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Thromb Haemost 1997; 77(05): 0818-0821
DOI: 10.1055/s-0038-1656059
Cinical Studies
Schattauer GmbH Stuttgart

The Mutation Ala677→Val in the Methylene Tetrahydrofolate Reductase Gene: A Risk Factor for Arterial Disease and Venous Thrombosis

Valder R Arruda
The Hematology-Hemotherapy Center, Department of Clinical Medicine, State University of Campinas, Campinas, São Paulo, Brazil
,
Paula M von Zuben
The Hematology-Hemotherapy Center, Department of Clinical Medicine, State University of Campinas, Campinas, São Paulo, Brazil
,
Luiz C Chiaparini
The Hematology-Hemotherapy Center, Department of Clinical Medicine, State University of Campinas, Campinas, São Paulo, Brazil
,
Joyce M Annichino-Bizzacchi
The Hematology-Hemotherapy Center, Department of Clinical Medicine, State University of Campinas, Campinas, São Paulo, Brazil
,
Fernando F Costa
The Hematology-Hemotherapy Center, Department of Clinical Medicine, State University of Campinas, Campinas, São Paulo, Brazil
› Author Affiliations
Further Information

Publication History

Received 15 October 1996

Accepted after revision 20 January 1997

Publication Date:
11 July 2018 (online)

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Summary

Mild hyperhomocysteinemia has been identified as a risk factor for arterial disease and for venous thrombosis. Individuals homozygous for the thermolabile variant of the methylene tetrahydrofolate reductase gene (MTHFR) which results from a common mutation Ala677→Val and is found in 5-15% of the general population, have significantly elevated plasma homocysteine levels and may account for one of the genetic risk factors in vascular disease. We have analyzed the prevalence of MTHFR-T homozygotes in patients with arterial disease or venous thrombosis. We studied 191 patients with arterial disease and 127 individuals with venous thrombosis and compared with 296 unmatched controls. The results showed that there was a high prevalence of homozygotes for the mutated MTHFR-T allele among a group of patients with arterial disease (19%) in the absence of hyperlipoproteinemia, hypertension, and diabetes mellitus when compared to controls (4%), odds ratio of 5.52 (95% C.I., 2.27 to 13.51). The prevalence of homozygotes among patients with venous thrombosis was 11%, odds ratio of 2.93 (95% C.I., 1.23 to 7.01). The risk of venous thrombosis remained high, odds ratio of 2.63, even after we excluded 27 patients with hereditary thrombophilia (e.g. factor V Leiden, dysfibrinogene- mia, deficiency of protein C, protein S, antithrombin III, or factor XII) from the 127 overall cases with venous thrombosis. These data support the hypothesis that being a homozygote for the MTHFR-T is a risk factor for the development of arterial diasease and also for venous thrombosis.

 

