QJM, Vol 89, Issue 8 571-577, Copyright © 1996 by Oxford University Press
D Harmon, J Woodside, J Yarnell, D McMaster, I Young, E McCrum, K Gey, A Whitehead and A Evans
Mild hyperhomocysteinaemia is a major risk factor for vascular disease and
neural tube defects (NTDs), conferring an approximately three-fold relative
risk for each condition. It has several possible causes: heterozygosity for
rare loss of function mutations in the genes for 5,10-methylene
tetrahydrofolate reductase (MTHFR) or cystathionine-&bgr;-synthase
(CBS); dietary insufficiency of vitamin co-factors B6, B12 or folates; or
homozygosity for a common 'thermolabile' mutation in the MTHFR gene which
has also been associated with vascular disease and NTDs. We quantified the
contribution of the thermolabile mutation to the hyperhomocysteinaemic
phenotype in a working male population (625 individuals). Serum folate and
vitamin B12 concentrations were also measured and their relationship with
homocysteine status and MTHFR genotype assessed. The homozygous
thermolabile genotype occurred in 48.4, 35.5, and 23.4% for the top 5, 10
and 20% of individuals repectively) ranked by plasma homocysteine levels,
compared with a frequency of 11.5% in the study population as a whole
establishing that the mutation is a major determinant of homocystein levels
at the upper end of the range. Serum folate concentrations also varied with
genotype, being lowest in thermolabile homozygotes. The MTHFR thermolabile
genotype should be considered when population studies are designed to
determine the effective homocysteine-lowering dose of dietary folate
supplements, and when prophylactic doses of folate are recommended for
individuals.
ORIGINAL ARTICLES
The common 'thermolabile' variant of methylene tetrahydrofolate reductase is a major dtermininant of mild hyperhomocysteinaemia
Department of Genetics and Biotechnology Institute, Trinity College, Dublin 2, Ireland; Departments of Epidemiology and Public Health, Medicine, and Clinical Biochemistry, the Queen's University of Belfast, UK; Vitamin Unit, Department of Biochemistry and Molecular Biology, University of Berne, Switzerland
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  T. Forges, P. Monnier-Barbarino, J.M. Alberto, R.M. Gueant-Rodriguez, J.L. Daval, and J.L. Gueant Impact of folate and homocysteine metabolism on human reproductive health Hum. Reprod. Update, May 1, 2007; 13(3): 225 - 238. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. McGimpsey, J. V. Woodside, L. Bamford, S. E. C. M. Gilchrist, R. Graydon, G. C. McKeeman, I. S. Young, A. E. Hughes, C. C. Patterson, D. O'Reilly, et al. Retinal Vein Occlusion, Homocysteine, and Methylene Tetrahydrofolate Reductase Genotype Invest. Ophthalmol. Vis. Sci., December 1, 2005; 46(12): 4712 - 4716. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-K. Kuo, F. A. Sorond, J.-H. Chen, A. Hashmi, W. P. Milberg, and L. A. Lipsitz The Role of Homocysteine in Multisystem Age-Related Problems: A Systematic Review J. Gerontol. A Biol. Sci. Med. Sci., September 1, 2005; 60(9): 1190 - 1201. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. L.J. Kelly, O. R. Neaga, B. C. Schwahn, R. Rozen, and J. M. Trasler Infertility in 5,10-Methylenetetrahydrofolate Reductase (MTHFR)-Deficient Male Mice Is Partially Alleviated by Lifetime Dietary Betaine Supplementation Biol Reprod, March 1, 2005; 72(3): 667 - 677. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. B. Kelly, A. P. McDonnell, T. G. Johnston, C. Mulholland, S. J. Cooper, D. McMaster, A. Evans, and A. S. Whitehead The MTHFR C677T polymorphism is associated with depressive episodes in patients from Northern Ireland J Psychopharmacol, December 1, 2004; 18(4): 567 - 571. [Abstract] [PDF]
|
|
|
|
 |
|
