Journal of Nutrition and Health

The Korean Nutrition Society (한국영양학회)
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Effects of Maternal 5, 10-Methylenetetrahydrofolate Reductase (MTHFR) Genotypes, Serum Homocysteine and B Vitamin Levels on Postnatal Growth in Their Offsprings

임신부의 MTHFR 유전자형, 호모시스테인 및 비타민 B군 영양상태가 영아 성장에 미치는 영향

  • Kim Hye-Sook (Department of Food and Nutritional Sciences, Asia Food and Nutrition Institute, Ewha Womans University) ;
  • Kim Young-Ju (Department of Obstetrics & Gynecology, Ewha Womans Medical Center) ;
  • Chang Nam-Soo (Department of Food and Nutritional Sciences, Asia Food and Nutrition Institute, Ewha Womans University)
  • 김혜숙 (이화여자대학교 생활환경대학 식품영양학과, 아시아 식품영양연구소) ;
  • 김영주 (이화여자대학교 의과대학 산부인과학교실) ;
  • 장남수 (이화여자대학교 생활환경대학 식품영양학과, 아시아 식품영양연구소)
  • Published : 2006.04.01
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Abstract

Elevated maternal plasma homocysteine concentrations have been associated with adverse pregnancy outcomes. Serum homocysteine levels may be affected by the MTHFR genotypes and the nutritional status of B vitamins including vitamin $B_2,\;B_6$, folate and vitamin $B_{12}$. We investigated whether postnatal growth measurements were influenced by maternal MTHFR genotypes and their mid-pregnancy serum vitamin B and homocysteine levels. In 130 pregnant women of 24-28 wks of gestation, the MTHFR genotypes, serum B vitamins and homocysteine concentrations were analyzed. Physical growth status was assessed in their offsprings by measuring height, weight, and head and chest circumferences from birth up to 24 months. Serum homocysteine levels were higher in the subjects with T/T genotype than those with the C/T or C/C. Heights and head and chest circumferences of offsprings from the T/T mothers were significantly lower than those from the C/C or C/T mothers only when the serum homocysteine levels were above the median. The mean height of offsprings from the T/T mothers was significantly lower than those from the C/C and C/T mothers. The mean weight and head circumferences of offsprings born from the mothers whose mid-term pregnancy PLP levels were in the lowest quartile was significantly lower than those from mothers in the highest quartile. Heights and head circumferences of offsprings from the T/T mothers were significantly lower than those from the C/C or C/T mothers only when the serum FAD levels were in the lowest quartile. These results suggest that postnatal growth up to 24 months may be influenced by the maternal C677T MTHFR genotypes, and mid-pregnancy serum homocysteine and vitamin B status.

