Investigation of inter-individual variability of the one-carbon folate pathway: A bioinformatic and genetic review

Pharmacogenomics Journal

Volumn 9, Issue 5, 2009, Pages 291-305

  Carr, D F ^a   Whiteley, G ^a   Alfirevic, A ^a   Pirmohamed, M ^a  

^a UNIVERSITY OF LIVERPOOL   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

5 AMINO 4 IMIDAZOLECARBOXAMIDE RIBOSIDE; 5 METHYLTETRAHYDROFOLATE HOMOCYSTEINE METHYLTRANSFERASE; 5 METHYLTETRAHYDROFOLATE HOMOCYSTEINE METHYLTRANSFERASE REDUCTASE; ADENOSYLHOMOCYSTEINASE; AMINOMETHYLTRANSFERASE; CYSTATHIONINE BETA SYNTHASE; DEAMINASE; DIHYDROFOLATE REDUCTASE; FLUOROURACIL; FOLATE RECEPTOR; FOLATE RECEPTOR 1; FOLIC ACID; FORMIMINOTRANSFERASE CYCLODEAMINASE; GAMMA GLUTAMYL HYDROLASE; HOMOCYSTEINE; METHIONINE; METHIONINE ADENOSYLTRANSFERASE; METHOTREXATE; METHYLENETETRAHYDROFOLATE REDUCTASE (NADPH2); OXIDOREDUCTASE; REDUCED FOLATE CARRIER; S ADENOSYLMETHIONINE; THYMIDYLATE SYNTHASE; UNCLASSIFIED DRUG;

ACUTE LYMPHOBLASTIC LEUKEMIA; ADJUVANT THERAPY; ALOPECIA; AMINO ACID SUBSTITUTION; AMINO ACID SYNTHESIS; BIOINFORMATICS; CARBON METABOLISM; CARCINOGENESIS; CARDIOVASCULAR DISEASE; COLORECTAL CANCER; COMPUTER MODEL; DEPRESSION; DISEASE ACTIVITY; EPIGENETICS; FOLATE METABOLISM; FOLIC ACID DEFICIENCY; GENE FREQUENCY; GENETIC ASSOCIATION; GENETIC DATABASE; GENETIC VARIABILITY; HOMOCYSTINURIA; HUMAN; HYPERMETHIONINEMIA; HYPOMETHIONEMIA; MOLECULAR GENETICS; NEOPLASM; NEURAL TUBE DEFECT; NONHUMAN; ONE CARBON FOLATE PATHWAY; POPULATION GENETICS; PREDICTION; PRIORITY JOURNAL; REVIEW; RHEUMATOID ARTHRITIS; SINGLE NUCLEOTIDE POLYMORPHISM; STOMACH CANCER;

ANIMALS; COMPUTATIONAL BIOLOGY; DATABASES, GENETIC; EPIGENESIS, GENETIC; FOLIC ACID; GENE FREQUENCY; GENETIC PREDISPOSITION TO DISEASE; GENETICS, POPULATION; HUMANS; HYPERHOMOCYSTEINEMIA; METABOLOMICS; METHYLENETETRAHYDROFOLATE REDUCTASE (NADPH2); MICE; MICE, TRANSGENIC; MODELS, ANIMAL; PHARMACOGENETICS; PHENOTYPE; POLYMORPHISM, SINGLE NUCLEOTIDE;

EID: 70349829518     PISSN: 1470269X     EISSN: 14731150     Source Type: Journal    
DOI: 10.1038/tpj.2009.29     Document Type: Review

References (141)

1. Fredriksen A, Meyer K, Ueland PM, Vollset SE, Grotmol T, Schneede J. Large-scale population-based metabolic phenotyping of thirteen genetic polymorphisms related to one-carbon metabolism. Hum Mutat 2007; 28: 856-865.
2. Koushik A, Kraft P, Fuchs CS, Hankinson SE, Willett WC, Giovannucci EL et al. Nonsynonymous polymorphisms in genes in the one-carbon metabolism pathway and associations with colorectal cancer. Cancer Epidemiol Biomarkers Prev 2006; 15: 2408-2417.
3. Lissowska J, Gaudet MM, Brinton LA, Chanock SJ, Peplonska B, Welch R et al. Genetic polymorphisms in the one-carbon metabolism pathway and breast cancer risk: A population-based case-control study and meta-analyses. Int J Cancer 2007; 120: 2696-2703.
4. Moore LE, Malats N, Rothman N, Real FX, Kogevinas M, Karami S et al Polymorphisms in one-carbon metabolism and trans-sulfuration pathway genes and susceptibility to bladder cancer. Int J Cancer 2007; 120: 2452-2458.
