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Effects of the interaction between the C677T 5,10-methylenetetrahydrofolate reductase polymorphism and serum B vitamins on homocysteine levels in pregnant women

European Journal of Clinical Nutrition volume 58, pages 10–16 (2004)Cite this article

Abstract

Objective: The purpose of this study was to investigate the effect of the interaction between the C677T mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) genotypes and serum levels of B vitamins on serum homocysteine levels in pregnant women.

Design: A cross-sectional study.

Setting: Ewha Womans University Hospital, Seoul, Korea.

Subjects: A total of 177 normal pregnant women, 24.6±1.1 weeks of gestation, in a 6-month period during 2001–2002.

Interventions: Serum vitamin B2, vitamin B6, and homocysteine analyses were conducted using high-performance liquid chromatography methods. Serum folate and vitamin B12 concentrations were determined using a radioimmunoassay kit. MTHFR gene mutation was investigated by the polymerase chain reaction of a genomic DNA fragment.

Results: Serum homocysteine was higher in women with the T/T genotype than those with the C/T or C/C genotype of the MTHFR gene (P<0.05). Serum homocysteine was negatively correlated with serum folate in all MTHFR genotypes (P<0.001), and the correlation between the two serum levels was the strongest in the T/T genotype. Serum homocysteine was higher in the subjects with the T/T MTHFR genotype only when the serum folate was below the median level. Explanatory power of B vitamin status as predictors of serum homocysteine levels was more pronounced in the T/T genotypes (68.5%) compared with the C/T (37.9%) or C/C genotypes (20.6%).

Conclusions: Serum homocysteine levels in pregnant women varied significantly with MTHFR genotype and the serum B vitamin status. Higher serum folate, vitamin B2, and vitamin B12 concentrations may lessen the MTHFR genotypic effect on serum homocysteine levels.

Sponsorship: This study was supported by a grant from the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (01-PJ1-PG1-01CH15-0009).

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References

  • Araki A & Sako Y (1987): Determination of free and total homocysteine in human plasma by high performance liquid chromatography with fluorescence detection. J. Chromatogr. 422, 43–52.

    Article  CAS  Google Scholar 

  • Aubard Y, Darodes N & Cantaloube M (2000): Hyperhomocysteinemia and pregnancy—review of our present understanding and therapeutic implications. Eur. J. Obstet. Gynecol. 93, 157–165.

    Article  CAS  Google Scholar 

  • Bailey LB & Gregory III JF (1999): Polymorphisms of methylenetetrahydrofolate reductase and other enzymes: metabolic significance, risks and impact on folate requirement. J. Nutr. 129, 919–922.

    Article  CAS  Google Scholar 

  • Bates CJ & Fuller NJ (1986): The effect of riboflavin deficiency on methylenetetrahydrofolate reductase (NADPH) (EC 1.5.1.20) and folate metabolism in the rat. Br. J. Nutr. 55, 455–464.

    Article  CAS  Google Scholar 

  • van den Berg M, Franken DG & Boers GHJ (1994): Combined vitamin B6 plus folic acid therapy in young patients with arteriosclerosis and hyperhomocysteinemia. J. Vasc. Surg. 20, 933–940.

    Article  CAS  Google Scholar 

  • Botticher B & Botticher D (1987): A new HPLC-method for the simultaneous determination of B1-, B2- and B6-vitamers in serum and whole blood. Int. J. Vitam. Nutr. Res. 57, 273–298.

    CAS  PubMed  Google Scholar 

  • Brattstrom L, Wilcken DEL, Ohrvik J & Brudin L (1998): Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease. The result of a meta-analysis. Circulation 98, 2520–2526.

    Article  CAS  Google Scholar 

  • Bruinse HW & van den Berg H (1995): Changes of some vitamin levels during and after normal pregnancy. Eur. J. Obstet. Gynecol. 61, 31–37.

    Article  CAS  Google Scholar 

  • Burke G, Robinson K, Refsum H, Stuart B, Drumm J & Graham I (1992): Intrauterine growth retardation, perinatal death, and maternal homocysteine levels. N. Engl. J. Med. 326, 69–70.

    CAS  PubMed  Google Scholar 

  • Chango A, Emery-Fillon N, de Courcy GP, Lambert D, Pfister M, Rosenblatt DS & Nicolas JP (2000): A polymorphism (80G → A) in the reduced folate carrier gene and its associations with folate status and homocysteinemia. Mol. Genet. Metab. 70, 310–315.

    Article  CAS  Google Scholar 

  • Chen J, Stampfer MJ, Ma J, Selhub J, Malinow MR, Hennekens CH & Hunter DJ (2001): Influence of a methionine synthase (D919G) polymorphism on plasma homocysteine and folate levels and relation to risk of myocardial infarction. Atherosclerosis 154, 667–672.

    Article  CAS  Google Scholar 

  • Cikot RJLM, Steegers-Theunissen RPM, Thomas CMG, de Boo TM, Merkus HMWM & Steegers EAP (2001): Longitudinal vitamin and homocysteine levels in normal pregnancy. Br. J. Nutr. 85, 19–58.

