Abstract
Purpose
We investigated the roles of age, vitamin B12 markers, and the 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism as determinants of folate forms in serum.
Methods
We measured the serum concentrations of (6S)-5-CH3–H4folate, (6S)-H4folate, (6S)-5-HCO–H4folate, (6R)-5,10-CH+–H4folate, and folic acid in 146 non-supplemented older participants (median age 74 years). The concentrations of total vitamin B12, holotranscobalamin (holoTC), methylmalonic acid (MMA), and total homocysteine (tHcy) were also measured.
Results
Elevated metabolites (MMA > 271 nmol/L and tHcy > 12.0 μmol/L) were found in 24.0 and 63.0 % of the participants, respectively. We found a significant age-dependent decrease (participants with a median age of 87 years compared with participants with a median age of 60 years) in the sum of serum folate levels, the (6S)-5-CH3–H4folate concentration, and the (6S)-5-CH3–H4folate proportion. In addition, participants with elevated metabolite levels were older, had lower concentrations of the sum of folates and (6S)-5-CH3–H4folate, and had higher concentrations of (6S)-5-CHO–H4folate and creatinine but had a comparable holoTC/total vitamin B12 ratio. No association was found between the MTHFR C677T genotype and serum folate forms.
Conclusion
Low serum (6S)-5-CH3–H4folate concentrations and the proportion of (6S)-5-CH3–H4folate (percentage of the sum of folate forms) are related to older age and elevated MMA and tHcy levels.
Similar content being viewed by others
Abbreviations
- holoTC:
-
Holotranscobalamin
- MMA:
-
Methylmalonic acid
- MTHFR:
-
5,10-Methylenetetrahydrofolate reductase
- tHcy:
-
Total homocysteine
- UPLC–MS/MS:
-
Ultra-performance liquid chromatography/tandem mass spectrometry
References
Pfeiffer CM, Fazili Z, McCoy L, Zhang M, Gunter EW (2004) Determination of folate vitamers in human serum by stable-isotope-dilution tandem mass spectrometry and comparison with radioassay and microbiologic assay. Clin Chem 50:423–432
Kirsch SH, Knapp JP, Herrmann W, Obeid R (2010) Quantification of key folate forms in serum using stable-isotope dilution ultra performance liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 878:68–75
Smulders YM, Smith DE, Kok RM, Teerlink T, Gellekink H, Vaes WH, Stehouwer CD, Jakobs C (2007) Red blood cell folate vitamer distribution in healthy subjects is determined by the methylenetetrahydrofolate reductase C677T polymorphism and by the total folate status. J Nutr Biochem 18:693–699
Blencowe H, Cousens S, Modell B, Lawn J (2010) Folic acid to reduce neonatal mortality from neural tube disorders. Int J Epidemiol 39(Suppl 1):i110–i121
Herrmann W, Herrmann M, Obeid R (2007) Hyperhomocysteinaemia: a critical review of old and new aspects. Curr Drug Metab 8:17–31
Wang X, Qin X, Demirtas H, Li J, Mao G, Huo Y, Sun N, Liu L, Xu X (2007) Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet 369:1876–1882
Cui R, Iso H, Date C, Kikuchi S, Tamakoshi A (2010) Dietary folate and vitamin b6 and B12 intake in relation to mortality from cardiovascular diseases: Japan collaborative cohort study. Stroke 41:1285–1289
Ulrich CM (2007) Folate and cancer prevention: a closer look at a complex picture. Am J Clin Nutr 86:271–273
Kennedy DA, Stern SJ, Moretti M, Matok I, Sarkar M, Nickel C, Koren G (2011) Folate intake and the risk of colorectal cancer: a systematic review and meta-analysis. Cancer Epidemiol 35:2–10
Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM (1998) Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol 55:1449–1455
Yang Q, Botto LD, Erickson JD, Berry RJ, Sambell C, Johansen H, Friedman JM (2006) Improvement in stroke mortality in Canada and the United States, 1990 to 2002. Circulation 113:1335–1343
Obeid R, Schadt A, Dillmann U, Kostopoulos P, Fassbender K, Herrmann W (2009) Methylation status and neurodegenerative markers in Parkinson disease. Clin Chem 55:1852–1860
Herrmann W, Quast S, Ullrich M, Schultze H, Bodis M, Geisel J (1999) Hyperhomocysteinemia in high-aged subjects: relation of B-vitamins, folic acid, renal function and the methylenetetrahydrofolate reductase mutation. Atherosclerosis 144:91–101
Selhub J, Jacques PF, Wilson PW, Rush D, Rosenberg IH (1993) Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA 270:2693–2698