5. Gellekink H, den Heijer M, Heil SG, Blom HJ. Genetic determinants of plasma total homocysteine. Semin Vasc Med 2005; 5: 98-109.
6. Molloy AM. Folate and homocysteine interrelationships including genetics of the relevant enzymes. Curr Opin Lipidol 2004; 15: 49-57.
7. Shaw GM, Schaffer D, Velie EM, Morland K, Harris JA. Periconceptional vitamin use, dietary folate, and the occurrence of neural tube defects. Epidemiology 1995; 6: 219-226.
8. Milunsky A, Jick H, Jick SS, Bruell CL, MacLaughlin DS, Rothman KJ et al. Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects. JAMA 1989; 262 2847-2852.
9. Mulinare J, Cordero JF, Erickson JD, Berry RJ. Periconceptional use of multivitamins and the occurrence of neural tube defects. JAMA 1988; 260: 3141-3145.
10. Honein MA, Paulozzi LJ, Mathews TJ, Erickson JD, Wong LY. Impact of folic acid fortification of the US food supply on the occurrence of neural tube defects. JAMA 2001; 285: 2981-2986.
11. Williams LJ, Mai CT, Edmonds LD, Shaw GM, Kirby RS, Hobbs CA et al Prevalence of spina bifida and anencephaly during the transition to mandatory folic acid fortification in the United States. Teratology 2002; 66: 33-39.
12. Williams LJ, Rasmussen SA, Flores A, Kirby RS, Edmonds LD. Decline in the prevalence of spina bifida and anencephaly by race/ethnicity: 1995-2002. Pediatrics 2005; 116: 580-586.
13. Kim YI. Folate and colorectal cancer: An evidence-based critical review. Mol Nutr Food Res 2007; 51: 267-292.
14. Sanjoaquin MA, Allen N, Couto E, Roddam AW, Key TJ. Folate intake and colorectal cancer risk: A meta-analytical approach. Int J Cancer 2005; 113: 825-828.
15. Larsson SC, Giovannucci E, Wolk A. Folate intake, MTHFR polymorphisms, and risk of esophageal, gastric, and pancreatic cancer: A meta-analysis. Gastroenterology 2006; 131: 1271-1283.
16. Pelucchi C, Talamini R, Negri E, Levi F, Conti E, Franceschi S et al Folate intake and risk of oral and pharyngeal cancer. Ann Oncol 2003; 14: 1677-1681.
17. Navarro Silvera SA, Jain M, Howe GR, Miller AB, Rohan TE. Dietary folate consumption and risk of ovarian cancer: A prospective cohort study. Eur J Cancer Prev 2006; 15: 511-515.
18. Cole BF, Baron JA, Sandler RS, Haile RW, Ahnen DJ, Bresalier RS et al Folic acid for the prevention of colorectal adenomas: A randomized clinical trial. JAMA 2007; 297: 2351-2359.
19. Stolzenberg-Solomon RZ, Chang SC, Leitzmann MF, Johnson KA, Johnson C, Buys SS et al. Folate intake, alcohol use, and postmenopausal breast cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Am J Clin Nutr 2006; 83: 895-904.
20. Taylor MJ, Carney SM, Goodwin GM, Geddes JR. Folate for depressive disorders: Systematic review and meta-analysis of randomized controlled trials. J Psychopharmacol 2004; 18: 251-256.
21. Roberts SH, Bedson E, Hughes DA, Lloyd KR, Moat S, Pirmohamed M et al Folate Augmentation of Treatment - Evaluation for Depression (FolATED): Protocol of a randomised controlled trial. BMC Psychiatry 2007; 7: 65.
22. Muntjewerff JW, Blom HJ. Aberrant folate status in schizophrenic patients: What is the evidence? Prog Neuropsychopharmacol Biol Psychiatry 2005; 29: 1133-1139.
23. Durga J, van Boxtel MP, Schouten EG, Kok FJ, Jolles J, Katan MB et al Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: A randomised, double blind, controlled trial. Lancet 2007; 369: 208-216.
24. Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 2002; 325: 1202.
25. Wald DS, Bishop L, Wald NJ, Law M, Hennessy E, Weir D et al. Randomized trial of folic acid supplementation and serum homocysteine levels. Arch Intern Med 2001; 161: 695-700.
26. Bonaa KH, Njolstad I, Ueland PM, Schirmer H, Tverdal A, Steigen T et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med 2006; 354: 1578-1588.
27. Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 2006; 354: 1567-1577.
28. Campbell NR. How safe are folic acid supplements? Arch Intern Med 1996; 156: 1638-1644.
29. Institute of Medicine. Folate. In: Dietary reference intakes of thiamin, roboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. National Academy Press: Washington, DC, 1998. pp 196-305.
