Inoue-Choi, Maki2013-03-262013-03-262013-02https://hdl.handle.net/11299/146755University of Minnesota Ph.D dissertation. February 2013. Advisors: Kim Robien, Aaron Folsom. 1 computer file (PDF); xi, 164 pages, appendices p. 153-164. Major: Epidemiology.Breast cancer is the most common cancer among women in the United States. Nutrients in one-carbon metabolism (OCM) have been examined as potential modifiable risk factors because of OCM’s important role in DNA methylation and DNA synthesis. However, biologic mechanisms between OCM and carcinogenesis are still not clarified. The first manuscript tested the hypothesis that OCM nutrient status and genetic variation in methionine adenosyltransferases (MAT1A, MAT2A and MAT2B) are associated with plasma S-adenosylmethionine (SAM) levels in a cross-sectional analysis among healthy Singapore Chinese adults. Choline and methionine were strongly and positively associated with plasma SAM levels (ptrend<0.0001), and folate and betaine were positively associated with plasma SAM only in men (ptrend=0.02). The association between MAT1A rs2993763 and plasma SAM was modified by gender and plasma methionine levels. In the same study population, the second manuscript cross-sectionally tested the hypothesis that plasma SAM levels alone or in combination with genetic variation in DNA methyltransferases (DNMT1, DNMT3A and DNMT3B) are associated with global DNA methylation measured at long interspersed nucleotide element-1 (LINE-1). The LINE-1 methylation index was positively associated with plasma SAM levels (p≤0.01), with a plateau at approximately 78% and 77% methylation in men and women, respectively. Among men, there were statistically significant positive or negative associations between DNMT1 rs2114724 or DNMT3A rs758127 genotype and the LINE 1 methylation index, respectively (ptrend<0.01). The SAM-LINE-1 methylation association was modulated by DNMT1 rs2114724 genotype in men only. In a prospective cohort study, the third manuscript attempted to replicate increased breast cancer risk related to higher dietary nitrate intake only among those with low folate intake, which was previously reported by a case-control study. Opposite my hypothesis, among women with total folate intake 400 μg/day or above, breast cancer risk was statistically significantly higher among women in the highest quintile of nitrate intake from public water (HR=1.40, 95%CI=1.05-1.87) and private well users (HR=1.38, 95%CI=1.05-1.82) than those with the lowest nitrate intake from public water. The projects described in this dissertation contribute evidence describing how OCM may be related to cancer risk, and are a step in pursuit of my long-term goal to enhance our understanding of cancer etiology through OCM.en-USBreast cancerCancerFolateGenetic polymorophismNitrateOne-carbon metabolismThesis or Dissertation