Influence of MTHFR polymorphism, alone or in combination with smoking and alcohol consumption, on cancer susceptibility
Authors: Huang Yonghui , Hu Qiurui , Wei Zhenxia , Chen Li , Luo Ying , Li Xiaojie , Li Cuiping 
Published: September 2023

Abstract
5,10-methylenetetrahydrofolate reductase (MTHFR) mutations play a significant role in various types of cancers, serving as crucial regulators of folate levels in this process. Several studies have examined the effects of smoking and drinking on MTHFR-related cancers, yielding inconsistent results. Therefore, the objective of this study was to evaluate the magnitude of the effects of gene-smoking or gene-drinking interactions on cancer development. We conducted a comprehensive literature search in PubMed, Web of Science, CNKI, and Wan Fang databases up until May 10th, 2022, to identify relevant articles that met our inclusion criteria. The extracted data from these studies were used to calculate the overall odds ratio (OR) and corresponding 95% confidence interval (95% CI) using either a fixed-effect or random-effect model in Stata version 11.2. Stratified analyses were performed based on ethnicity, control group origin, and cancer classification to assess the risk of cancers associated with gene-smoking or gene-drinking interactions. Sensitivity analyses were conducted to investigate potential sources of heterogeneity, and publication bias was assessed using the Begg’s test and Egger’s test. Additionally, regression analysis was employed to explore the influence of relevant variables on heterogeneity. To evaluate the statistical correlations, analytical methods such as the false-positive report probability and the Bayesian false discovery probability were applied to assess the reliability of the findings. In our meta-analysis, a total of 47 articles were included, comprising 13,701 cases and 21,995 controls for the C677T polymorphism and 5,149 cases and 8,450 controls for the A1298C polymorphism. The results indicated a significant association between C677T polymorphism and cancer risks when combined with smoking (CT + TT vs CC, OR [95% CI] = 1.225 [1.009–1.487], p = 0.041). Stratified analysis further revealed a significant increase in liver cancer risk for individuals with the C677T when combined with smoking (liver cancer: CT + TT vs CC, OR [95% CI] = 1.564 [1.014–2.413], p = 0.043), particularly among Asian smokers (CT + TT vs CC, OR [95% CI] = 1.292 [1.007–1.658], p = 0.044). Regarding the A1298C polymorphism, an elevated risk of cancer was observed in mixed populations alone (CC + AC vs AA, OR [95% CI] = 1.609 [1.087–2.381], p = 0.018), as well as when combined with smoking (CC + AC vs AA, OR [95% CI] = 1.531 [1.127–2.080], p = 0.006). In non-drinkers, C677T polymorphism was found to be associated with esophageal cancer risk (C677T: CT + TT vs CC, OR [95% CI] = 1.544 [1.011–2.359], p = 0.044) and colon cancer risk (CC + AC vs AA, OR [95% CI] = 1.877 [1.166–3.054], p = 0.010), but there was no clear link between this polymorphism and cancer risk among drinkers. The association between the C677T polymorphism and cancer risk among smokers was found to be significant, suggesting that the combination of tobacco and the C677T polymorphism may enhance the carcinogenic process, particularly in liver cancer. However, no similar relationship was observed for the A1298C polymorphism. Interestingly, significantly increased cancer risk was observed in individuals with C677T genetic variants who were nondrinkers, but not among drinkers. These findings highlight the potential role of the C677T polymorphism in modifying cancer risk in specific contexts, such as smoking and alcohol consumption.