30. Shane B. Folate fortification: Enough already? Am J Clin Nutr 2003; 77: 8-9.
31. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG et al A candidate genetic risk factor for vascular disease: A common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10: 111-113.
32. Ueland PM, Hustad S, Schneede J, Refsum H, Vollset SE. Biological and clinical implications of the MTHFR C677T polymorphism. Trends Pharmacol Sci 2001; 22: 195-201.
33. Horie N, Aiba H, Oguro K, Hojo H, Takeishi K. Functional analysis and DNA polymorphism of the tandemly repeated sequences in the 5′-terminal regulatory region of the human gene for thymidylate synthase. Cell Struct Funct 1995; 20: 191-197.
34. Horie N, Takeishi K. Functional structure of the promoter region of the human thymidylate synthase gene and nuclear factors that regulate the expression of the gene. Nucleic Acids Symp Ser 1995: 34: 77-78.
35. Kawakami K, Omura K, Kanehira E, Watanabe Y. Polymorphic tandem repeats in the thymidylate synthase gene is associated with its protein expression in human gastrointestinal cancers. Anticancer Res 1999; 19(4B): 3249-3252.
36. Mandola MV, Stoehlmacher J, Muller-Weeks S, Cesarone G, Yu MC, Lenz HJ et al. A novel single nucleotide polymorphism within the 5′ tandem repeat polymorphism of the thymidylate synthase gene abolishes USF-1 binding and alters transcriptional activity. Cancer Res 2003; 63: 2898-2904.
37. Ulrich CM, Bigler J, Velicer CM, Greene EA, Farin FM, Potter JD. Searching expressed sequence tag databases: Discovery and confirmation of a common polymorphism in the thymidylate synthase gene. Cancer Epidemiol Biomarkers Prev 2000; 9: 1381-1385.
38. Mandola MV, Stoehlmacher J, Zhang W, Groshen S, Yu MC, Iqbal S et al A 6 bp polymorphism in the thymidylate synthase gene causes message instability and is associated with decreased intratumoral TS mRNA levels. Pharmacogenetics 2004; 14: 319-327.
39. Kealey C, Brown KS, Woodside JV, Young I, Murray L, Boreham CA et al A common insertion/deletion polymorphism of the thymidylate synthase (TYMS) gene is a determinant of red blood cell folate and homocysteine concentrations. Hum Genet 2005; 116: 347-353.
40. Gellekink H, Blom HJ, van der Linden IJ, den Heijer M. Molecular genetic analysis of the human dihydrofolate reductase gene: Relation with plasma total homocysteine, serum and red blood cell folate levels. Eur J Hum Genet 2007; 15: 103-109.
41. Johnson WG, Stenroos ES, Spychala JR, Chatkupt S, Ming SX, Buyske S. New 19 bp deletion polymorphism in intron-1 of dihydrofolate reductase (DHFR): A risk factor for spina bifida acting in mothers during pregnancy? Am J Med Genet A 2004; 124: 339-345.
42. Xu X, Gammon MD, Wetmur JG, Rao M, Gaudet MM, Teitelbaum SL et al. A functional 19-base pair deletion polymorphism of dihydrofolate reductase (DHFR) and risk of breast cancer in multivitamin users. Am J Clin Nutr 2007; 85: 1098-1102.
43. van der Linden IJ, Nguyen U, Heil SG, Franke B, Vloet S, Gellekink H et al. Variation and expression of dihydrofolate reductase (DHFR) in relation to spina bifida. Mol Genet Metab 2007; 91: 98-103.
44. Goto Y, Yue L, Yokoi A, Nishimura R, Uehara T, Koizumi S et al. A novel single-nucleotide polymorphism in the 3′-untranslated region of the human dihydrofolate reductase gene with enhanced expression. Clin Cancer Res 2001; 7: 1952-1956.
45. Gerritsen T, Vaughn JG, Waisman HA. The identification of homocysteine in the urine. Biochem Biophys Res Commun 1962; 9: 493-496.
46. Boers GH, Fowler B, Smals AG, Trijbels FJ, Leermakers AI, Kleijer WJ et al. Improved identification of heterozygotes for homocystinuria due to cystathionine synthase deficiency by the combination of methionine loading and enzyme determination in cultured fibroblasts. Hum Genet 1985; 69: 164-169.
47. Mudd SH, Skovby F, Levy HL, Pettigrew KD, Wilcken B, Pyeritz RE et al The natural history of homocystinuria due to cystathionine betasynthase deficiency. Am J Hum Genet 1985; 37: 1-31.
48. Wang J, Huff AM, Spence JD, Hegele RA. Single nucleotide polymorphism in CTH associated with variation in plasma homocysteine concentration. Clin Genet 2004; 65: 483-486.
