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Thromb Haemost 1997; 78(05): 1357-1359
DOI: 10.1055/s-0038-1665411
Review Article
Schattauer GmbH Stuttgart

Factor V Leiden and Thermolabile Methylenetetrahydrofolate Reductase in Extreme Old Age

D C Rees
1   The MRC Molecular Haematology Unit, Institute of Molecular Medicine, The John Radcliffe, Headington, Oxford, UK
,
Y T Liu
1   The MRC Molecular Haematology Unit, Institute of Molecular Medicine, The John Radcliffe, Headington, Oxford, UK
,
M J Cox
1   The MRC Molecular Haematology Unit, Institute of Molecular Medicine, The John Radcliffe, Headington, Oxford, UK
,
P Elliott
2   Department of Haematology, The John Radcliffe, Headington, Oxford, UK
,
J S Wainscoat
2   Department of Haematology, The John Radcliffe, Headington, Oxford, UK
› Author Affiliations
Further Information

Publication History

Received 28 1997

Accepted after resubmission 15 July 1997

Publication Date:
12 July 2018 (online)

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Summary

Both factor V Leiden and the C677T methylenetetrahydrofolate reductase (MTHFR) gene mutation are associated with premature vascular disease, and yet are found at surprisingly high allele frequencies in European populations, 2.7% and 35% respectively. We have investigated the prevalence of these mutations in 87 UK residents over the age of ninety, to look for any evidence of their association with premature death.

Five factor V Leiden heterozygotes were found, giving an allele frequency of 2.9%, similar to that in the general UK population. The frequency of the thermolabile C677T MTHFR mutation was 36% with 11% homozygotes, again similar to that in the UK population; these genotypes are in Hardy-Weinberg equilibrium, suggesting that there is not strong selection against the homozygous state. One person was both heterozygous for factor V Leiden and homozygous for the C677T mutation. This study suggests that neither factor V Leiden nor thermolabile MTHFR are risk factors for premature death.

 

