Low folate levels and thermolabile methylenetetrahydrofolate reductase as primary determinant of mild hyperhomocystinemia in normal and thromboembolic subjects

Arteriosclerosis, Thrombosis, and Vascular Biology

Volumn 19, Issue 7, 1999, Pages 1761-1767

  Gemmati, Donato ^a   Previati, Maurizio ^a   Serino, Maria L ^a   Moratelli, Stefano ^a   Guerra, Severino ^b   Capitani, Silvano ^a   Forini, Elena ^b   Ballerini, Giorgio ^a   Scapoli, Gian L ^a  

^a UNIVERSITY OF FERRARA   (Italy)

^b Thrombosis University of Ferrara ^*

Author keywords

C677T mutation; Homocysteine; Hyperhomocystinemia; Metabolism; Thermolabile MTHFR; Venous thrombosis

Indexed keywords

FOLIC ACID; METHYLENETETRAHYDROFOLATE DEHYDROGENASE;

ADULT; ARTICLE; DISEASE ASSOCIATION; FEMALE; GENE MUTATION; GENOTYPE; HOMOZYGOSITY; HUMAN; HYPERHOMOCYSTEINEMIA; MAJOR CLINICAL STUDY; MALE; POLYMERASE CHAIN REACTION; PRIORITY JOURNAL; RISK ASSESSMENT; RISK FACTOR; THROMBOEMBOLISM;

EID: 0032997449     PISSN: 10795642     EISSN: None     Source Type: Journal    
DOI: 10.1161/01.ATV.19.7.1761     Document Type: Article

References (42)

