Alcohol consumption, DNA methylation and colorectal cancer risk: Results from pooled cohort studies and Mendelian randomization analysis. Issue 1 (31st January 2022)

• Record Type: Journal Article
• Authors: Zhou, Xuan; Wang, Lijuan; Xiao, Jiarui; Sun, Jing; Yu, Lili; Zhang, Han; Meng, Xiangrui; Yuan, Shuai; Timofeeva, Maria; Law, Philip J.; Houlston, Richard S.; Ding, Kefeng; Dunlop, Malcolm G.; Theodoratou, Evropi; Li, Xue
• Is Part Of: International journal of cancer. Volume 151:Issue 1(2022)
• Page Start: 83
• Page End: 94
• Publication Date: 2022-01-31
• Subjects: alcohol -- colorectal cancer -- DNA methylation -- Mendelian randomization; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.33945
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract: 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 ( P Interaction = .027 and P Interaction = .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. Abstract : What's new? While alcohol consumption is suspected of being a modifiable risk factor for colorectal cancer (CRC), causal relationships and carcinogenic mechanisms linked to alcohol consumption remain unclear. In this study, investigation of interactions between alcohol consumption and susceptibility genes revealed associations between genetic predisposition to alcohol drinking and increased CRC risk. Epigenetic analyses showed that the pathogenic effect of alcohol can be attributed in part to DNA methylation via regulation of the expression of the COLCA1 / COLCA2 gene. Polymorphisms in risk alleles in COLCA1/COLCA2 interacted with alcohol consumption to increase CRC risk, providing insight into how alcohol modulates CRC tumorigenesis.