  • References

  • 1 Dahlbäck B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognised mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci 1993; 90: 1004-1008
    CrossrefPubMedSearch in Google Scholar
  • 2 Svensson PJ, Dahlbäck B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994; 330: 517-521
    CrossrefPubMedSearch in Google Scholar
  • 3 Voorberg J, Roelse J, Koopman R, Büller H, Berends F, ten CateJW, Mertens K, Mourik JAV. Association of idiopathic thromboembolism with single point mutation at Arg506 of factor V. Lancet 1994; 1994 (343) 1535-1536
    PubMedSearch in Google Scholar
  • 4 Greengard JS, Sun X, Xu X, Fenandez JA, Griffin JH, Evatt BL. Activated protein C resistance caused by Arg 506Gln mutation in factor Va. Lancet 1994; 343: 1362-1363
    PubMedSearch in Google Scholar
  • 5 Bertina RM, Koeleman BPC, Koster T, Rosendaal FR, Dirven RJ, de ROn-deH, van derVeldenPA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-67
    CrossrefPubMedSearch in Google Scholar
  • 6 Rosendaal FR, Koster T, Vandenbroucke JP, Reitsma PH. High risk of thrombosis in patients homozygous for factor V Leiden (Activated protein C resistance). Blood 1995; 85 (06) 1504-1508
    CrossrefPubMedSearch in Google Scholar
  • 7 Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet 1995; 346: 1133-1134
    CrossrefPubMedSearch in Google Scholar
  • 8 Rees DC. The population genetics of factor V Leiden (Arg506Gln). Br J Haematol 1996; 95: 579-586
    CrossrefPubMedSearch in Google Scholar
  • 9 Wilcken DEL, Wilcken B. The pathogenesis of coronary disease: a possible role for methionine metabolism. J Clin Invest 1976; 57: 1079-1082
    CrossrefPubMedSearch in Google Scholar
  • 10 Kluijtmans LAJ, van denHeuvel LPWJ, Boers GHJ, Frosst P, Stevens EMB, van OostBA, den HeijerM, Trijbels FJM, Rozen R, Blom HJ. Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor vor cardiovascular disease. Am J Hum Genet 1996; 58: 35-41
    PubMedSearch in Google Scholar
  • 11 Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Mathews RG, Boers GHJ, den HeijerM, Kluijtmans LAJ, van denHeuvel LP, Rozen R. A candidate genetic risk factor for vascular disease: a common mutation in methylene tetrahydroflate reductase: isolation of cDNA, mapping and mutation identification. Nature Genetics 1995; 10: 111-113
    CrossrefPubMedSearch in Google Scholar
  • 12 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
    PubMedSearch in Google Scholar
  • 13 Rozen R. Genetic predisposition to hyperhomocysteinemia: deficiency of methylenetetrahydrofolate reductase (MTHFR). Thromb Haemost 1997; 78 (01) 523-526
    Thieme ConnectPubMedSearch in Google Scholar
  • 14 Old JM, Higgs DR. In: The Thalassaemias Gene Analysisi. Weatherall DJ. ed. Churchill Livingstone: 1993: 74-103
  • 15 Koeleman BPC, Reitsma PH, Allaart CF, Bertina RM. Activated protein C resistance as an additional risk factor for thrombosis in protein C-deficient families. Blood 1994; 84 (04) 1031-1035
    PubMedSearch in Google Scholar
  • 16 Rees DC, Cox M, Clegg JB. Detection of the factor V Leiden mutation using whole blood PCR (letter). Thromb Haemost 1996; 75 (03) 520-521
    Thieme ConnectPubMedSearch in Google Scholar
  • 17 Rees DC, Grimwade D, Langabeer S, Burnett A, Goldstone A. Influence of genetic predisposition to thrombosis on natural history of acute promyelocytic leukaemia. Br J Haematol 1997; 96: 490-492
    CrossrefPubMedSearch in Google Scholar
  • 18 Motulsky AG. Nutritional ecogenetics: homocysteine-related arteriosclerotic vascular disease, neural tube defects, and folic acid. Am J Hum Genet 1996; 58: 17-20
    PubMedSearch in Google Scholar
  • 19 Mari D, Mannucci PM, Duca F, Bertolini S, Franceschi C. Mutant factor V (Arg506Gln) in healthy centenarians (letter). Lancet 1996; 347: 1044
    PubMedSearch in Google Scholar
  • 20 Adams M, Smith PD, Martin D, Thompson JR, Lodwick D, Samani NJ. Genetic analysis of thermolabile methylenetetrahydrofolate reductase as a risk factor for myocardial infarction. Q J Med 1996; 89: 437-434
    CrossrefPubMedSearch in Google Scholar
  • 21 Heijer MD, Koster T, Blom HJ, Bos GMJ, Briet E, Reitsma PH, Vandenbroucke JP, Rosendaal FR. Hyperhomocysteinemia as a risk factor deep- vein thrombosis. N Engl J Med 1996; 334 (12) 759-762
    CrossrefPubMedSearch in Google Scholar
  • 22 van derPut NMJ, Steegers-Theunissen RPM, Frosst P, Trijbels FJM, Eskes TKAB, van denHeuvelLP, Mariman ECM, den HeyerM, Rozen R, Blom HJ. Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. Lancet 1995; 346: 1070-1071
    CrossrefPubMedSearch in Google Scholar
  • 23 Posey DL. Is mutated MTHFR a risk factor neural tube defects. Lancet 1996; 347: 686-687
    CrossrefPubMedSearch in Google Scholar
  • 24 Franchis Rd, Sebastio G, Mandato C, Andria G, Mastroiacovo P. Spina bifida, 677T→C mutation, and role of folate. Lancet 1995; 346: 1703
    PubMedSearch in Google Scholar
  • 25 van derPutNMJ, Eskes TKAB, Blom HJ. Is the common 677C→T mutation in the methylenetetrahydrofolate reductase gene a risk factor for neural tube defects? A meta-analysis. Q J Med 1997; 90: 111-115
    CrossrefPubMedSearch in Google Scholar