  • References

  • 1 Ueland PM, Refsum H. Plasma homocysteine, a risk factor for vascular disease: plasma levels in health, disease, and drug therapy. J Lab Clin Med 1989; 114: 473-501
    PubMedGoogle Scholar
  • 2 Kang SS, Wong PWK, Malinow MR. Hyperhomocysteinemia as a risk factor for occlusive vascular disease. Annu Rev Nutr 1992; 12: 279-298
    CrossrefPubMedGoogle Scholar
  • 3 Brattstrom L, Lindgren A. Hyperhomocysteinemia as a risk factor for stroke. Neurol Res 1992; 14: 81-4
    CrossrefPubMedGoogle Scholar
  • 4 Verhoef P, Hennekens CH, Malinow R, Kok FJ, Willet WC, Stampfer MJ. A prospective study of plasma homocysteine and risk of ischemic stroke. Stroke 1994; 25: 1924-1930
    CrossrefPubMedGoogle Scholar
  • 5 Boers GHJ, Smals AGH, Trijbels FJM, Fowler B, Bakkeren JAJM, Schoonderwaldt HC, Kleijer WJ, Kloppenborg PWC. Heterozygosity for homocystinuria in peripheral and cerebral occlusive arterial disease. N Engl J Med 1985; 313: 709-715
    CrossrefPubMedGoogle Scholar
  • 6 Boushey CJ, Beresford SSA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. JAMA 1995; 274: 1049-1057
    CrossrefPubMedGoogle Scholar
  • 7 Clarke R, Daly L, Robinson K, Naughten E, Cahalane S, Fowler B, Graham I. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 1991; 324: 1149-1155
    CrossrefPubMedGoogle Scholar
  • 8 Falcon CR, Cattaneo M, Panzeri D, Martinelli I, Mannucci PM. High prevalence of hyperhomocyst(e)inemia in patients with juvenile venous thrombosis. Arterioscler Thromb 1994; 14: 1080-1083
    CrossrefPubMedGoogle Scholar
  • 9 den HeijerM, Blom HJ, Gerrits WBJ, Rosendaal FR, Haak HL, Wijermans PW, Bos GMJ. Is hyperhomocysteinemia a risk factor for recurrent venous thrombosis?. Lancet 1995; 345: 882-885
    CrossrefPubMedGoogle Scholar
  • 10 den HeijerM, Koster T, Blom HJ, Bos GMJ, Briët E, Reitsma PH, Vanden-broucke JP, Rosendaal FR. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med 1996; 334: 759-762
    CrossrefPubMedGoogle Scholar
  • 11 Ubbink JB, Vermaak WJH, van derMerwe A, Becker PJ. Vitamin B12, vitamin B6, and folate nutritional status in men with hyperhomocysteinemia. Am J Clin Nutr 1993; 57: 47-53
    CrossrefPubMedGoogle Scholar
  • 12 Stabler SP, Marcell PD, Podell ER, Allen RH, Savage DG, Lindenbaum J. Elevation of total homocysteine in the serum of patients with cobalamin or folate deficiency detected by capillary gas chromatography-mass spectrometry. J Clin Invest 1988; 81: 466-474
    CrossrefPubMedGoogle Scholar
  • 13 Kraus JP. Molecular basis of phenotype expression in homocystinuria. J Inherit Metab Dis 1994; 17: 383-390
    CrossrefPubMedGoogle Scholar
  • 14 Daly L, Robinson K, Tan KS, Graham I. Hyperhomocysteinemia: a metabolic risk factor for coronary heart disease determined by both genetic and environmental influences?. Q J Med 1993; 86: 685-689
    CrossrefPubMedGoogle Scholar
  • 15 Mudd SH, Havlik R, Levy HL, McKusick VA, Feinleib M. A study of cardiovascular risk in heterozygotes for homocystinuria. Am J Hum Genet 1981; 33: 883-893
    PubMedGoogle Scholar
  • 16 Engbersen AMT, Franken DG, Boers GHJ, Stevens EMB, Trijbels FJM, Blom HJ. Thermolabile 5,10-methylenetetrahydrofolate reductase as a cause of mild hyperhomocysteinemia. Am J Hum Genet 1995; 56: 142-150
    PubMedGoogle Scholar
  • 17 Goyette P, Frosst P, Rosenblatt DS, Rozen R. Seven novel mutations in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency. Am J Hum Genet 1995; 56: 1052-1059
    PubMedGoogle Scholar
  • 18 Kang SS, Wong PWK, Susmano A, Sora J, Norusis M, Ruggie N. Thermolabile methylenetetrahydrofolate reductase: an inherited risk factor for coronary artery disease. Am J Hum Genet 1991; 48: 536-545
    PubMedGoogle Scholar
