Genetic polymorphisms in folate and alcohol metabolism, nutrients and the risk of stomach cancer: A pathway approach.

摘要

Despite the decreasing trend in incidence and mortality, stomach cancer remains the second leading cause of cancer-related death in men and the third leading cause of cancer-related death in women worldwide. Marked geographic variations and temporal trends point to the importance of environmental factors in stomach-cancer etiology. Both infection with H. pylori infection and dietary factors, particularly low consumption of fruits and vegetables, have been implicated as important environmental factors contributing to stomach-cancer risk. Folate, an important nutrient in fruits and vegetables, plays a critical role in DNA methylation, synthesis and repair. Alcohol consumption interferes with folate metabolism, and its primary metabolite---acetaldehyde---is a carcinogen. Both dietary folate intake and alcohol consumption are modifiable factors and hold great promise for stomach cancer prevention. However, epidemiologic data examining their roles in stomach cancer has been inconsistent. Using data from a population-based study of 464 cases and 480 controls in Warsaw, Poland, collected between 1994 and 1996, I evaluated the role of interactions between folate, alcohol and their metabolizing genes in determining the risk of stomach cancer.; In the first study of this dissertation (Chapter 2), I assessed the effect of 10 single-nucleotide polymorphisms in three folate-metabolizing genes ( MTHFR, MTR, MTRR) on stomach-cancer risk, and find borderline significant associations for MTR Ex26-20A>G and MTRR Ex5+123C>T polymorphisms (AG/GG vs. AA, OR=1.35, 95%CI: 0.96-1.90; CT/TT vs. CC, OR=1.30, 95%CI: 0.93-1.82 respectively). The results did not point to significant interactions between polymorphisms in MTHFR, MTR and MTRR genes and dietary folate and alcohol consumption.; In the second study of this dissertation (Chapter 3), I examined the effect of seven single-nucleotide polymorphisms in three alcohol-metabolizing genes (ADH1B, ADH1C and ALDH2) on stomach-cancer risk. None of these polymorphisms had a measurable effect on stomach-cancer risk. However, our results showed that carrying the G allele in ALDH2 Ex1+82A>G polymorphism was associated with a significant decreasing trend of alcohol consumption (weekly alcohol consumption for AA, GA and GG genotypes were 3.75, 2.26 and 1.53 drinks respectively, p=0.04), suggesting that the polymorphism may have functional effects on acetaldehyde elimination. When stratified by genotype, alcohol-related increases in stomach-cancer risk were restricted to individuals with the AG/GG genotypes of the ALDH2 Ex1+82 A>G polymorphism.; The first and second investigations of this dissertation (Chapters 2 and 3) used conventional approaches to evaluate genetic associations by assessing one polymorphism at a time. However, conventional approaches assume each polymorphism acts independently, and do not take into consideration how the different polymorphisms may work in a biologic pathway. Conventional analysis of dietary data also poses the same challenges. In the third analysis (Chapter 4), I compare hierarchical-modeling approaches with conventional approaches to empirically evaluate whether methods that incorporate pathway-based information can improve inferences drawn from empirical data. Specifically, I examine the effect of 13 single-nucleotide polymorphisms in folate metabolism and 18 nutrients on stomach-cancer risk. Overall, hierarchical and conventional modeling approaches yielded similar results, suggesting that none of the SNPs in folate metabolism (MTHFR, MTR, MTRR, MTHFD1, TYMS and cSHMT1) have an effect on stomach cancer and that retinol, an antioxidant nutrient that is essential for normal cell differentiation and immune function, may act independently from other nutrients in reducing the risk of stomach cancer.; In summary, this dissertation does not identify strong associations between genetic polymorphisms in folate metabolism and stomach-cancer risk. Although the ALDH2 Ex1+82 A>G polym