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Choline metabolism and risk of breast cancer in a population-based study

Xinran Xu^*, Marilie D. Gammon^¶, Steven H. Zeisel^#, Yin Leng Lee^*, James G. Wetmur^,, Susan L. Teitelbaum^*, Patrick T. Bradshaw^¶, Alfred I. Neugut^**,, Regina M. Santella and Jia Chen^*,,||,1

Department of
^* Community and Preventive Medicine,

Department of Microbiology,

Department of Genetics and Genomic Sciences,

Department of Pediatrics, and

^|| Department of Oncological Science, Mount Sinai School of Medicine, New York, New York, USA;

^¶ Department of Epidemiology and

^# Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina, USA; and Department of

^** Epidemiology,

Department of Medicine, and

Department of Environmental Health Sciences, Columbia University, New York, New York, USA

¹Correspondence: Department of Community and Preventive Medicine, Box 1043, Mt. Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA. E-mail: jia.chen{at}mssm.edu

Choline is an essential nutrient required for methyl group metabolism, but its role in carcinogenesis and tumor progression is not well understood. By utilizing a population-based study of 1508 cases and 1556 controls, we investigated the associations of dietary intake of choline and two related micronutrients, methionine and betaine, and risk of breast cancer. The highest quintile of choline consumption was associated with a lower risk of breast cancer [odds ratio (OR): 0.76; 95% confidence interval (CI): 0.58–1.00] compared with the lowest quintile. Two putatively functional single nucleotide polymorphisms of choline-metabolizing genes, PEMT –774G>C (rs12325817) and CHDH +432G>T (rs12676), were also found be related to breast cancer risk. Compared with the PEMT GG genotype, the variant CC genotype was associated with an increased risk of breast cancer (OR: 1.30; 95% CI: 1.01–1.67). The CHDH minor T allele was also associated with an increased risk (OR: 1.19; 95% CI: 1.00–1.41) compared with the major G allele. The BHMT rs3733890 polymorphism was also examined but was found not to be associated with breast cancer risk. We observed a significant interaction between dietary betaine intake and the PEMT rs7926 polymorphism (P_interaction=0.04). Our findings suggest that choline metabolism may play an important role in breast cancer etiology.—Xu, X., Gammon, M. D., Zeisel, S. H., Lee, Y. L., Wetmur, J. G., Teitelbaum, S. L., Bradshaw, P. T., Neugut, A. I., Santella, R. M., Chen, J. Choline metabolism and risk of breast cancer in a population-based study.

Key Words: methyl diet • methylation • genetic polymorphism • phosphatidylethanolamine N-methyltransferase • choline dehydrogenase • betaine-homocysteine methyltransferase