  • 19 Kang SS, Wong PWK, Zhou J, Sora J, Lessick M, Ruggie N, Grcevich G. Thermolabile methylenetetrahydrofolate reductase in patients with coronay artery disease. Metabolism 1988; 37: 611-613
    CrossrefPubMedGoogle Scholar
  • 20 Kang SS, Zhou J, Wong PWK, Kowalisyn J, Strokosch G. Intermediate homocysteinemia: a thermolabile variant of methylenetetrahydrofolate reductase. Am J Hum Genet 1988; 43: 414-421
    PubMedGoogle Scholar
  • 21 Franken DG, Boers GHJ, Blom HJ, Trijbels JMF, Kloppemborg PWC. Treatment of mild hyperhomocysteinemia in vascular disease patients. Arterioscler Thromb 1994; 14: 465-470
    CrossrefPubMedGoogle Scholar
  • 22 Froost P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GHJ, den HeijerM, Kluijtmans LAJ, van denHeuvel LP, Rozen R. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahidrofolate reductase. Nature Genetics 1995; 10: 111-113
    CrossrefPubMedGoogle Scholar
  • 23 Kluijtmans LAJ, van denHeuvel LPWJ, Boers GHJ, Frosst P, Stevens EMB, van OostBA, den HeijerM, Trijbels FJM, Rozen Rl. Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. Am J Human Genet 1996; 58: 35-41
    PubMedGoogle Scholar
  • 24 Motulsky AG. Nutritional ecogenetics: homocysteine-related arteriosclerotic vascular disease, neural tube defects, and folic acid. Am J Hum Genet 1996; 58: 17-20
    PubMedGoogle Scholar
  • 25 Ubbink JB, Vermaak WJH, Delport R, van derMerwe A, Becker PJ, Potgieter H. Effective homocysteine metabolism may protect South African blacks against coronary heart disease. Am J Clin Nutr 1995; 62: 802-808
    CrossrefPubMedGoogle Scholar
  • 26 Stein EA. Lipids, Lipoproteins, and Apolipoprotrein. In: Tieftz NW. editor Fundamentals of Clinical Chemistry Philadelphia, PA:: W B Saunders; 1987: 449-481
    Google Scholar
  • 27 Lupus Anticoagulant Working Party. Guidelines on testing for the lupus anticoagulant. J Clin Pathol 1991; 44: 885-889
    CrossrefPubMedGoogle Scholar
  • 28 Arruda VR, Annichino-Bizzacchi JM, Costa FF, Reitsma FF. Factor V Leiden (FVQ506) is common in Brazilian population. Am J Hematol 1995; 39: 242-243
    PubMedGoogle Scholar
  • 29 Wolf M, Boyer-Neumann C, Martinoli J-L. et al. A new functional assay for human protein S activity using activated factor V as substrate. Thromb Haemost 1989; 62: 1144-1145
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Odegaard OR, Try K, Abilgaard U. Protein C: a simplified semi-automated activity assay. Thromb Res 1986; 42: 257-262
    CrossrefPubMedGoogle Scholar
  • 31 Abildgaard U, Lie M, Oldergaard OR. Antithrombin (heparin cofactor) assay with new chromogenic substrates. Thromb Res 1977; 11: 549-553
    CrossrefPubMedGoogle Scholar
  • 32 Bowie EJW, Owen JCA. Clinical and laboratory diagnosis of hemorrhagic disorders. In: Ratnoff OD, Forbes CD. editors Disorders of Hemostasis Philadelphia: W B Saunders Company; 1991: 48-74
    Google Scholar
  • 33 Millar SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from nucleated cell. Nucleic Acids Res 1988; 16: 1215
    CrossrefPubMedGoogle Scholar
  • 34 Saiki RK, Gelfand DH, Stoffel S, Scharf SJ, Higuchi R, Horn GT, Mullis KB, Erlich HA. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science 1988; 239: 487-491
    CrossrefPubMedGoogle Scholar
  • 35 Dean AG, Dean JA, Coulombier D, Brendel KA, Smith DC, Burton AH, Dicker RC, Sullivan KM, Fagan RF, Amer TG. Epi Info, version 6: a word processing, database, and statistics program for epidemiology on microcomputers. Atlanta: Center for Disease Control and Prevention; 1994
    Google Scholar
  • 36 Wilcken DEL, Wang XL, Sim AS, Mc Credie. Distribution in healthy and coronary populations of the methylenetetrahydrofolate reductase (MTHFR) C677T mutation. Arterioscler Thromb Vase Biol 1996; 16: 878-882
    CrossrefPubMedGoogle Scholar