar results. MUTYH bi-allelic carriers demonstrated a 28-fold increase in risk (95% confidence interval (CI): 6.95-115). Significant bi-allelic effects were also observed for G396D and Y179C/G396D compound heterozygotes and a marginal mono-allelic effect for variant Y179C (odds ratio (OR)=1.34; 95% CI: 1.00-1.80). A pooled meta-analysis of all published and unpublished datasets submitted showed bi-allelic effects for MUTYH, G396D and Y179C (OR=10.8, 95% CI: 5.02-23.2; OR=6.47, 95% CI: 2.33-18.0; OR=3.35, 95% CI: 1.14-9.89) and marginal mono-allelic effect for variants MUTYH (OR=1.16, 95% CI: 1.00-1.34) and Y179C alone (OR=1.34, 95% CI: 1.01-1.77).overall, this large study refines estimates of disease risk associated with mono-allelic and bi-allelic MUTYH carriers.
Project description:<h4>Background and aim</h4>TP53 encodes p53, which has a crucial role in modulating genes that regulate defense against cancer development. This study investigated whether TP53 polymorphisms are associated with colorectal cancer (CRC) in patients with Lynch syndrome and whether TP53 interacts with lifestyle factors to modify CRC risk.<h4>Methods</h4>We identified 260 MLH1 and MSH2 germline mutation carriers from the Taiwan Hereditary Nonpolyposis Colorectal Cancer Consortium. A weighted Cox proportional hazard model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) to determine the association of TP53 polymorphisms with CRC development.<h4>Results</h4>The carriers of the variant C allele of rs1042522 were associated with a decreased CRC risk (GC genotype: HR = 0.35, 95% CI = 0.14-0.86; CC genotype: HR = 0.28, 95% CI = 0.13-0.57). In addition, the dominant model of rs1042522 was associated with a decreased CRC risk (HR = 0.32, 95% CI = 0.15-0.67). The CRC risk was decreased in carriers with the CT and TT genotypes of rs12947788 (HR = 0.20, 95% CI = 0.08-0.46 and HR = 0.25, 95% CI = 0.09-0.65, respectively). Moreover, the dominant model of rs12947788 was significantly associated with a decreased CRC risk (HR = 0.21, 95% CI = 0.09-0.46). A haplotype analysis indicated that compared with the most common GC haplotype, the CT haplotype was associated with a decreased CRC risk (HR = 0.26, 95% CI = 0.11-0.59). However, no significant interaction was observed between TP53 polymorphisms and lifestyle factors.<h4>Conclusion</h4>The study results revealed that the rs1042522 genotype with the C allele and the rs12947788 genotype with the T allele in TP53 were associated with a decreased CRC risk in patients with Lynch syndrome in Taiwan.
Project description:BACKGROUND:Colorectal cancer (CRC) is the fourth leading cause of cancer-related death around the world and accumulated evidence indicates the association between CRC and obesity and insulin resistance. OBJECTIVES:Regarding the role of adiponectin in obesity and insulin resistance, we explored whether genetic variants in adiponectin (ADIPOQ) and adiponectin receptor 1 (ADIPOR1) are associated with CRC risk. MATERIALS AND METHODS:ADIPOQ (rs2241766) and ADIPOR1 (rs2275738) gene variants were genotyped in 261 cases with CRC and 339 controls using PCR-RFLP method. RESULTS:In this study, no significant difference was observed for ADIPOQ gene rs2241766 variant between the cases and controls. However, carriers of the ADIPOR1 (rs2275738) "CC + CT" genotype compared with "TT" genotype occurred more frequently in the cases with CRC than the controls, and the difference remained significant after adjustment for age, BMI, sex, smoking status, NSAID use, and family history of CRC (P = 0.048; OR = 1.49, 95%CI = 1.01-2.20). Interestingly, after adjustment for confounding factors the ADIPOR1 "CC + TC" genotype compared with "TT" genotype was also associated with an increased risk for obesity in the cases (P = 0.040; OR = 1.86, 95%CI = 1.03-3.36). CONCLUSIONS:Our findings suggest for the first time that the - 106 C > T (rs2275738) variant of ADIPOR1 gene may be a genetic contributor to CRC and obesity risk in the cases with CRC. However, further studies with bigger sample size are needed to validate these findings.