1. Clarke R, Daly L, Robinson K, Naughten E, Cahalane S, Fowler B, Graham I. Hyperhomocystinemia: an independent risk factor for vascular disease. N Engl J Med. 1991;324:1149-1155.
2. Mudd SH, Levy HL, Skovby F. Disorders of transulfuration. In: Scrivers CS, Beaudet AL, Sly WL eds. The Metabolic Basis of Inherited Disease. New York, NY: McGrow-Hill International Book Co; 1995;1279-1327.
3. Mudd SH, Skovby F, Levy HL, Pettigrew KD, Wilcken B, Pyeritz RE, Andria G, Boers GH, Bromberg IL, Cerone R, Fowler B, Grobe H, Schmidt H, Schweitzer L. The natural history of homocystinuria due to cystathionine β-synthase deficiency. Am J Hum Genet. 1985;37:1-31.
4. Stampfer MJ, Willett WC. Homocysteine and marginal vitamin deficiency: the importance of adequate vitamin intake. JAMA. 1993;270: 2726-2727.
5. Engbersen AMT, Franken DG, Boers GHJ, Stevens EMB, Trijbels FJM, Blom HJ. Thermolabile 5,10-methylene tetrahydrofolate reductase as cause of mild hyperhomocystinemia. Am J Hum Genet. 1995;56:142-150.
6. Fryer RH, Wilson BD, Gubler DB, Fitzgerald LA, Rodgers GM. Homocysteine, a risk factor for premature vascular disease and thrombosis, induces tissue factor activity in endothelial cells. Arterioscler Thromb Vasc Biol. 1993;13:1327-1333.
7. Malinow MR, Kang SS, Taylor LM, Wong PWK, Coull B, Inahara T, Mukerjee D, Sexton G, Upson B. Prevalence of hyperhomocyst(e)inaemia in patients with peripheral arterial occlusive disease. Circulation. 1989;79:1180-1188.
8. Fermo I, Viganò D'Angelo S, Paroni R, Mazzola G, Calori G, D'Angelo A. Prevalence of moderate hyperhomocystinemia in patients with early-onset venous and arterial occlusive disease. Ann Intern Med. 1995; 123:747-753.
9. den Heijer M, Blom HJ, Gerrits WBJ, Rosendaal FR, Haak HL, Wijermans PW. Is hyperhomocysteinaemia a risk factor for recurrent venous thrombosis? Lancet. 1995;345:882-885.
10. den Heijer M, Koster T, Blom HJ, Bos GMJ, Briët E, Reitsma PH, Vandenbroucke JP, Rosendaal FR. Hyperhomocystinemia as a risk factor for deep vein thrombosis. N Engl J Med. 1996;334:759-762.
11. Simioni P, Prandoni P, Burlina A, Tormene D, Sardella C, Ferrari V, Benedetti L, Girolami A. Hyperhomocystinemia and deep vein thrombosis. Thromb Haemost. 1996;76:883-886.
12. Falcon CR, Cattaneo M, Panzeri D, Martinelli I, Mannucci PM. High prevalence of hyperhomocyst(e)inemia in patients with juvenile venous thrombosis. Arterioscler Thromb Vasc Biol. 1994;14:1080-1083.
13. Brattström L, Tengborn L, Lagerstedt C, Israelsson B, Hultberg B. Plasma homocysteine in venous thromboembolism. Haemostasis. 1991; 21:51-57.
14. Amundsen T, Ueland PM, Waage A. Plasma homocysteine levels in patients with deep venous thrombosis. Arterioscler Thromb Vasc Biol. 1995;15:1321-1323.
15. 223Val MTHFR) in patients with inherited thrombophilic coagulation defects. Arterioscler Thromb Vasc Biol. 1997;17:2924-2929.
16. Ridker PM, Hennekens CH, Selhub J, Milethic JP, Malinow MR, Stampfer MJ. Interrelation of hyperhomocyst(e)inemia, factor V Leiden, and risk of future venous thromboembolism. Circulation. 1997;95: 1777-1782.
17. Kang SS, Wong PWK, Susmano A, Sora J, Norusis M, Ruggie N. Thermolabile methylene tetrahydrofolate reductase: an inherited risk factor for coronary artery disease. Am J Hum Genet. 1991;48:536-545.
18. Kluijtmans LAJ, van den Heuvel LPWJ, Boers GHJ, Frosst P, Stevens EMB, van Oost BA, den Heijer M, Trijbels FJM, Rozen R, Blom HJ. Molecular genetic analysis in mild hyperhomocystinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. Am J Hum Genet. 1996;58:35-41.
19. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJH, den Heijer M, Kluijtmans LAJ, va den Heuvel LP, Rozen R. A candidate genetic risk factor for vascular disease: a common mutation in methylene tetrahydrofolate reductase. Nat Genet. 1995;10:111-113.
20. Tosetto A, Missiaglia E, Frezzato M, Rodeghiero F. The VITA project: C677T mutation in the methylene tetrahydrofolate reductase gene and risk of venous thromboembolism. Br J Haematol. 1997;97:804-806.
21. Arruda VR, von Zuben PM, Chiaparini LC, Annichino-Bizzacchi JM, Costa FF. The mutation Ala677→Val in the methylene tetrahydrofolate reductase gene: a risk factor for arterial disease and venous thrombosis. Thromb Haemost. 1977;77:818-821.
22. Austin H, Hooper WC, Dilley A, Drews C, Renshaw M, Ellingsen D, Evatt B. The prevalence of two genetic traits related to venous thrombosis in Whites and African-Americans. Thromb Res. 1997;86:409-415.