49. Gallagher PM, Ward P, Tan S, Naughten E, Kraus JP, Sellar GC et al High frequency (71%) of cystathionine beta-synthase mutation G307S in Irish homocystinuria patients. Hum Mutat 1995; 6: 177-180.
50. Hu FL, Gu Z, Kozich V, Kraus JP, Ramesh V, Shih VE. Molecular basis of cystathionine beta-synthase deficiency in pyridoxine responsive and nonresponsive homocystinuria. Hum Mol Genet 1993; 2: 1857-1860.
51. Shih VE, Fringer JM, Mandell R, Kraus JP, Berry GT, Heidenreich RA et al. A missense mutation (I278T) in the cystathionine beta-synthase gene prevalent in pyridoxine-responsive homocystinuria and associated with mild clinical phenotype. Am J Hum Genet 1995; 57: 34-39.
52. Leclerc D, Campeau E, Goyette P, Adjalla CE, Christensen B, Ross M et al. Human methionine synthase: CDNA cloning and identification of mutations in patients of the cblG complementation group of folate/ cobalamin disorders. Hum Mol Genet 1996; 5: 1867-1874.
53. Gulati S, Baker P, Li YN, Fowler B, Kruger W, Brody LC et al. Defects in human methionine synthase in cblG patients. Hum Mol Genet 1996; 5: 1859-1865.
54. Watkins D, Ru M, Hwang HY, Kim CD, Murray A, Philip NS et al. Hyperhomocysteinemia due to methionine synthase deficiency, cblG: structure of the MTR gene, genotype diversity, and recognition of a common mutation, P1173L. Am J Hum Genet 2002; 71: 143-153.
55. Zavadakova P, Fowler B, Zeman J, Suormala T, Pristoupilova K, Kozich V et al. CblE type of homocystinuria due to methionine synthase reductase deficiency: Clinical and molecular studies and prenatal diagnosis in two families. J Inherit Metab Dis 2002; 25: 461-476.
56. Leclerc D, Wilson A, Dumas R, Gafuik C, Song D, Watkins D et al. Cloning and mapping of a cDNA for methionine synthase reductase, a flavoprotein defective in patients with homocystinuria. Proc Natl Acad Sci USA 1998; 95: 3059-3064.
57. Gaull GE, Tallan HH, Lonsdale D, Przyrembel H, Schaffner F, von Bassewitz DB. Hypermethioninemia associated with methionine adenosyltransferase deficiency: Clinical, morphologic, and biochemical observations on four patients. J Pediatr 1981; 98: 734-741.
58. Surtees R, Leonard J, Austin S. Association of demyelination with deficiency of cerebrospinal-fluid S-adenosylmethionine in inborn errors of methyl-transfer pathway. Lancet 1991; 338: 1550-1554.
59. Hazelwood S, Bernardini I, Shotelersuk V, Tangerman A, Guo J, Mudd H et al. Normal brain myelination in a patient homozygous for a mutation that encodes a severely truncated methionine adenosyltransferase I/III. Am J Med Genet 1998; 75: 395-400.
60. Chamberlin ME, Ubagai T, Mudd SH, Wilson WG, Leonard JV, Chou JY. Demyelination of the brain is associated with methionine adenosyltransferase I/III deficiency. J Clin Invest 1996; 98 1021-1027.
61. Chamberlin ME, Ubagai T, Mudd SH, Levy HL, Chou JY. Dominant inheritance of isolated hypermethioninemia is associated with a mutation in the human methionine adenosyltransferase 1A gene. Am J Hum Genet 1997; 60: 540-546.
62. Baric I, Fumic K, Glenn B, Cuk M, Schulze A, Finkelstein JD et al. S-adenosylhomocysteine hydrolase deficiency in a human: A genetic disorder of methionine metabolism. Proc Natl Acad Sci USA 2004; 101: 4234-4239.
63. Gellekink H, den Heijer M, Kluijtmans LA, Blom HJ. Effect of genetic variation in the human S-adenosylhomocysteine hydrolase gene on total homocysteine concentrations and risk of recurrent venous thrombosis. Eur J Hum Genet 2004; 12: 942-948.
64. Ananth CV, Elsasser DA, Kinzler WL, Peltier MR, Getahun D, Leclerc D et al. Polymorphisms in methionine synthase reductase and betaine-homocysteine S-methyltransferase genes: Risk of placental abruption. Mol Genet Metab 2007; 91: 104-110.
65. Boyles AL, Billups AV, Deak KL, Siegel DG, Mehltretter L, Slifer SH et al. Neural tube defects and folate pathway genes: Family-based association tests of gene-gene and gene-environment interactions. Environ Health Perspect 2006; 114: 1547-1552.