 M. S. Cicek, N. L. Nock, L. Li, D. V. Conti, G. Casey, and J. S. Witte Relationship between Methylenetetrahydrofolate Reductase C677T and A1298C Genotypes and Haplotypes and Prostate Cancer Risk and Aggressiveness Cancer Epidemiol. Biomarkers Prev., August 1, 2004; 13(8): 1331 - 1336. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Refsum, A. D. Smith, P. M. Ueland, E. Nexo, R. Clarke, J. McPartlin, C. Johnston, F. Engbaek, J. Schneede, C. McPartlin, et al. Facts and Recommendations about Total Homocysteine Determinations: An Expert Opinion Clin. Chem., January 1, 2004; 50(1): 3 - 32. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Kishi, J. Griener, C. Cheng, S. Das, E. H. Cook, D. Pei, M. Hudson, J. Rubnitz, J. T. Sandlund, C.-H. Pui, et al. Homocysteine, Pharmacogenetics, and Neurotoxicity in Children With Leukemia J. Clin. Oncol., August 15, 2003; 21(16): 3084 - 3091. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Inamoto, T. Katsuya, Y. Kokubo, T. Mannami, T. Asai, S. Baba, J. Ogata, H. Tomoike, and T. Ogihara Association of Methylenetetrahydrofolate Reductase Gene Polymorphism With Carotid Atherosclerosis Depending on Smoking Status in a Japanese General Population Stroke, July 1, 2003; 34(7): 1628 - 1633. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. de Bree, W. M. Verschuren, A.-L. Bjorke-Monsen, N. M. van der Put, S. G Heil, F. J. Trijbels, and H. J Blom Effect of the methylenetetrahydrofolate reductase 677C->T mutation on the relations among folate intake and plasma folate and homocysteine concentrations in a general population sample Am. J. Clinical Nutrition, March 1, 2003; 77(3): 687 - 693. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. L. Carroll, D. Bhojwani, D.-J. Min, E. Raetz, M. Relling, S. Davies, J. R. Downing, C. L. Willman, and J. C. Reed Pediatric Acute Lymphoblastic Leukemia Hematology, January 1, 2003; 2003(1): 102 - 131. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Klerk, P. Verhoef, R. Clarke, H. J. Blom, F. J. Kok, E. G. Schouten, and and the MTHFR Studies Collaboration Group MTHFR 677C->T Polymorphism and Risk of Coronary Heart Disease: A Meta-analysis JAMA, October 23, 2002; 288(16): 2023 - 2031. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Reyes-Engel, E. Munoz, M.J. Gaitan, E. Fabre, M. Gallo, J.L. Dieguez, M. Ruiz, and M. Morell Implications on human fertility of the 677C->T and 1298A->C polymorphisms of the MTHFR gene: consequences of a possible genetic selection Mol. Hum. Reprod., October 1, 2002; 8(10): 952 - 957. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. McNulty, M. C McKinley, B. Wilson, J. McPartlin, J. Strain, D. G Weir, and J. M Scott Impaired functioning of thermolabile methylenetetrahydrofolate reductase is dependent on riboflavin status: implications for riboflavin requirements Am. J. Clinical Nutrition, August 1, 2002; 76(2): 436 - 441. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. A. Ashfield-Watt, C. H Pullin, J. M Whiting, Z. E Clark, S. J Moat, R. G Newcombe, M. L Burr, M. J Lewis, H. J Powers, and I. F. McDowell Methylenetetrahydrofolate reductase 677C->T genotype modulates homocysteine responses to a folate-rich diet or a low-dose folic acid supplement: a randomized controlled trial Am. J. Clinical Nutrition, July 1, 2002; 76(1): 180 - 186. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Stevenson, M. Redlinger, L. A.J. Kluijtmans, W. Sun, K. Algazy, B. Giantonio, D. G. Haller, C. Hardy, A. S. Whitehead, and P. J. O'Dwyer Phase I Clinical and Pharmacogenetic Trial of Irinotecan and Raltitrexed Administered Every 21 Days to Patients With Cancer J. Clin. Oncol., October 15, 2001; 19(20): 4081 - 4087. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.-L. Silaste, M. Rantala, M. Sampi, G. Alfthan, A. Aro, and Y. A. Kesaniemi Polymorphisms of Key Enzymes in Homocysteine Metabolism Affect Diet Responsiveness of Plasma Homocysteine in Healthy Women J. Nutr., October 1, 2001; 131(10): 2643 - 2647. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Weger, O. Stanger, H. Deutschmann, M. Simon, W. Renner, O. Schmut, J. Semmelrock, and A. Haas Hyperhomocyst(e)inaemia, but not MTHFR C677T mutation, as a risk factor for non-arteritic ischaemic optic neuropathy Br. J. Ophthalmol., July 1, 2001; 85(7): 803 - 806. