Alcohol consumption, DNA methylation and colorectal cancer risk: Results from pooled cohort studies and Mendelian randomization analysis.
Date
2022-07-01Author
Zhou, X
Wang, L
Xiao, J
Sun, J
Yu, L
Zhang, H
Meng, X
Yuan, S
Timofeeva, M
Law, PJ
Houlston, RS
Ding, K
Dunlop, MG
Theodoratou, E
Li, X
Type
Journal Article
Metadata
Show full item recordAbstract
Alcohol consumption is thought to be one of the modifiable risk factors for colorectal cancer (CRC). However, the causality and mechanisms by which alcohol exerts its carcinogenic effect are unclear. We evaluated the association between alcohol consumption and CRC risk by analyzing data from 32 cohort studies and conducted two-sample Mendelian randomization (MR) analysis to examine for casual relationship. To explore the effect of alcohol related DNA methylation on CRC risk, we performed an epigenetic MR analysis with data from an epigenome-wide association study (EWAS). We additionally performed gene-alcohol interaction analysis nested in the UK Biobank to assess effect modification between alcohol consumption and susceptibility genes. We discovered distinct effects of alcohol on CRC incidence and mortality from the meta-analyses, and genetic predisposition to alcohol drinking was causally associated with an increased CRC risk (OR = 1.79, 95% CI: 1.23-2.61) using two-sample MR approaches. In epigenetic MR analysis, two alcohol-related CpG sites (cg05593667 and cg10045354 mapped to COLCA1/COLCA2 gene) were identified causally associated with an increased CRC risk (P < 8.20 × 10-4 ). Gene-alcohol interaction analysis revealed that carriage of the risk allele of the eQTL (rs3087967) and mQTL (rs11213823) polymorphism of COLCA1/COLCA2 would interact with alcohol consumption to increase CRC risk (PInteraction = .027 and PInteraction = .016). Our study provides comprehensive evidence to elucidate the role of alcohol in CRC and highlights that the pathogenic effect of alcohol on CRC could be partly attributed to DNA methylation by regulating the expression of COLCA1/COLCA2 gene.
Collections
Subject
DNA methylation
Mendelian randomization
alcohol
colorectal cancer
Alcohol Drinking
Cohort Studies
Colorectal Neoplasms
DNA Methylation
Genome-Wide Association Study
Humans
Mendelian Randomization Analysis
Neoplasm Proteins
Polymorphism, Single Nucleotide
Research team
Cancer Genomics
Language
eng
Date accepted
2022-01-11
License start date
2022-07-01
Citation
International Journal of Cancer, 2022, 151 (1), pp. 83 - 94
Publisher
WILEY