66. Dervieux T, Kremer J, Lein DO, Capps R, Barham R, Meyer G et al. Contribution of common polymorphisms in reduced folate carrier and gamma-glutamylhydrolase to methotrexate polyglutamate levels in patients with rheumatoid arthritis. Pharmacogenetics 2004; 14: 733-739.
67. Cheng Q, Wu B, Kager L, Panetta JC, Zheng J, Pui CH et al. A substrate specific functional polymorphism of human gamma-glutamyl hydrolase alters catalytic activity and methotrexate polyglutamate accumulation in acute lymphoblastic leukaemia cells. Pharmacogenetics 2004; 14: 557-567.
68. Dervieux T, Furst D, Lein DO, Capps R, Smith K, Walsh M et al. Polyglutamation of methotrexate with common polymorphisms in reduced folate carrier, aminoimidazole carboxamide ribonucleotide transformylase, and thymidylate synthase are associated with methotrexate effects in rheumatoid arthritis. Arthritis Rheum 2004; 50: 2766-2774.
69. Marie S, Heron B, Bitoun P, Timmerman T, Van Den Berghe G, Vincent MF. AICA-ribosiduria: A novel, neurologically devastating inborn error of purine biosynthesis caused by mutation of ATIC. Am J Hum Genet 2004; 74: 1276-1281.
70. Kure S, Kato K, Dinopoulos A, Gail C, DeGrauw TJ, Christodoulou J et al. Comprehensive mutation analysis of GLDC, AMT, and GCSH in nonketotic hyperglycinemia. Hum Mutat 2006; 27: 343-352.
71. Kure S, Mandel H, Rolland MO, Sakata Y, Shinka T, Drugan A et al. A missense mutation (His42Arg) in the T-protein gene from a large Israeli-Arab kindred with nonketotic hyperglycinemia. Hum Genet 1998; 102: 430-434.
72. Kure S, Shinka T, Sakata Y, Osamu N, Takayanagi M, Tada K et al. A one-base deletion (183delC) and a missense mutation (D276H) in the T-protein gene from a Japanese family with nonketotic hyperglycinemia. J Hum Genet 1998; 43: 135-137.
73. Nanao K, Okamura-Ikeda K, Motokawa Y, Danks DM, Baumgartner ER, Takada G et al. Identification of the mutations in the T-protein gene causing typical and atypical nonketotic hyperglycinemia. Hum Genet 1994; 93: 655-658.
74. Toone JR, Applegarth DA, Coulter-Mackie MB, James ER. Recurrent mutations in P- and T-proteins of the glycine cleavage complex and a novel T-protein mutation (N145I): A strategy for the molecular investigation of patients with nonketotic hyperglycinemia (NKH). Mol Genet Metab 2001; 72: 322-325.
75. Hilton JF, Christensen KE, Watkins D, Raby BA, Renaud Y, de la Luna S et al. The molecular basis of glutamate formiminotransferase deficiency. Hum Mutat 2003; 22: 67-73.
76. Laverdiere C, Chiasson S, Costea I, Moghrabi A, Krajinovic M. Polymorphism G80A in the reduced folate carrier gene and its relationship to methotrexate plasma levels and outcome of childhood acute lymphoblastic leukemia. Blood 2002; 100: 3832-3834.
77. De Marco P, Calevo MG, Moroni A, Merello E, Raso A, Finnell RH et al Reduced folate carrier polymorphism (80A-4G) and neural tube defects. Eur J Hum Genet 2003; 11: 245-252.
78. Morin I, Devlin AM, Leclerc D, Sabbaghian N, Halsted CH, Finnell R et al. Evaluation of genetic variants in the reduced folate carrier and in glutamate carboxypeptidase II for spina bifida risk. Mol Genet Metab 2003; 79: 197-200.
79. Shaw GM, Lammer EJ, Zhu H, Baker MW, Neri E, Finnell RH. Maternal periconceptional vitamin use, genetic variation of infant reduced folate carrier (A80G), and risk of spina bifida. Am J Med Genet 2002; 108: 1-6.
80. Dufficy L, Naumovski N, Ng X, Blades B, Yates Z, Travers C et al. G80A reduced folate carrier SNP influences the absorption and cellular translocation of dietary folate and its association with blood pressure in an elderly population. Life Sci 2006; 79: 957-966.
81. Zhang G, Zhang QY, Miao XP, Lin DX, Lu YY. Polymorphisms and mutations of the folate receptor-alpha gene and risk of gastric cancer in a Chinese population. Int J Mol Med 2005; 15: 627-632.
82. Hooijberg JH, Jansen G, Assaraf YG, Kathmann I, Pieters R, Laan AC et al. Folate concentration dependent transport activity of the multidrug resistance protein 1 (ABCC1). Biochem Pharmacol 2004; 67: 1541-1548.
