Polymorphisms within Autophagy-Related Genes Influence the Risk of Developing Colorectal Cancer: A Meta-Analysis of Four Large Cohorts.
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ABSTRACT:
SUBMITTER: Sainz J
PROVIDER: S-EPMC7998818 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In the last four years, Genome-Wide Association Studies (GWAS) have identified sixteen low-penetrance polymorphisms on fourteen different loci associated with colorectal cancer (CRC). Due to the low risks conferred by known common variants, most of the 35% broad-sense heritability estimated by twin studies remains unexplained. Recently our group performed a case-control study for eight Single Nucleotide Polymorphisms (SNPs) in 4 CRC genes. The present investigation is a follow-up of that study. We have genotyped six SNPs that showed a positive association and carried out a meta-analysis based on eight additional studies comprising in total more than 8000 cases and 6000 controls. The estimated recessive odds ratio for one of the SNPs, rs3219489 (MUTYH Q338H), decreased from 1.52 in the original Swedish study, to 1.18 in the Swedish replication, and to 1.08 in the initial meta-analysis. Since the corresponding summary probability value was 0.06, we decided to retrieve additional information for this polymorphism. The incorporation of six further studies resulted in around 13000 cases and 13000 controls. The newly updated OR was 1.03. The results from the present large, multicenter study illustrate the possibility of decreasing effect sizes with increasing samples sizes. Phenotypic heterogeneity, differential environmental exposures, and population specific linkage disequilibrium patterns may explain the observed difference of genetic effects between Sweden and the other investigated cohorts.
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Project description:BACKGROUND: Chronic inflammation is a risk factor for colorectal cancer and polymorphisms in the inflammatory genes could modulate the levels of inflammation. We have investigated ten single nucleotide polymorphisms (SNPs) in the following inflammation-related genes: TLR4 (Asp299Gly), CD14 (-260 T>C), MCP1 (-2518 A>G), IL12A (+7506 A>T, +8707 A>G, +9177 T>A, +9508 G>A), NOS2A (+524T>C), TNF (-857C>T), and PTGS1 (V444I) in 377 colorectal (CRC) cancer cases and 326 controls from Barcelona (Spain). RESULTS: There was no statistically significant association between the SNPs investigated and colorectal cancer risk. CONCLUSION: The lack of association may show that the inflammatory genes selected for this study are not involved in the carcinogenic process of colorectum. Alternatively, the negative results may derive from no particular biological effect of the analysed polymorphisms in relation to CRC. Otherwise, the eventual biological effect is so little to go undetected, unless analysing a much larger sample size.
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Project description:Our meta-analysis aggregated existing results from relevant studies to comprehensively investigate the correlations between genetic polymorphisms in dihydropyrimidine dehydrogenase (DPYD) gene and 5-fluorouracil (5-FU) toxicities in patients with colorectal cancer (CRC). The MEDLINE (1966∼2013), the Cochrane Library Database (Issue 12, 2013), EMBASE (1980∼2013), CINAHL (1982∼2013), Web of Science (1945∼2013), and the Chinese Biomedical Database (CBM) (1982∼2013) were searched without language restrictions. Meta-analyses were conducted with the use of STATA software (Version 12.0, Stata Corporation, College Station, TX, USA). Seven clinical cohort studies with a total of 946 CRC patients met our inclusion criteria, and NOS scores of each of the included studies were ≥5. Our findings showed that DPYD genetic polymorphisms were significantly correlated with high incidences of 5-FU-related toxicity in CRC patients. SNP-stratified analysis indicated that there were remarkable connections of IVS14+1G>A, 464T>A, and 2194G>A polymorphisms with the incidence of marrow suppression in CRC patients receiving 5-FU chemotherapy. Furthermore, we found that IVS14+1G>A, 496A>G, and 2194G>A polymorphisms were correlated with the incidence of gastrointestinal reaction. Ethnicity-stratified analysis also revealed that DPYD genetic polymorphisms might contribute to the development of marrow suppression and gastrointestinal reaction among Asians, but not among Caucasians. The present meta-analysis suggests that DPYD genetic polymorphisms may be correlated with the incidence of 5-FU-related toxicity in CRC patients.
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Project description:BackgroundPrevious studies have shown a positive association between type 2 diabetes (T2D) and colorectal cancer (CRC) risk. However, it is uncertain whether this association differs by duration of T2D or sex. We thus investigated the associations of T2D and its duration with the risk of incident CRC.MethodsWe followed 87,523 women from the Nurses' Health Study (1980-2012) and 47,240 men from the Health Professionals Follow-up Study (1986-2012). Data on physician-diagnosed T2D was collected at baseline with a questionnaire and updated biennially. Cox regression models were used to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs).ResultsWe documented 3000 CRC cases during up to 32 years of follow-up. Among men, T2D was associated with increased risk of CRC compared to those without T2D (HR: 1.42; 95% CI: 1.12-1.81). This positive association persisted in sensitivity analyses by excluding CRC identified within 1 year of diabetes diagnosis and patients with T2D who used hypoglycaemic medications. Among women, T2D was positively, but not statistically significantly, associated with CRC risk (HR: 1.17; 95% CI: 0.98-1.39).ConclusionsOur findings support that T2D was associated with a moderately higher risk of developing CRC in men; a weaker, nonsignificant positive association was observed in women.
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Project description:ObjectiveThe adiponectin gene (ADIPOQ) has been suggested to be associated with the pathogenesis of colorectal cancer (CRC). However, the results have been inconsistent. In this study, we performed a meta-analysis to investigate the association between adiponectin polymorphisms and CRC risk.MethodsAll eligible case-control studies published up to March 2013 were identified by searching PubMed, Web of Science and CNKI. Effect sizes of odds ratio (OR) and 95% confidence interval (95% CI) were calculated by using a fixed- or random-effect model.ResultsA total of 9 case-control studies were included, Of those studies, there were eight studies (2024 cases and 2777 controls) for rs1501299G/T polymorphism, five studies (1401 cases and 1691 controls) for rs2241766T/G polymorphism, five studies (2945 cases and 3361 controls) for rs266729C/G polymorphism, three studies (1221 cases and 1579 controls) for rs822395A/C polymorphism and three studies (1222 cases and 1575 controls) for rs822396A/G polymorphism. Overall, a significant association was observed for rs2241766T/G polymorphism under heterozygote comparison (TG vs. TT: OR=1.22, 95%CI: 1.05-1.43); while there was no significant association for rs2241766 polymorphism under other genetic models, and for other four polymorphisms under all genetic models. Besides, when stratified analyses by ethnicity, no significant association between five polymorphisms and CRC risk were observed under all genetic models among Asian, Caucasian and African-American.ConclusionsThis meta-analysis indicated that adiponectin rs2241766T/G rather than rs1501299G/T, rs266729C/G, rs822395A/C and rs822396A/G polymorphism was associated with the risk of colorectal cancer.
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2017-12-04 | PXD006281 | Pride