Abstract
Purpose
Choline and betaine are important for DNA methylation and synthesis, and may affect tumor carcinogenesis. To our knowledge, no previous study has examined the association between serum choline and betaine and breast cancer risk. This study aimed to examine whether serum choline and betaine were inversely associated with breast cancer risk among Chinese women.
Methods
This hospital-based case–control study consecutively recruited 510 breast cancer cases and 518 frequency-matched (age and residence) controls, and blood samples were available for 500 cases and 500 controls. Serum choline and betaine were assayed by high-performance liquid chromatography–tandem mass spectrometry. Multiple unconditional logistic regression was used to estimate odds ratios (ORs) and 95 % confidence intervals (CIs).
Results
An inverse association with breast cancer risk was observed for serum betaine (fourth vs first quartile adjusted OR 0.68, 95 % CI 0.47–0.97) and for the ratio of serum betaine to choline (fourth vs first quartile adjusted OR 0.70, 95 % CI 0.48–1.00), but not for serum choline (fourth vs first quartile adjusted OR 0.80, 95 % CI 0.56–1.15). Serum betaine was inversely associated with breast cancer risk in subjects with below-median dietary folate intake (fourth vs first quartile adjusted OR 0.48, 95 % CI 0.30–0.77).
Conclusions
This study suggested that serum betaine but not choline was inversely associated with breast cancer risk. This result needed to be further confirmed by the prospective studies.
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References
Ueland PM (2011) Choline and betaine in health and disease. J Inherit Metab Dis 34:3–15
Ueland PM, Holm PI, Hustad S (2005) Betaine: a key modulator of one-carbon metabolism and homocysteine status. Clin Chem Lab Med 43:1069–1075
Zeisel SH (2006) Choline: critical role during fetal development and dietary requirements in adults. Annu Rev Nutr 26:229–250
da Costa KA, Niculescu MD, Craciunescu CN, Fischer LM, Zeisel SH (2006) Choline deficiency increases lymphocyte apoptosis and DNA damage in humans. Am J Clin Nutr 84:88–94
Zeisel SH (2012) Dietary choline deficiency causes DNA strand breaks and alters epigenetic marks on DNA and histones. Mutat Res 733:34–38
Beilby J, Ingram D, Hahnel R, Rossi E (2004) Reduced breast cancer risk with increasing serum folate in a case–control study of the C677T genotype of the methylenetetrahydrofolate reductase gene. Eur J Cancer 40:1250–1254
Rossi E, Hung J, Beilby JP, Knuiman MW, Divitini ML, Bartholomew H (2006) Folate levels and cancer morbidity and mortality: prospective cohort study from Busselton, Western Australia. Ann Epidemiol 16:206–212
Zhang SM, Willett WC, Selhub J, Hunter DJ, Giovannucci EL, Holmes MD, Colditz GA, Hankinson SE (2003) Plasma folate, vitamin B-6, vitamin B-12, homocysteine, and risk of breast cancer. J Natl Cancer Inst 95:373–380
Lin J, Lee IM, Cook NR, Selhub J, Manson JE, Buring JE, Zhang SM (2008) Plasma folate, vitamin B-6, vitamin B-12, and risk of breast cancer in women. Am J Clin Nutr 87:734–743
Wu K, Helzlsouer KJ, Comstock GW, Hoffman SC, Nadeau MR, Selhub J (1999) A prospective study on folate, B12, and pyridoxal 5′-phosphate (B6) and breast cancer. Cancer Epidemiol Biomarkers Prev 8:209–217
Bae S, Ulrich CM, Neuhouser ML, Malysheva O, Bailey LB, Xiao L, Brown EC, Cushing-Haugen KL, Zheng Y, Cheng TY, Miller JW, Green R, Lane DS, Beresford SA, Caudill MA (2014) Plasma choline metabolites and colorectal cancer risk in the Women’s Health Initiative Observational Study. Cancer Res 74:7442–7452
de Vogel S, Schneede J, Ueland PM, Vollset SE, Meyer K, Fredriksen A, Midttun O, Bjorge T, Kampman E, Bretthauer M, Hoff G (2011) Biomarkers related to one-carbon metabolism as potential risk factors for distal colorectal adenomas. Cancer Epidemiol Biomarkers Prev 20:1726–1735
Nitter M, Norgard B, de Vogel S et al (2014) Plasma methionine, choline, betaine, and dimethylglycine in relation to colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). Ann Oncol 25:1609–1615
de Vogel S, Ulvik A, Meyer K, Ueland PM, Nygard O, Vollset SE, Tell GS, Gregory JF 3rd, Tretli S, Bjorge T (2014) Sarcosine and other metabolites along the choline oxidation pathway in relation to prostate cancer—a large nested case–control study within the JANUS cohort in Norway. Int J Cancer 134:197–206
Johansson M, Van Guelpen B, Vollset SE, Hultdin J, Bergh A, Key T, Midttun O, Hallmans G, Ueland PM, Stattin P (2009) One-carbon metabolism and prostate cancer risk: prospective investigation of seven circulating B vitamins and metabolites. Cancer Epidemiol Biomarkers Prev 18:1538–1543
Yan J, Winter LB, Burns-Whitmore B, Vermeylen F, Caudill MA (2012) Plasma choline metabolites associate with metabolic stress among young overweight men in a genotype-specific manner. Nutr Diabetes 2:e49
Resseguie M, Song J, Niculescu MD, da Costa KA, Randall TA, Zeisel SH (2007) Phosphatidylethanolamine N-methyltransferase (PEMT) gene expression is induced by estrogen in human and mouse primary hepatocytes. FASEB J 21:2622–2632