83. Warren RB, Smith RL, Campalani E, Eyre S, Smith CH, Barker JN et al Genetic variation in efflux transporters influences outcome to methotrexate therapy in patients with psoriasis. J Invest Dermatol 2008; 128: 1925-1929.
84. Stempak JM, Sohn KJ, Chiang EP, Shane B, Kim YI. Cell and stage of transformation-specific effects of folate deficiency on methionine cycle intermediates and DNA methylation in an in vitro model. Carcinogenesis 2005; 26: 981-990.
85. Chen Z, Karaplis AC, Ackerman SL, Pogribny IP, Melnyk S, Lussier-Cacan S et al. Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition. Hum Mol Genet 2001; 10: 433-443.
86. Stern LL, Mason JB, Selhub J, Choi SW. Genomic DNA hypomethylation, a characteristic of most cancers, is present in peripheral leukocytes of individuals who are homozygous for the C677T polymorphism in the methylenetetrahydrofolate reductase gene. Cancer Epidemiol Biomarkers Prev 2000; 9: 849-853.
87. Axume J, Smith SS, Pogribny IP, Moriarty DJ, Caudill MA. The MTHFR 677TT genotype and folate intake interact to lower global leukocyte DNA methylation in young Mexican American women. Nutr Res 2007; 27 1365-1317.
88. Wang L, Zhang J, Wang S. [Demethylation in the promoter region of MTHFR gene and its mRNA expression in cultured human vascular smooth muscle cells induced by homocysteine]. Wei Sheng Yan Jiu 2007; 36: 291-294.
89. Chen L, Zeng Y, Yang H, Lee TD, French SW, Corrales FJ et al. Impaired liver regeneration in mice lacking methionine adenosyltransferase 1A. FASEB J 2004; 18: 914-916.
90. Piedrahita JA, Oetama B, Bennett GD, van Waes J, Kamen BA, Richardson J et al. Mice lacking the folic acid-binding protein Folbp1 are defective in early embryonic development. Nat Genet 1999; 23 228-232.
91. Hubner RA, Houlston RS. MTHFR C677T and colorectal cancer risk: A meta-analysis of 25 populations. Int J Cancer 2007; 120: 1027-1035.
92. Chen K, Jiang QT, He HQ. Relationship between metabolic enzyme polymorphism and colorectal cancer. World J Gastroenterol 2005; 11: 331-335.
93. Huang Y, Han S, Li Y, Mao Y, Xie Y. Different roles of MTHFR C677T and A1298C polymorphisms in colorectal adenoma and colorectal cancer: A meta-analysis. J Hum Genet 2007; 52: 73-85.
94. Lewis SJ, Harbord RM, Harris R, Smith GD. Meta-analyses of observational and genetic association studies of folate intakes or levels and breast cancer risk. J Natl Cancer Inst 2006; 98: 1607-1622.
95. Zintzaras E. Methylenetetrahydrofolate reductase gene and susceptibility to breast cancer: A meta-analysis. Clin Genet 2006; 69: 327-336.
96. Gilbody S, Lewis S, Lightfoot T. Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: A HuGE review. Am J Epidemiol 2007; 165: 1-13.
97. Lewis SJ, Lawlor DA, Davey Smith G, Araya R, Timpson N, Day IN et al The thermolabile variant of MTHFR is associated with depression in the British Women's Heart and Health Study and a meta-analysis. Mol Psychiatry 2006; 11: 352-360.
98. Zintzaras E. Association of methylenetetrahydrofolate reductase (MTHFR) polymorphisms with genetic susceptibility to gastric cancer: A meta-analysis. J Hum Genet 2006; 51: 618-624.
99. Zintzaras E. C677T and A1298C methylenetetrahydrofolate reductase gene polymorphisms in schizophrenia, bipolar disorder and depression: A meta-analysis of genetic association studies. Psychiatr Genet 2006; 16: 105-115.
100. Muntjewerff JW, Kahn RS, Blom HJ, den Heijer M. Homocysteine, methylenetetrahydrofolate reductase and risk of schizophrenia: A meta-analysis. Mol Psychiatry 2006; 11: 143-149.
101. Lewis SJ, Zammit S, Gunnell D, Smith GD. A meta-analysis of the MTHFR C677T polymorphism and schizophrenia risk. Am J Med Genet B Neuropsychiatr Genet 2005; 135: 2-4.
102. Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE. Systematic meta-analyses of Alzheimer disease genetic association studies: The AlzGene database. Nat Genet 2007; 39: 17-23.