Project description:Methionine synthase (MTR), which plays a central role in maintaining adequate intracellular folate, methionine and normal homocysteine concentrations, was thought to be involved in the development of colorectal cancer (CRC) and colorectal adenoma (CRA) by affecting DNA methylation. However, studies on the association between MTR A2756G polymorphism and CRC/CRA remain conflicting. We conducted a meta-analysis of 27 studies, including 13465 cases and 20430 controls for CRC, and 4844 cases and 11743 controls for CRA. Potential sources of heterogeneity and publication bias were also systematically explored. Overall, the summary odds ratio of G variant for CRC was 1.03 (95% CI: 0.96-1.09) and 1.05 (95% CI: 0.99-1.12) for CRA. No significant results were observed in heterozygous and homozygous when compared with wild genotype for these polymorphisms. In the stratified analyses according to ethnicity, source of controls, sample size, sex, and tumor site, no evidence of any gene-disease association was obtained. Results from the meta-analysis of four studies on MTR stratified according to smoking and alcohol drinking status showed an increased CRC risk in heavy smokers (OR?=?2.06, 95% CI: 1.32-3.20) and heavy drinkers (OR?=?2.00, 95% CI: 1.28-3.09) for G allele carriers. This meta-analysis suggests that the MTR A2756G polymorphism is not associated with CRC/CRA susceptibility and that gene-environment interaction may exist.
Project description:The aim of this study was to investigate the effect of a polymorphism rs4705341 in the flanking region of miR-143/145 on the risk of colorectal cancer (CRC). The rs4705341 polymorphism was analyzed in 1002 cases and 1062 controls using a polymerase chain reaction-restriction fragment length polymorphism method. We found a significantly reduced CRC susceptibility with miR-143/145 rs4705341 in homozygote comparison (adjusted OR = 0.66, 95%CI, 0.50-0.88, P = 0.004), dominant genetic model (adjusted OR = 0.80, 95%CI, 0.67-0.96, P = 0.015), recessive genetic model (adjusted OR = 0.73, 95%CI, 0.56-0.94, P = 0.016), and allele comparison (adjusted OR = 0.83, 95%CI, 0.73-0.94, P = 0.004). Stratification analysis showed that the rs4705341 was related to differentiated status, clinical stage I-II, and patients without lymph node metastasis. Moreover, patients with rs4705341GG had a longer overall survival (adjusted HR = 5.57, 95%CI, 0.95-32.68). These findings indicate that the miR-143/145 rs4705341 may be used as a potential biomarker for the development and prognosis of CRC.
Project description:Glucose-regulated protein 78 (GRP78), an endoplasmic reticulum chaperone, up-regulation serves as an efficient mechanism to promote malignant transformation of colorectal cancer (CRC) and protect CRC cells against apoptosis. Recently, the analysis of GRP78 polymorphisms has already determined that GRP78 rs391957 polymorphism could predict clinical outcome in CRC patients. Thus, we tested whether GRP78 polymorphisms are related to the risk of CRC. In this study, we detected two GRP78 polymorphisms (rs391957 (C>T) and rs430397 (G>A)) in 414 CRC cases and 502 hospital-based cancer-free healthy controls in Southwest China using a polymerase chain reaction-restriction fragment length polymorphism technique. Compared with the CC genotype, carriers of CT and TT genotypes of rs391957 polymorphism had higher risks of CRC (odds ratio (OR) = 1.39, 95% confidence interval (CI) = 1.06-1.83 for CT genotype and OR = 2.10, 95% CI = 1.06-4.14 for TT genotype, respectively). In CRC cases, the variant T allele was significantly associated with tumor invasion stage (P = 0.030), but not with status of lymph nodes metastasis (P = 0.052). Compared with the GG genotype, carriers of GA and AA genotypes of rs430397 polymorphism had higher risks of CRC (OR = 1.63, 95% CI = 1.23-2.15 for GA genotype and OR = 2.92, 95% CI = 1.23-6.94 for AA genotype, respectively). The rs430397 polymorphism was not associated with the clinicopathological characteristics of CRC. These data provide the first evidence that GRP78 rs391957 and rs430397 polymorphisms could serve as markers to predict the risk of CRC.