    Article  Google Scholar 

  • de Falco M, Scaramellino M, Pontillo M & Di Lieto A (2000): Homocysteinaemia during pregnancy and placental disease. Clin. Exp. Obstet. Gynecol. 27, 188–190.

    CAS  PubMed  Google Scholar 

  • Frosst P, Blom HJ, Milos R, Goyette P, Sheppard C, Matthews R, Boers GJ, den Heijer M, Kluijtmans LA, van den Heuvel LP & Rozen R (1995): A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat. Genet. 10, 111–113.

    Article  CAS  Google Scholar 

  • Gaughan DJ, Kluijtmans LA, Barbaux S, McMaster D, Young IS, Yarnell JW, Evans A & Whitehead AS (2001): The methionine synthase reductase (MTRR) A66G polymorphism is a novel genetic determinant of plasma homocysteine concentrations. Atherosclerosis 157, 451–456.

    Article  CAS  Google Scholar 

  • Goddijn-Wessel TAW, Wouters MGAJ, van den Molen EF, Spuijbroek MDEH, Steegers-Theunissen RPM, Blom HJ, Boers GHJ & Eskes TKAB (1996): Hyperhomocysteinemia: a risk factor for placental abruption or infarction. Eur. J. Obstet. Gynecol. 66, 23–29.

    Article  CAS  Google Scholar 

  • Gudnason V, Stansble D, Scott J, Browron A, Nicaud V & Humphries S (1998): C677T (thermolabile alanine/valine) polymorphism in methylenetetrahydrofolate reductase (MTHFR): its frequency and impact on plasma homocysteine concentration in different European populations. Atherosclerosis 136, 347–354.

    Article  CAS  Google Scholar 

  • Guenther BD, Sheppard CA, Tran P, Rozen R, Matthews RG & Ludwig ML (1999): The structure and properties of methylenetetrahydrofolate reductase from Escherichia coli suggest how folate ameliorates human hyperhomocysteinemia. Nat. Struct. Biol. 6, 359–365.

    Article  CAS  Google Scholar 

  • Guttormsen AB, Ueland PM, Nesthus I, Nygard O, Schneede J, Vollset SE & Refsum H (1996): Determinants and vitamin responsiveness of intermediate hyperhomocysteinemia (&gt; or =40 micromol/liter). The Hordaland Homocysteine Study. J. Clin. Invest. 98, 2174–2183.

    Article  CAS  Google Scholar 

  • Hustad S, Ueland PM, Vollset SE, Zhang Y, Bjorke-Monsen AL & Schneede J (2000): Riboflavin as a determinant of plasma total homocysteine: effect modification by the methylenetetrahydrofolate reductase C677T polymorphism. Clin. Chem. 46(8 Part 1), 1065–1071.

    CAS  Google Scholar 

  • Jacques PF, Bostom AG, William RR, Ellison C, Eckfeldt JH, Rosenberg IH, Selhub J & Rozen R (1996): Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation 93, 7–9.

    Article  CAS  Google Scholar 

  • Jacques PF, Kambach R, Bagley P, Russo GT, Rogers G, Wilson PWF, Roseberg IH & Selhub J (2002): The relationship between riboflavin and plasma total homocysteine in the Framingham offspring cohort is influenced by folate status and the C677T transition in the methylenetetrahydrofolate reductase gene. J. Nutr. 132, 283–288.

    Article  CAS  Google Scholar 

  • Leeda M, Riyazi N, de Vries JIP, Jakobs C, van Geijn HP & Dekker GA (1998): Effects of folic acid and vitamin B6 supplementation on women with hyperhomocysteinemia and a history of preeclampsia or fetal growth restriction. Am. J. Obstet. Gynecol. 179, 135–139.

    Article  CAS  Google Scholar 

  • Lucock M, Daskalakis I & Yates Z (2001): C677T MTHFR genotypes show graded response to vitamin B12 dependent regeneration of tetrahydrofolate, the main congener of all cellular folates. Nutr. Res 21, 1357–1362.

    Article  CAS  Google Scholar 

  • McNulty H, McKinley MC, Wilson B, McPartlin J, Strain JJ, Weir DG & Scott JM (2002): Impaired functioning of thermolabile methylenetetrahydrofolate reductase is dependent on riboflavin status: implications for riboflavin requirements. Am. J. Clin. Nutr. 76, 436–441.

    Article  CAS  Google Scholar 

  • Mill JL, McPartlin JM & Kirke PN (1995): Homocysteine metabolism in pregnancies complicated by neural tube defects. Lancet 345, 149–151.

    Article  Google Scholar 

  • Moriyama Y, Okamura T, Kjinami K, Iso H, Inazu A, Kawashiri M, Mizuno M, Takeda Y, Sakamoto Y, Kimura H, Suzuki H & Mabuchi H (2002): Effects of serum B vitamins on elevated plasma homocysteine levels associated with the mutation of methylenetetrahydrofolate reductase gene in Japanese. Atherosclerosis 164, 321–328.