103. Pereira TV, Rudnicki M, Pereira AC, Pombo-de-Oliveira MS, Franco RF. 5,10-Methylenetetrahydrofolate reductase polymorphisms and acute lymphoblastic leukemia risk: A meta-analysis. Cancer Epidemiol Biomarkers Prev 2006; 15: 1956-1963.
104. Zintzaras E, Koufakis T, Ziakas PD, Rodopoulou P, Giannouli S, Voulgarelis M. A meta-analysis of genotypes and haplotypes of methylenetetrahydrofolate reductase gene polymorphisms in acute lymphoblastic leukemia. Eur J Epidemiol 2006; 21: 501-510.
105. Cronin S, Furie KL, Kelly PJ. Dose-related association of MTHFR 677T allele with risk of ischemic stroke: Evidence from a cumulative meta-analysis. Stroke 2005; 36: 1581-1587.
106. Kim RJ, Becker RC. Association between factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations and events of the arterial circulatory system: A meta-analysis of published studies. Am Heart J 2003; 146: 948-957.
107. Haywood S, Liesner R, Pindora S, Ganesan V. Thrombophilia and first arterial ischaemic stroke: A systematic review. Arch Dis Child 2005; 90: 402-405.
108. Lewis SJ, Ebrahim S, Davey Smith G. Meta-analysis of MTHFR 677C← T polymorphism and coronary heart disease: Does totality of evidence support causal role for homocysteine and preventive potential of folate? BMJ 2005; 331: 1053.
109. Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG. MTHFR 677C← T polymorphism and risk of coronary heart disease: A meta-analysis. JAMA 2002; 288: 2023-2031.
110. Kluijtmans LA, Kastelein JJ, Lindemans J, Boers GH, Heil SG, Bruschke AV et al. Thermolabile methylenetetrahydrofolate reductase in coronary artery disease. Circulation 1997; 96: 2573-2577.
111. Wu AH, Tsongalis GJ. Correlation of polymorphisms to coagulation and biochemical risk factors for cardiovascular diseases. Am J Cardiol 2001; 87: 1361-1366.
112. Zintzaras E, Chatzoulis DZ, Karabatsas CH, Stefanidis I. The relationship between C677T methylenetetrahydrofolate reductase gene polymorphism and retinopathy in type 2 diabetes: A meta-analysis. J Hum Genet 2005; 50: 267-275.
113. Cahill MT, Stinnett SS, Fekrat S. Meta-analysis of plasma homocysteine, serum folate, serum vitamin B(12), and thermolabile MTHFR genotype as risk factors for retinal vascular occlusive disease. Am J Ophthalmol 2003; 136: 1136-1150.
114. Janssen MC, den Heijer M, Cruysberg JR, Wollersheim H, Bredie SJ. Retinal vein occlusion: A form of venous thrombosis or a complication of atherosclerosis? A meta-analysis of thrombophilic factors. Thromb Haemost 2005; 93: 1021-1026.
115. Den Heijer M, Lewington S, Clarke R. Homocysteine, MTHFR and risk of venous thrombosis: A meta-analysis of published epidemiological studies. J Thromb Haemost 2005; 3: 292-299.
116. Ray JG, Shmorgun D, Chan WS. Common C677T polymorphism of the methylenetetrahydrofolate reductase gene and the risk of venous thromboembolism: Meta-analysis of 31 studies. Pathophysiol Haemost Thromb 2002; 32: 51-58.
117. Kosmas IP, Tatsioni A, Ioannidis JP. Association of C677T polymorphism in the methylenetetrahydrofolate reductase gene with hypertension in pregnancy and pre-eclampsia: A meta-analysis. J Hypertens 2004; 22: 1655-1662.
118. Lin J, August P. Genetic thrombophilias and preeclampsia: A meta-analysis. Obstet Gynecol 2005; 105: 182-192.
119. van der Put NM, Eskes TK, Blom HJ. Is the common 677C← T mutation in the methylenetetrahydrofolate reductase gene a risk factor for neural tube defects? A meta-analysis. QJM 1997; 90: 111-115.
120. Ren A, Wang J. Methylenetetrahydrofolate reductase C677T polymorphism and the risk of unexplained recurrent pregnancy loss: A meta-analysis. Fertil Steril 2006; 86: 1716-1722.
121. Nelen WL, Blom HJ, Steegers EA, den Heijer M, Eskes TK. Hyperhomocysteinemia and recurrent early pregnancy loss: A meta-analysis. Fertil Steril 2000; 74: 1196-1199.
122. Ott K, Vogelsang H, Marton N, Becker K, Lordick F, Kobl M et al. The thymidylate synthase tandem repeat promoter polymorphism: A predictor for tumor-related survival in neoadjuvant treated locally advanced gastric cancer. Int J Cancer 2006; 119: 2885-2894.