Keywords

References

  1. Burke G, Robinson K, Refsum H, Stuart B, Drumm J, Graham I. Intrauterine growth retardation, perinatal death, and maternal homocysteine levels. N Engl J Ned 326: 69-70, 1992
  2. Vollset SE, Refsum H, Irgens LM, Enblem BM, Tverdal A, Gjessing HK, Monsen ALB, Ueland PM. Plasma total homocysteine, pregnancy complications and adverse pregnancy outcomes: the Hordaland Homocysteine Study. Am J Clin Nutr 71: 962-968, 2000 https://doi.org/10.1093/ajcn/71.4.962
  3. Mills JL, McPartlin JM, Kirke PN, Lee YJ, Conley MR, Weir DG, Scott JM. Homocysteine metabolism in pregnancies complicated by neural-tube defects. Lancet 345: 149-151, 1995 https://doi.org/10.1016/S0140-6736(95)90165-5
  4. Rosenquist TH, Ratashak SA, Selhub J. Homocysteine induces congenital defects of the heart and neural tube: effect of folic acid. Proc Natl Acad Sci USA 93: 15227-15232, 1996
  5. Wouters MG, Boers GH, Blom HJ, Trijbels FJ, Thomas CM, Borm GF, Steegers-Theunissen RP, Eskes TK. Hyperhomocysteinemia: a risk factor in women with unexplained recurrent early pregnancy loss. Fertil Steril 60: 820-825. 1993 https://doi.org/10.1016/S0015-0282(16)56282-7
  6. Goddijn-Wessel TA, Wouters MG, van de Molen EF, Spuijbroek MD, Steegers-Theunissen RP, Blom HJ, Boers GH, Eskes TK. Hyperhomocysteinemia: a risk factor for placental abruption or infarction. Eur J Obstet Gynecol Reprod Biol 66: 23-29, 1996 https://doi.org/10.1016/0301-2115(96)02383-4
  7. Martin PM, Ola MS, Agarwal N, Ganapathy V, Smith SB. The sigma receptor ligand(+)-pentazocine prevents apoptotic retinal ganglion cell death induced in vitro by homocysteine and glutamate. Mol Brain Res 123: 66-75, 2004 https://doi.org/10.1016/j.molbrainres.2003.12.019
  8. Perry DJ. Hyperhomocysteinaemia. Baillieres Best Pract Res Clin Haematol 12: 451-477, 1999
  9. Kang SS, Wong PW, Glickman PB, MacLeod CM, Jaffe IA. Protein-bound homocyst(e)ine in patients with rheumatoid arthritis undergoing D-penicillamine treatment. J Clin Pharmacol 26: 712-715, 1986 https://doi.org/10.1002/j.1552-4604.1986.tb02978.x
  10. Bailcy LB, Gregory JF. Polymorphism of methylenetetrahydrofolate reductase and other enzyme: metabolic significance, risks and impact on folate requirement. J Nutr 129: 919-922, 1999
  11. Powers RW, Minich LA, Lykins DL, Ness RB, Crombleholme WR, Roberts JM. Methylenetetrahydrofolate reductase polymorphism, folate, and susceptibility to preeclampsia. J Soc Gynecol Investig 6: 74-79, 1999 https://doi.org/10.1016/S1071-5576(98)00052-5
  12. Mason JB. Biomarkers of nutrient exposure and status in onecarbon (methyl) metabolism. J Nutr 3: 941S-947S, 2003
  13. Shils ME, Olson JA, Shike M, Ross AC. Choline and phosphatidylcholine. In: Modern Nutrition in Health and Disease, 9th Ed. Williams & Wilkins, Baltimore, MD, pp.514, 1999
  14. Ueland PM, Hustad S, Schneede J, Refsum H, Vollset SE. Biological and clinical implications of the MTHFR C677T polymorphism. Trends Pharmacol Sci 22: 195-201, 2001 https://doi.org/10.1016/S0165-6147(00)01675-8
  15. Chang NS, Kang M, Paik HY, Kim IH, Cho YW, Park SC, Shin YW. Serum folate and iron levels of pregnant, lactating and nonpregnant, non-lactating women. Korean J Nutrition 26(1): 67-75, 1993
  16. Lim HS, Lee JI, Lee JA, Folate status of Korean pregnant women and their pregnancy outcomes. Korean J Nutrition 32(5): 592- 597, 1999
  17. Ahn HS, Kim JS, Lee GJ, Kim YT. Serum folate levels of maternal-umbilical cord blood and pregnancy outcomes. Korean J Nutrition 33(8): 840-847, 2000
  18. Ahn HS, Lee GJ, Kim YT. Relationship between vitamin $B_{6}$ status of maternal-umbilical cord plasma and pregnancy outcomes. Korean J Nutrition 33(3): 263-270, 2000
  19. Park KS, Podskarbi T, Yoo EA, Shin YS. The C677T mutation in the methylenetetrahydrofolate reductase gene in Koreans. Korean J Genetics 20(1): 23-28, 1998