Flynn A, Hirvonen T, Mensink GB, Ocke MC, Serra-Majem L, Stos K, Szponar L, Tetens I, Turrini A, Fletcher R, Wildemann T (2009) Intake of selected nutrients from foods, from fortification and from supplements in various European countries. Food Nutr Res 53. doi:10.3402/fnr.v53i0.2038
Drogan D, Klipstein-Grobusch K, Dierkes J, Weikert C, Boeing H (2006) Dietary intake of folate equivalents and risk of myocardial infarction in the European Prospective Investigation into Cancer and Nutrition (EPIC)–Potsdam study. Public Health Nutr 9:465–471
Obeid R, Schorr H, Eckert R, Herrmann W (2004) Vitamin B12 status in the elderly as judged by available biochemical markers. Clin Chem 50:238–241
Clarke R, Grimley EJ, Schneede J, Nexo E, Bates C, Fletcher A, Prentice A, Johnston C, Ueland PM, Refsum H, Sherliker P, Birks J, Whitlock G, Breeze E, Scott JM (2004) Vitamin B12 and folate deficiency in later life. Age Ageing 33:34–41
Baik HW, Russell RM (1999) Vitamin B12 deficiency in the elderly. Annu Rev Nutr 19:357–377
Homocysteine Lowering Trialists’ Collaboration (2005) Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials. Am J Clin Nutr 82:806–812
Fried LF, Shlipak MG, Crump C, Bleyer AJ, Gottdiener JS, Kronmal RA, Kuller LH, Newman AB (2003) Renal insufficiency as a predictor of cardiovascular outcomes and mortality in elderly individuals. J Am Coll Cardiol 41:1364–1372
Stabler SP, Lindenbaum J, Savage DG, Allen RH (1993) Elevation of serum cystathionine levels in patients with cobalamin and folate deficiency. Blood 81:3404–3413
Orning L, Rian A, Campbell A, Brady J, Fedosov SN, Bramlage B, Thompson K, Quadros EV (2006) Characterization of a monoclonal antibody with specificity for holo-transcobalamin. Nutr Metab (Lond) 3:3. doi:10.1186/1743-7075-3-3
Ronaghi M, Uhlen M, Nyren P (1998) A sequencing method based on real-time pyrophosphate. Science 281:363–365
Verri A, Focher F, Tettamanti G, Grazioli V (2005) Two-step genetic screening of thrombophilia by pyrosequencing. Clin Chem 51:1282–1284
Herrmann W, Obeid R, Schorr H, Geisel J (2003) Functional vitamin B12 deficiency and determination of holotranscobalamin in populations at risk. Clin Chem Lab Med 41:1478–1488
Obeid R, Kirsch SH, Kasoha M, Eckert R, Herrmann W (2011) Concentrations of unmetabolized folic acid and primary folate forms in plasma after folic acid treatment in older adults. Metabolism 60:673–680
Fazili Z, Pfeiffer CM, Zhang M (2007) Comparison of serum folate species analyzed by LC–MS/MS with total folate measured by microbiologic assay and Bio-Rad radioassay. Clin Chem 53:781–784
Shane B, Stokstad EL (1985) Vitamin B12-folate interrelationships. Annu Rev Nutr 5:115–141
Bailey RL, Mills JL, Yetley EA, Gahche JJ, Pfeiffer CM, Dwyer JT, Dodd KW, Sempos CT, Betz JM, Picciano MF (2010) Unmetabolized serum folic acid and its relation to folic acid intake from diet and supplements in a nationally representative sample of adults aged ≥60 y in the United States. Am J Clin Nutr 92:383–389
Reed LS, Archer MC (1980) Oxidation of tetrahydrofolic acid by air. J Agric Food Chem 28:801–805
De Meer K, Smulders YM, Dainty JR, Smith DE, Kok RM, Stehouwer CD, Finglas PM, Jakobs C (2005) [6S]5-methyltetrahydrofolate or folic acid supplementation and absorption and initial elimination of folate in young and middle-aged adults. Eur J Clin Nutr 59:1409–1416
Tisman G, Herbert V (1973) B 12 dependence of cell uptake of serum folate: an explanation for high serum folate and cell folate depletion in B 12 deficiency. Blood 41:465–469
Nixon PF, Bertino JR (1972) Impaired utilization of serum folate in pernicious anemia. A study with radiolabeled 5-methyltetrahydrofolate. J Clin Invest 51:1431–1439
Acknowledgments
We thank Mrs. Marion Bodis and Mrs. Vera Kruse for their excellent assistance in the course of this study.
Conflict of interest
None.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kirsch, S.H., Herrmann, W., Eckert, R. et al. Factors affecting the distribution of folate forms in the serum of elderly German adults. Eur J Nutr 52, 497–504 (2013). https://doi.org/10.1007/s00394-012-0351-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00394-012-0351-3