    Article  CAS  Google Scholar 

  • Nakamura T, Saionji K, Hiejima Y, Hirayama H, Tago K, Takano H, Tajiri M, Hayash K, Kawabata M, Funamizu M, Makita Y & Hata A (2002): Methylenetetrahydrofolate reductase genotype, vitamin B12, and folate influence plasma homocysteine in hemodialysis patients. Am. J. Kidney Dis 39, 1032–1039.

    Article  CAS  Google Scholar 

  • Nelen WLDM, Blom HJ, Thomas CMG, Steegers EAP, Boers GHJ & Eskes TKAB (1998): Methylenetetrahydrofolate reductase polymorphism affects the change in homocysteine and folate concentrations resulting from low dose folic acid supplementation in women with unexplained recurrent miscarriages. J. Nutr. 128, 1336–1341.

    Article  CAS  Google Scholar 

  • Ozcan T, Mendilcioglu I, Karne A, Copel JA & Magriples U (2002): MTHFR heterozygosity carries the same risk of poor pregnancy outcomes as homozygosity. Monday Posters 99, 17S.

    Google Scholar 

  • Perry DJ (1999): Hyperhomocysteinaemia. Bailliere's Clin. Haematol. 12, 451–477.

    Article  CAS  Google Scholar 

  • Powers RW, Minich LA, Lykins DL, Ness RB, Crombleholme WR & Roberts JM (1999): Methylenetetrahydrofolate reductase polymorphism, folate, and susceptibility to preeclampsia. J. Soc. Gynecol. Invest. 6, 74–79.

    Article  CAS  Google Scholar 

  • van der Put NM, Steegers-Theunissen RP, Frosst P, Trijbels FJ, Eskes TK, van den Heuvel LP, Mariman EC, den Heyer M, Rozen R & Blom HJ (1995): Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. Lancet 21, 1070–1071.

    Article  Google Scholar 

  • van der Put NM, Gabreels F, Stevens EMB, Smeitink JAM, Trijbels FJM, Eskes TKAB, van den Heuvel LP & Blom HJ (1998): A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am. J. Hum. Genet. 62, 1044–1051.

    Article  CAS  Google Scholar 

  • Rady PL, Szucs S, Grady J, Hudnall SD, Kellner LH, Nitowsky H, Tyring SK & Matalon RK (2002): Genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) in ethnic populations in Texas; a report of a novel MTHFR polymorphic site, G1793A. Am. J. Med. Genet. 107, 162–168.

    Article  Google Scholar 

  • Ray JG & Lastin CA (1999): Folic acid and homocysteine metabolic defects and the risk of placental abruption, pre-eclampsia and spontaneous pregnancy loss: a systematic review. Placenta 20, 519–529.

    Article  CAS  Google Scholar 

  • Rosenquist TH, Ratashak SA & Selhub J (1995): Homocysteine induces congenital defects of the heart and neural tube: effect of folic acid. Proc. Natl. Acad. Sci. USA 93, 15227–15232.

    Article  Google Scholar 

  • Scholl TO & Johnson WC (2000): Folic acid: influence on the outcome of pregnancy. Am. J. Clin. Nutr. 71(Suppl). 1295S–1303S.

    Article  CAS  Google Scholar 

  • Ueland PM, Hustad S, Schneede J, Refsum H & Vollset SE (2001): Biological and clinical implications of the MTHFR C677T polymorphism. Trends Pharmacol. Sci. 22, 195–201.

    Article  CAS  Google Scholar 

  • Woodside JV, Yarnell JWG, McMaster D, Young IS, Harmon DL, McCrum EE, Patterson CC, Gey KF, Whitehead AS & Evans A (1998): Effect of B-group vitamins and antioxidant vitamins on hyperhomocysteinemia: a double-blind, randomized, factorial-design, controlled trial. Am. J. Clin. Nutr. 67, 858–866.

    Article  CAS  Google Scholar 

  • Wouters MG, Boers GH, Blom HJ, Trijbels FJ, Thomas CM, Borm GF, Steegers-Theunissen RP & Eskes TK (1993): Hyperhomocysteinemia: a risk factor in women with unexplained recurrent early pregnancy loss. Fertil. Steril. 60, 820–825.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Food and Nutritional Sciences, Ewha Womans University, Seoul, Korea

    K N Kim & N Chang

  2. Department of Obstetrics and Gynecology, Medical Research Center, Ewha Womans University, Seoul, Korea

    Y J Kim

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  1. K N Kim
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Contributions

Guarantors: Ki Nam Kim, Namsoo Chang.

Contributors: NSC and YJK contributed to the design of the study, subject recruiting, and manuscript preparation. KNK carried out the data analysis and the biochemical analyses of serum B vitamins and homocysteine. YJK was responsible for clinical data collection and the analysis of the MTHFR polymorphism. NSC was the main person responsible for all stages of the study. All took part in the writing of the paper.

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Correspondence to N Chang.

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Kim, K., Kim, Y. & Chang, N. Effects of the interaction between the C677T 5,10-methylenetetrahydrofolate reductase polymorphism and serum B vitamins on homocysteine levels in pregnant women. Eur J Clin Nutr 58, 10–16 (2004). https://doi.org/10.1038/sj.ejcn.1601729

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