Influence of Environmental Risk Factors of Colorectal Cancer and Gene-Environment Interactions on Line-1 DNA Methylation

Abstract

Introduction: This study examined the association between established colorectal cancer (CRC) risk factors and LINE-1 DNA methylation in healthy colon tissue, and whether genes involved in one-carbon metabolism modify relationships between established CRC risk factors and LINE-1 DNA methylation. This study was undertaken in order to inform on the role of LINE-1 DNA methylation as a mechanism by which established risk factors may lead to carcinogenesis. Reduced LINE-1 DNA methylation and one-carbon metabolism-related gene variants are both shown to increase CRC risk. Exposures related to LINE-1 DNA methylation may have a greater effect on methylation levels for individuals already susceptible to reduced methylation due to possession of a genetic variant. When considered together, these effects may impact methylation patterns in individuals beyond what would be expected if effects were purely additive. Methods: The study population consisted of 317 individuals scheduled for a routine colonoscopy. Multivariable linear regression was used to study the associations of alcohol consumption, smoking, body mass index, non-steroidal anti-inflammatory drug use, physical activity, and fruit and vegetable consumption with LINE-1 DNA methylation. Product terms between MTHFR 677C>T (rs1801133), MTR 2756A>G (rs1805087), and MTRR 66A>G (rs1801394) genotypes and exposures of interest were used to examine effect modification by genotype. Results: There were no statistically significant relationships observed between each risk factor of interest and LINE-1 DNA methylation. Statistically significant interactions between alcohol consumption and MTHFR and MTR genotypes were observed (p-value interaction=0.009, 0.003) in relation to LINE-1 DNA methylation. Conclusion: This thesis presents novel results on the relationships between a comprehensive set of CRC risk factors and LINE-1 DNA methylation in healthy colon tissue. We observed significant interactions by gene variants in the relationships between CRC risk factors and LINE-1 DNA methylation in the healthy colon. Although effects were not consistently in hypothesized directions, they suggest that one-carbon metabolism-related gene status is an important effect modifier in the relationship between alcohol consumption and LINE-1 DNA methylation.