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Ulrich, Y. Yasui, R. Storb, M. M. Schubert, J. L. Wagner, J. Bigler, K. S. Ariail, C. L. Keener, S. Li, H. Liu, et al. Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism Blood, July 1, 2001; 98(1): 231 - 234. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-M. Saw, J.-M. Yuan, C.-N. Ong, K. Arakawa, H.-P. Lee, G. A Coetzee, and M. C Yu Genetic, dietary, and other lifestyle determinants of plasma homocysteine concentrations in middle-aged and older Chinese men and women in Singapore Am. J. Clinical Nutrition, February 1, 2001; 73(2): 232 - 239. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M Cahill, M Karabatzaki, C Donoghue, R Meleady, L A Mynett-Johnson, D Mooney, I M Graham, A S Whitehead, and D C Shields Thermolabile MTHFR genotype and retinal vascular occlusive disease Br. J. Ophthalmol., January 1, 2001; 85(1): 88 - 90. [Abstract] [Full Text]
|
|
|
|
|
|
E. E Delvin, R. Rozen, A. Merouani, J. Genest Jr, and M. Lambert Influence of methylenetetrahydrofolate reductase genotype, age, vitamin B-12, and folate status on plasma homocysteine in children Am. J. Clinical Nutrition, December 1, 2000; 72(6): 1469 - 1473. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. L JOHANNING, T TAMURA, K. E JOHNSTON, and K. D WENSTROM Comorbidity of 5,10-methylenetetrahydrofolate reductase and methionine synthase gene polymorphisms and risk for neural tube defects J. Med. Genet., December 1, 2000; 37(12): 949 - 951. [Full Text]
|
|
|
|
|
|
V. Shpichinetsky, I. Raz, Y. Friedlander, N. Goldschmidt, I. D. Wexler, A. Ben-Yehuda, and G. Friedman The Association between Two Common Mutations C677T and A1298C in Human Methylenetetrahydrofolate Reductase Gene and the Risk for Diabetic Nephropathy in Type II Diabetic Patients J. Nutr., October 1, 2000; 130(10): 2493 - 2497. [Abstract] [Full Text]
|
|
|
|
|
|
A. J. Levine, K. D. Siegmund, C. M. Ervin, A. Diep, E. R. Lee, H. D. Frankl, and R. W. Haile The Methylenetetrahydrofolate Reductase 677C{->}T Polymorphism and Distal Colorectal Adenoma Risk Cancer Epidemiol. Biomarkers Prev., July 1, 2000; 9(7): 657 - 663. [Abstract] [Full Text]
|
|
|
|
|
|
S. Barbaux, L. A.J. Kluijtmans, and A. S. Whitehead Accurate and Rapid ""Multiplex Heteroduplexing"" Method for Genotyping Key Enzymes Involved in Folate/Homocysteine Metabolism Clin. Chem., July 1, 2000; 46(7): 907 - 912. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Ulrich, E. Kampman, J. Bigler, S. M. Schwartz, C. Chen, R. Bostick, L. Fosdick, S. A. A. Beresford, Y. Yasui, and J. D. Potter Lack of Association between the C677T MTHFR Polymorphism and Colorectal Hyperplastic Polyps Cancer Epidemiol. Biomarkers Prev., April 1, 2000; 9(4): 427 - 433. [Abstract] [Full Text]
|
|
|
|
 |
|
 C. F. Skibola, M. T. Smith, E. Kane, E. Roman, S. Rollinson, R. A. Cartwright, and G. Morgan Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults PNAS, October 26, 1999; 96(22): 12810 - 12815. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N Mahmud, A Molloy, J McPartlin, R Corbally, A S Whitehead, J M Scott, and D G Weir Increased prevalence of methylenetetrahydrofolate reductase C677T variant in patients with inflammatory bowel disease, and its clinical implications Gut, September 1, 1999; 45(3): 389 - 394. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Friedman, N. Goldschmidt, Y. Friedlander, A. Ben-Yehuda, J. Selhub, S. Babaey, M. Mendel, M. Kidron, and H. Bar-On A Common Mutation A1298C in Human Methylenetetrahydrofolate Reductase Gene: Association with Plasma Total Homocysteine and Folate Concentrations J. Nutr., September 1, 1999; 129(9): 1656 - 1661. [Abstract] [Full Text]
|
|
|
|
|
|
C. M. Ulrich, E. Kampman, J. Bigler, S. M. Schwartz, C. Chen, R. Bostick, L. Fosdick, S. A. A. Beresford, Y. Yasui, and J. D. Potter Colorectal Adenomas and the C677T MTHFR Polymorphism: Evidence for Gene-Environment Interaction? Cancer Epidemiol. Biomarkers Prev., August 1, 1999; 8(8): 659 - 668. [Abstract] [Full Text]