  20. Kim NK, Kang GD, Kim HJ, Kim JH, Nam YS, Lee S, Chung HM, Kang SH, Ahn JY, Choi BO, Hwang SG, Oh D. Genetic polymorphism of 5, 10-methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C in healthy. Korean J Genetics 24(2): 227-234, 2002
  21. Bondevik GT, Schneede J, Refsum H, Lie RT, Ulstein M, Kvale G. Homocysteine and methylmalonic acid levels in pregnant Nepali women. Should cobalamin supplementation be considered? Eur J Clin Nutr 55(10): 856-864, 2001 https://doi.org/10.1038/sj.ejcn.1601236
  22. Vollset SE, Refsum H, Irgens LM, Emblem BM, Tverdal A, Gjessing HK, Monsen AL, Ueland PM. Plasma total homocysteine, pregnancy complications, and adverse pregnancy outcomes: the Hordaland Homocysteine study. Am J Clin Nutr 71(4): 962- 968, 2000 https://doi.org/10.1093/ajcn/71.4.962
  23. Ronnenberg AG, Goldman MB, Chen D, Aitken IW, Willett WC, Selhub J, Xu X. Preconception homocysteine and B vitamin status and birth outcomes in Chinese women. Am J Clin Nutr 76(6): 1385-1391, 2002 https://doi.org/10.1093/ajcn/76.6.1385
  24. Leeda M, Riyazi N, de Vries JI, Jakobs C, van Geijn HP, Dekker GA. Effects of folic acid and vitamin $B_{6}$ supplementation on women with hyperhomocysteinemia and a history of preeclampsia or fetal growth restriction. Am J Obstet Gynecol 179(1): 135- 139, 1998
  25. Goddijn-Wessel TA, Wouters MG, van de Molen EF, Spuijbroek MD, Steegers-Theunissen RP, Blom HJ, Boers GH, Eskes TK. Hyperhomocysteinemia: a risk factor for placental abruption or infarction. Eur J Obstet Gynecol Reprod Biol 66(1): 23-29, 1996 https://doi.org/10.1016/0301-2115(96)02383-4
  26. Capo-Chichi CD, Gueant JL, Lefebvre E, Bennani N, Lorentz E, Vidailhet C, Vidailhet M. Riboflavin and riboflavin-derived cofactors in adolescent girls with anorexia nervosa. Am J Clin Nutr 69: 672-678, 1999 https://doi.org/10.1093/ajcn/69.4.672
  27. Araki A, Sako Y. Determination of free and total homocysteine in human plasma by high-performance liquid chromatography with fluorescence detection. J Chromatogr 422: 43-52, 1987 https://doi.org/10.1016/0378-4347(87)80438-3
  28. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, den Heijer M, Kluijtmans LA, van den Heuvel LP, Rozen R. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10: 111-113, 1995 https://doi.org/10.1038/ng0595-111
  29. Jacques PF, Bostom AG, Williams RR, Ellison RC, Eckfeldt JH, Rosenberg IH, Selhub J, Rozen R. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation 1; 93(1): 7-9, 1996
  30. Gudnason V, Stansbie D, Scott J, Bowron A, Nicaud V, Humphries S. C677T (thermolabile alanine/valine) polymorphism in methylenetetrahydrofolate reductase (MTHFR): its frequency and impact on plasma homocysteine concentration in different European populations. EARS group. Atherosclerosis 136(2): 347-354, 1998 https://doi.org/10.1016/S0021-9150(97)00237-2
  31. Brattstrom L, Wilcken DE, Ohrvik J, Brudin L. Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease: the result of a metaanalysis. Circulation 98(23): 2520-2526, 1998 https://doi.org/10.1161/01.CIR.98.23.2520
  32. Kim KN, Kim YJ, 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(1): 10-16, 2004 https://doi.org/10.1038/sj.ejcn.1601729
  33. Alfirevic Z, Mousa HA, Martlew V, Briscoe L, Perez-Casal M, Toh CH. Postnatal screening for thrombophilia in women with severe pregnancy complications. Obstet Gynecol 97(5 Pt 1): 753-759, 2001 https://doi.org/10.1016/S0029-7844(01)01190-5
  34. Gebhardt GS, Scholtz CL, Hillermann R, Odendaal HJ. Combined heterozygosity for methylenetetrahydrofolate reductase (MTHFR) mutations C677T and A1298C is associated with abruptio placentae but not with intrauterine growth restriction. Eur J Obstet Gynecol Reprod Biol 97(2): 174-177, 2001 https://doi.org/10.1016/S0301-2115(00)00540-6
  35. Wacker J, Fruhauf J, Schulz M, Chiwora FM, Volz J, Becker K. Riboflavin deficiency and preeclampsia. Obstet Gynecol 96(1): 38-44, 2000 https://doi.org/10.1016/S0029-7844(00)00847-4