123. Dotor E, Cuatrecases M, Martinez-Iniesta M, Navarro M, Vilardell F, Guino E et al. Tumor thymidylate synthase 1494del6 genotype as a prognostic factor in colorectal cancer patients receiving fluorouracil-based adjuvant treatment. J Clin Oncol 2006; 24 1603-1611.
124. Skibola CF, Forrest MS, Coppede F, Agana L, Hubbard A, Smith MT et al Polymorphisms and haplotypes in folate-metabolizing genes and risk of non-Hodgkin lymphoma. Blood 2004; 104: 2155-2162.
125. Krajinovic M, Costea I, Chiasson S. Polymorphism of the thymidylate synthase gene and outcome of acute lymphoblastic leukaemia. Lancet 2002; 359: 1033-1034.
126. Krajinovic M, Costea I, Primeau M, Dulucq S, Moghrabi A. Combining several polymorphisms of thymidylate synthase gene for pharmacogenetic analysis. Pharmacogenomics J 2005; 5: 374-380.
127. Weisman MH, Furst DE, Park GS, Kremer JM, Smith KM, Wallace DJ et al Risk genotypes in folate-dependent enzymes and their association with methotrexate-related side effects in rheumatoid arthritis. Arthritis Rheum 2006; 54: 607-612.
128. Justenhoven C, Hamann U, Pierl CB, Rabstein S, Pesch B, Harth V et al One-carbon metabolism and breast cancer risk: No association of MTHFR, MTR, and TYMS polymorphisms in the GENICA study from Germany. Cancer Epidemiol Biomarkers Prev 2005; 14: 3015-3018.
129. Zhai X, Gao J, Hu Z, Tang J, Qin J, Wang S et al. Polymorphisms in thymidylate synthase gene and susceptibility to breast cancer in a Chinese population: A case-control analysis. BMC Cancer 2006; 6 138.
130. Hishida A, Matsuo K, Hamajima N, Ito H, Ogura M, Kagami Y et al. Associations between polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and susceptibility to malignant lymphoma. Haematologica 2003; 88: 159-166.
131. Ramensky V, Bork P, Sunyaev S. Human non-synonymous SNPs: Server and survey. Nucleic Acids Res 2002; 30: 3894-3900.
132. Ng PC, Henikoff S. Predicting deleterious amino acid substitutions. Genome Res 2001; 11: 863-874.
133. Ferrer-Costa C, Gelpi JL, Zamakola L, Parraga I, de la Cruz X, Orozco M. PMUT: A web-based tool for the annotation of pathological mutations on proteins. Bioinformatics 2005; 21: 3176-3178.
134. Yue P, Melamud E, Moult J. SNPs3D: Candidate gene and SNP selection for association studies. BMC Bioinformatics 2006; 7: 166.
135. Capriotti E, Fariselli P, Casadio R. I-Mutant2.0: Predicting stability changes upon mutation from the protein sequence or structure. Nucleic Acids Res 2005; 33: W306-W310.
136. Karchin R, Diekhans M, Kelly L, Thomas DJ, Pieper U, Eswar N et al LS-SNP: Large-scale annotation of coding non-synonymous SNPs based on multiple information sources. Bioinformatics 2005; 21: 2814-2820.
137. Dayal S, Bottiglieri T, Arning E, Maeda N, Malinow MR, Sigmund CD et al. Endothelial dysfunction and elevation of S-adenosylhomocysteine in cystathionine beta-synthase-deficient mice. Circ Res 2001; 88: 1203-1209.
138. Lentz SR, Erger RA, Dayal S, Maeda N, Malinow MR, Heistad DD et al Folate dependence of hyperhomocysteinemia and vascular dysfunction in cystathionine beta-synthase-deficient mice. Am J Physiol Heart Circ Physiol 2000; 279: H970-H975.
139. Robert K, Maurin N, Ledru A, Delabar J, Janel N, Vitvitsky V et al Hyperkeratosis in cystathionine beta synthase-deficient mice: An animal model of hyperhomocysteinemia. Anat Rec A Discov Mol Cell Evol Biol 2004; 280: 1072-1076.
140. Vitvitsky V, Dayal S, Stabler S, Zhou Y, Wang H, Lentz SR et al. Perturbations in homocysteine-linked redox homeostasis in a murine model for hyperhomocysteinemia. Am J Physiol Regul Integr Comp Physiol 2004; 287: R39-R46.
141. Kelly TL, Neaga OR, Schwahn BC, Rozen R, Trasler JM. Infertility in 5,10-methylenetetrahydrofolate reductase (MTHFR)-deficient male mice is partially alleviated by lifetime dietary betaine supplementation. Biol Reprod 2005; 72: 667-677.