|
|
|
|
|
|
P B. Duell, M R. Malinow, J. V Woodside, I. S Young, J. W. Yarnell, D. McMaster, C. C Patterson, E. E McCrum, A. Evans, K F. Gey, et al. Effects of folic acid on homocysteine in persons classified by methylenetetrahydrofolate reductase genotype Am. J. Clinical Nutrition, June 1, 1999; 69(6): 1287 - 1289. [Full Text] [PDF]
|
|
|
|
 |
|
 B. M. McQuillan, J. P. Beilby, M. Nidorf, P. L. Thompson, and J. Hung Hyperhomocysteinemia but Not the C677T Mutation of Methylenetetrahydrofolate Reductase Is an Independent Risk Determinant of Carotid Wall Thickening : The Perth Carotid Ultrasound Disease Assessment Study (CUDAS) Circulation, May 11, 1999; 99(18): 2383 - 2388. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. C. de Jong, C. D. A. Stehouwer, M. van den Berg, P. J. Kostense, D. Alders, C. Jakobs, G. Pals, and J. A. Rauwerda Determinants of Fasting and Post-Methionine Homocysteine Levels in Families Predisposed to Hyperhomocysteinemia and Premature Vascular Disease Arterioscler. Thromb. Vasc. Biol., May 1, 1999; 19(5): 1316 - 1324. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. L. Harmon, R. M. Doyle, R. Meleady, M. Doyle, D. C. Shields, R. Barry, D. Coakley, I. M. Graham, and A. S. Whitehead Genetic Analysis of the Thermolabile Variant of 5,10-Methylenetetrahydrofolate Reductase as a Risk Factor for Ischemic Stroke Arterioscler. Thromb. Vasc. Biol., February 1, 1999; 19(2): 208 - 211. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Brattstrom, D. E. L. Wilcken, J. Ohrvik, and L. Brudin Common Methylenetetrahydrofolate Reductase Gene Mutation Leads to Hyperhomocysteinemia but Not to Vascular Disease : The Result of a Meta-Analysis Circulation, December 8, 1998; 98(23): 2520 - 2526. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. E. Clark, D. J. Bowen, S. D. Whatley, M. F. Bellamy, P. W. Collins, and I. F. W. McDowell Genotyping Method for Methylenetetrahydrofolate Reductase (C677T Thermolabile Variant) Using Heteroduplex Technology Clin. Chem., November 1, 1998; 44(11): 2360 - 2362. [Full Text] [PDF]
|
|
|
|
 |
|
 P. W. Siri, P. Verhoef, and F. J. Kok Vitamins B6, B12, and Folate: Association with Plasma Total Homocysteine and Risk of Coronary Atherosclerosis J. Am. Coll. Nutr., October 1, 1998; 17(5): 435 - 441. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. W. Jacobsen Homocysteine and vitamins in cardiovascular disease Clin. Chem., August 1, 1998; 44(8): 1833 - 1843. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. L.D.M. Nelen, H. J. Blom, C. M. G. Thomas, E. A. P. Steegers,, G. H. J. Boers, and T. K.A.B. Eskes 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., August 1, 1998; 128(8): 1336 - 1341. [Abstract] [Full Text]
|
|
|
|
 |
|
 N. J. Wald, H. C. Watt, M. R. Law, D. G. Weir, J. McPartlin, and J. M. Scott Homocysteine and Ischemic Heart Disease: Results of a Prospective Study With Implications Regarding Prevention Arch Intern Med, April 27, 1998; 158(8): 862 - 867. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. S. Omenn, S. A. A. Beresford, and A. G. Motulsky Preventing Coronary Heart Disease : B Vitamins and Homocysteine Circulation, February 10, 1998; 97(5): 421 - 424. [Full Text] [PDF]
|
|
|
|
|
|
L. A. J. Kluijtmans, J. J. P. Kastelein, J. Lindemans, G. H. J. Boers, S. G. Heil, A. V. G. Bruschke, J. W. Jukema, L. P. W. J. van den Heuvel, F. J. M. Trijbels, G. J. M. Boerma, et al. Thermolabile Methylenetetrahydrofolate Reductase in Coronary Artery Disease Circulation, October 21, 1997; 96(8): 2573 - 2577. [Abstract] [Full Text]
|
|
|
|
|
|
H. S. Markus, N. Ali, R. Swaminathan, A. Sankaralingam, J. Molloy, and J. Powell A Common Polymorphism in the Methylenetetrahydrofolate Reductase Gene, Homocysteine, and Ischemic Cerebrovascular Disease Stroke, September 1, 1997; 28(9): 1739 - 1743. [Abstract] [Full Text]
|
|