  36. Badart-Smook A, van Houwelingen AC, Al MD, Kester AD, Hornstra G. Fetal growth is associated positively with maternal intake of riboflavin and negatively with maternal intake of linoleic acid. J Am Diet Assoc 97(8): 867-870, 1997 https://doi.org/10.1016/S0002-8223(97)00211-3
  37. Sanchez DJ, Murphy MM, Bosch-Sabater J, Fernandez-Ballart J. Enzymic evaluation of thiamin, riboflavin and pyridoxine status of parturient mothers and their newborn infants in a Mediterranean area of Spain. Eur J Clin Nutr 53(1): 27-38, 1999 https://doi.org/10.1038/sj.ejcn.1600674
  38. Schuster K, Bailey LB, Mahan CS. Effect of maternal pyridoxine . HCl supplementation on the vitamin B-6 status of mother and infant and on pregnancy outcome. J Nutr 114(5): 977-988, 1984 https://doi.org/10.1093/jn/114.5.977
  39. Schuster K, Bailey LB, Mahan CS. Vitamin B6 status of lowincome adolescent and adult pregnant women and the condition of their infants at birth. Am J Clin Nutr 34(9): 1731-1735, 1981 https://doi.org/10.1093/ajcn/34.9.1731
  40. Chang SJ. Adequacy of maternal pyridoxine supplementation during pregnancy in relation to the vitamin $B_{6}$ status and growth of neonates at birth. J Nutr Sci Vitaminol (Tokyo) 45(4): 449- 58, 1999 https://doi.org/10.3177/jnsv.45.449
  41. Pagan K, Hou J, Goldenberg RL, Suzanne P, Tamura CT. Midpregnancy serum homocysteine and B-vitamin concentrations and fetal growth. Nutr Res 22: 1133-1141, 2002 https://doi.org/10.1016/S0271-5317(02)00433-5
  42. Neggers YH, Goldenberg RL, Tamura T, Cliver SP, Hoffman HJ. The relationship between maternal dietary intake and infant birthweight. Acta Obstet Gynecol Scand Suppl 165: 71-75, 1997
  43. Tamura T, Goldenberg RL, Freeberg LE, Cliver SP, Cutter GR, Hoffman HJ. Maternal serum folate and zinc concentrations and their relationships to pregnancy outcome. Am J Clin Nutr 56(2): 365-370, 1992 https://doi.org/10.1093/ajcn/56.2.365
  44. Tamura T, Goldenberg RL, Johnston KE, Cliver SP, Hoffman HJ. Serum concentrations of zinc, folate, vitamins A and E, and proteins, and their relationships to pregnancy outcome. Acta Obstet Gynecol Scand Suppl 165: 63-70, 1997
  45. Sutterlin M, Bussen S, Ruppert D, Steck T. Serum levels of folate and cobalamin in women with recurrent spontaneous abortion. Hum Reprod 12(10): 2292-2296, 1997 https://doi.org/10.1093/humrep/12.10.2292
  46. Lussier-Cacan S, Xhignesse M, Piolot A, Selhub J, Davignon J, Genest J Jr. Plasma total homocysteine in healthy subjects: sexspecific relation with biological traits. Am J Clin Nutr 64(4): 587-593, 1996 https://doi.org/10.1093/ajcn/64.4.587
  47. Skoupy S, Fodinger M, Veitl M, Perschl A, Puttinger H, Rohrer C, Schindler K, Vychytil A, Horl WH, Sunder-Plassmann G. Riboflavin is a determinant of total homocysteine plasma concentrations in end-stage renal disease patients. J Am Soc Nephrol 13(5): 1331-1337, 2002 https://doi.org/10.1097/01.ASN.0000013299.11876.F6
  48. Rozen R. Methylenetetrahydrofolate reductase: a link between folate and riboflavin? Am J Clin Nutr 76(2): 301-302, 2002 https://doi.org/10.1093/ajcn/76.2.301
  49. Luo ZC, Albertsson-Wikland K, Karlberg J. Length and body mass index at birth and target height influences on patterns of postnatal growth in children born small for gestational age. Pediatrics 102(6): E72, 1998
  50. Picciano MF. Is homocysteine a biomarker for identifying women at risk of complications and adverse pregnancy outcomes? Am J Clin Nutr 71(4): 857-858, 2000 https://doi.org/10.1093/ajcn/71.4.857
  51. Rasmussen KM. The 'fetal origins' hypothesis: challenges and opportunities for maternal and child nutrition. Annu Rev Nutr 21: 73-95, 2001 https://doi.org/10.1146/annurev.nutr.21.1.73
  52. Brooks AA, Johnson MR, Steer PJ, Pawson ME, Abdalla HI. Birth weight: nature or nurture? Early Hum Dev 42(1): 29-35, 1995 https://doi.org/10.1016/0378-3782(95)01637-I