23. Margaglione M, D'Andrea G, d'Addedda M, Giuliani N, Cappucci G, Iannaccone L, Vecchione G, Grandone E, Brancaccio V, Di Minno G. The methylenetetrahydrofolate reductase TT677 genotype is associated with venous thrombosis independently of the coexistence of the FV Leiden and the prothrombin A20210 mutation. Thromb Haemost. 1998; 79:907-911.
24. McAndrew PE, Brandt JT, Pearl DK, Prior TW. The incidence of the gene for thermolabile methylene tetrahydrofolate reductase in African Americans. Thromb Res. 1996;83:195-198.
25. Sacchi E, Tagliabue L, Duca F, Mannucci PM. High frequency of C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene in Northern Italy. Thromb Haemost. 1997;78:963-964.
26. Franco RF, Araújo AG, Guerreiro JF, Elion J, Zago MA. Analysis of the 677C→T mutation of the methylene tetrahydrofolate reductase gene in different ethnic groups. Thromb Haemost. 1998;79:119-121.
27. Jacques PF, Bostom AG, William RR, Ellison RC, Eckfeldt JH, Rosenberg IH, Selhub J, Rozen R. Relation between folate status, a common mutation in methylene tetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation. 1996;93:7-9.
28. Malinow MR, Nieto FJ, Kruger WD, Duell PB, Hess DL, Gluckman RA, Block PC, Holzgang CR, Anderson PH, Seltzer D, Upson B, Lin QR. The effects of folic acid supplementation on plasma total homocysteine are modulated by multivitamin use and methylenetetrahydrofolate reductase genotypes. Arterioscler Thromb Vasc Biol. 1997;17:1157-1162.
29. Gemmati D, Serino ML, Mari R, Verzola I, Moratelli S, Ballerini G. Different anticoagulant response to activated protein C (APC test) and to Agkistrodon Contortix Venom (ACV test) in a family with FV-R506Q substitution. Clin Appl Thromb Hemost. 1997;3:168-173.
30. Gemmati D, Serino ML, Scapoli GL. A modified functional Global test to measure protein C, protein S activities and the activated protein C resistance phenotype. Thromb Res. 1998;92:141-148.
31. Gemmati D, Serino ML, Verzola I, Mari R, Moratelli S, Ballerini G. Resistance to activated protein C and low levels of protein S activity in nine thrombophilic families: a correct diagnosis. Blood Coagul Fibrinolysis. 1997;8:118-123.
32. Exner T, Rickard KA, Kronenberg HA. Sensitive test demonstrating lupus anticoagulant and its behavioural patterns. Br J Haematol. 1978; 40:143-151.
33. Araki A, Sako Y. Determination of free and total homocysteine in human plasma by high-performance liquid chromatographic with fluorescence detection. J Chromatogr. 1987;422:43-52.
34. Anderson A, Brattström L, Israelsson B, Isaksson A, Hamfelt A, Hhultberg B. Plasma homocysteine before and after methionine loading with regard to age, gender, and menopausal status. Eur J Clin Inv. 1992;22:79-87.
35. Mandel H, Brenner B, Berant M, Rosenberg N, Lanir N, Jakobs C, Fowler B, Seligsohn U. Coexistence of hereditary homocystinuria and factor V Leiden: effect on thrombosis. N Engl J Med. 1996;334:763-768.
36. Gemmati D, Serino ML, Moratelli S, Mari R, Ballerini G, Scapoli GL. Coexistence of antithrombin deficiency, factor V Leiden and hyperhomocystinemia in a thrombotic family. Blood Coagul Fibrinolysis. 1998; 9:173-176.
37. Goyette P, Frosst P, Rosenblatt DS, Rozen R. Seven novel mutations in the Methylene tetrahydrofolate reductase gene and genotype/phenotype correlations in severe Methylene tetrahydrofolate reductase deficiency. Am J Hum Genet. 1995;56:1052-1059.
38. Sebastio G, Sperandeo MP, Panico M, de Franchis R, Kraus JP, Andria G. The molecular basis of homocystinuria due to Cystathionine β-synthase deficiency in Italian family, and report of four novel mutations. Am J Hum Genet. 1995;56:1324-1333.
39. Kang SS, Wong PWK, Bock HGO, Horwitz A, Grix A. Intermediate hyperhomocystinemia resulting from compound heterozygosity of methylene tetrahydrofolate reductase mutations. Am J Hum Genet. 1991;48:546-551.
40. Ma J, Stampfer MJ, Hennekens CH, Frosst P, Selhub J, Horsford J, Malinow MR, Willett WC, Rozen R. Methylenetetrahydrofolate reductase polymorphism, plasma folate, homocysteine, and risk of myocardial infarction in US physicians. Circulation. 1996;94:2410-2416.
41. Selhub J, Jacques PF, Wilson PWS, Rush D, Rosenberg IH. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA. 1993;270:2693-2698.
42. Joosten E, van den Berg A, Riezler R, Naurath HJ, Liendenbaum J, Stabler SP, Allen RH. Metabolic evidence that deficiencies of vitamin B-12 (cobalamin), folate, and vitamin B-6 occur commonly in elderly people. Am J Clin Nutr. 1993;58:468-476.