Zhang CX, Pan MX, Li B, Wang L, Mo XF, Chen YM, Lin FY, Ho SC (2013) Choline and betaine intake is inversely associated with breast cancer risk: a two-stage case–control study in China. Cancer Sci 104:250–258
Zhang CX, Ho SC (2009) Validity and reproducibility of a food frequency Questionnaire among Chinese women in Guangdong province. Asia Pac J Clin Nutr 18:240–250
Yang Y, Wang G, Pan X (2004) China food composition table. Peking University Medical Press, Beijing
Holm PI, Ueland PM, Kvalheim G, Lien EA (2003) Determination of choline, betaine, and dimethylglycine in plasma by a high-throughput method based on normal-phase chromatography–tandem mass spectrometry. Clin Chem 49:286–294
White E, Patterson RE, Kristal AR, Thornquist M, King I, Shattuck AL, Evans I, Satia-Abouta J, Littman AJ, Potter JD (2004) VITamins And Lifestyle cohort study: study design and characteristics of supplement users. Am J Epidemiol 159:83–93
Buchman AL, Jenden D, Suki WN, Roch M (2000) Changes in plasma free and phospholipid-bound choline concentrations in chronic hemodialysis patients. J Ren Nutr 10:133–138
McGregor DO, Dellow WJ, Lever M, George PM, Robson RA, Chambers ST (2001) Dimethylglycine accumulates in uremia and predicts elevated plasma homocysteine concentrations. Kidney Int 59:2267–2272
Schwahn BC, Chen Z, Laryea MD, Wendel U, Lussier-Cacan S, Genest J Jr, Mar MH, Zeisel SH, Castro C, Garrow T, Rozen R (2003) Homocysteine–betaine interactions in a murine model of 5,10-methylenetetrahydrofolate reductase deficiency. FASEB J 17:512–514
Holm PI, Ueland PM, Vollset SE, Midttun O, Blom HJ, Keijzer MB, den Heijer M (2005) Betaine and folate status as cooperative determinants of plasma homocysteine in humans. Arterioscler Thromb Vasc Biol 25:379–385
Cho E, Holmes MD, Hankinson SE, Willett WC (2010) Choline and betaine intake and risk of breast cancer among post-menopausal women. Br J Cancer 102:489–494
Cho EY, Holmes M, Hankinson SE, Willett WC (2007) Nutrients involved in one-carbon metabolism and risk of breast cancer among premenopausal women. Cancer Epidemiol Biomarkers Prev 16:2787–2790
Xu XR, Gammon MD, Zeisel SH, Lee YL, Wetmur JG, Teitelbaum SL, Bradshaw PT, Neugut AI, Santella RM, Chen J (2008) Choline metabolism and risk of breast cancer in a population-based study. FASEB J 22:2045–2052
Soares J, Pinto AE, Cunha CV, Andre S, Barao I, Sousa JM, Cravo M (1999) Global DNA hypomethylation in breast carcinoma: correlation with prognostic factors and tumor progression. Cancer 85:112–118
Ramirez de Molina A, Gutierrez R, Ramos MA, Silva JM, Silva J, Bonilla F, Sanchez JJ, Lacal JC (2002) Increased choline kinase activity in human breast carcinomas: clinical evidence for a potential novel antitumor strategy. Oncogene 21:4317–4322
Vineis P, Chuang SC, Vaissiere T, Cuenin C, Ricceri F, Johansson M, Ueland P, Brennan P, Herceg Z (2011) DNA methylation changes associated with cancer risk factors and blood levels of vitamin metabolites in a prospective study. Epigenetics 6:195–201
Katz-Brull R, Seger D, Rivenson-Segal D, Rushkin E, Degani H (2002) Metabolic markers of breast cancer: enhanced choline metabolism and reduced choline–ether–phospholipid synthesis. Cancer Res 62:1966–1970
Lever M, Sizeland PC, Frampton CM, Chambers ST (2004) Short and long-term variation of plasma glycine betaine concentrations in humans. Clin Biochem 37:184–190
Zeisel SH, Growdon JH, Wurtman RJ, Magil SG, Logue M (1980) Normal plasma choline responses to ingested lecithin. Neurology 30:1226–1229
Eckernas SA, Aquilonius SM (1977) Free choline in human plasma analysed by simple radio-enzymatic procedure: age distribution and effect of a meal. Scand J Clin Lab Invest 37:183–187
Savendahl L, Mar MH, Underwood LE, Zeisel SH (1997) Prolonged fasting in humans results in diminished plasma choline concentrations but does not cause liver dysfunction. Am J Clin Nutr 66:622–625
Hustad S, Eussen S, Midttun O, Ulvik A, van de Kant PM, Morkrid L, Gislefoss R, Ueland PM (2012) Kinetic modeling of storage effects on biomarkers related to B vitamin status and one-carbon metabolism. Clin Chem 58:402–410
Acknowledgments
This study was supported by Science and Technology Program of Guangzhou, China (no. 201510010151), and the National Natural Science Foundation of China (no. 81102188). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We gratefully acknowledge the cooperation of the study participants.
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Yu-Feng Du and Fang-Yu Lin contributed equally to this work.
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Du, YF., Lin, FY., Long, WQ. et al. Serum betaine but not choline is inversely associated with breast cancer risk: a case–control study in China. Eur J Nutr 56, 1329–1337 (2017). https://doi.org/10.1007/s00394-016-1183-3
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DOI: https://doi.org/10.1007/s00394-016-1183-3