Download PDF
Thromb Haemost 1999; 82(03): 1100-1105
DOI: 10.1055/s-0037-1614336
Letters to the Editor
Schattauer GmbH

Longevity Is Independent of Common Variations in Genes Associated with Cardiovascular Risk

Else M. Bladbjerg
1   From the Department of Thrombosis Research, University of Southern Denmark and Department of Clinical Biochemistry, Ribe County Hospital in Esbjerg, Odense, Denmark
,
Karen Andersen-Ranberg
2   Centre for Health and Social Policy, Odense University Hospital, and Department of Clinical Chemistry, Odense University Hospital, Odense, Denmark
,
Moniek P. M. de Maat
1   From the Department of Thrombosis Research, University of Southern Denmark and Department of Clinical Biochemistry, Ribe County Hospital in Esbjerg, Odense, Denmark
,
Søren Risom Kristensen
3   Department of Clinical Chemistry, Odense University Hospital, Odense, Denmark
,
Bernard Jeune
2   Centre for Health and Social Policy, Odense University Hospital, and Department of Clinical Chemistry, Odense University Hospital, Odense, Denmark
,
Jørgen Gram
1   From the Department of Thrombosis Research, University of Southern Denmark and Department of Clinical Biochemistry, Ribe County Hospital in Esbjerg, Odense, Denmark
,
Jørgen Jespersen
1   From the Department of Thrombosis Research, University of Southern Denmark and Department of Clinical Biochemistry, Ribe County Hospital in Esbjerg, Odense, Denmark
› Author Affiliations
Further Information

Publication History

Received 24 November 1998

Accepted after resubmission 23 March 1999

Publication Date:
09 December 2017 (online)

    Permissions and Reprints

Summary

Do extremely old persons have a genetically favourable profile which has protected them from cardiovascular death? We have tried to answer this question by measuring DNA polymorphisms of selected cardiovascular risk indicators [factor VII, FVII (R/Q353, intron 7 (37bp)n, and -323ins10), β fibrinogen (-455G/A), plasminogen activator inhibitor type 1, PAI-1 (-675(4G/5G)), tissue plasminogen activator, t-PA (intron 8 ins311), platelet receptor glycoprotein IIb/IIIa, GPIIb/IIIa (L/P33), prothrombin (20210G/A), methylene tetrahydrofolate reductase, MTHFR (A/V114), angiotensin converting enzyme, ACE (intron 16 ins287), and angiotensinogen (M/T235)]. Blood was collected from 187 unselected Danish centenarians, and 201 healthy Danish blood donors, aged 20-64 years (mean age 42 years). Genomic DNA was amplified using PCR and the genotype was determined by RFLP methods or allele-specific amplification followed by agarose gel electrophoresis. The frequencies of the high-risk alleles in centenarians were: for FVII R/Q353 0.91; for FVII intron 7 (37bp)n 0.67; for FVII-323 ins10 0.90; for fibrinogen 0.16; for PAI-1 0.52; for t-PA 0.59; for GPllb/llla 0.16; for prothrombin 0.008; for MTHFR 0.33; for ACE 0.52; and for angiotensinogen 0.36. Comparable frequencies were observed in the blood donors. Subgroup analysis of men and women separately gave similar results. The genotype frequencies in the centenarians and the blood donors were similar for all polymorphisms, and this study suggests that common variations in genes associated with cardiovascular risk do not contribute significantly to longevity.

 

  • References

  • 1 Herskind AM, McGue M, Holm NV, Sørensen TI, Harvald B, Vaupel JW. The heritability of human longevity: a population-based study of 2872 Danish twin pairs born 1870-1900. Hum Genet 1996; 97: 319-23.
    CrossrefPubMedGoogle Scholar
  • 2 Schächter F, Faure-Delanef L, Guenot F, Rouger H, Froguel P, Lesueur-Ginot L, Cohen D. Genetic associations with human longevity at the APOE and ACE loci. Nat Genet 1994; 6: 29-32.
    CrossrefPubMedGoogle Scholar
  • 3 Louhija J, Miettinen HE, Kontula K, Tikkanen MJ, Miettinen TA, Tilvis RS. Aging and genetic variation of plasma apolipoproteins. Relative loss of the apolipoprotein E4 phenotype in centenarians. Arterioscler Thromb Vasc Biol 1994; 14: 1084-9.
    CrossrefPubMedGoogle Scholar
  • 4 Baggio G, Franceschi C, Mari D, Herskind AM, Andersen-Ranberg K, Jeune B. Biology and genetics of human longetivity. Australas J Ageing 1998; 17: 8-10.
    CrossrefPubMedGoogle Scholar
  • 5 Iacoviello L, Di Castelnuovo A, de Knijff P, D’Orazio A, Amore C, Arboretti R, Kluft C, Donati MB. Polymorphisms in the coagulation factor VII gene and the risk of myocardial infarction. N Engl J Med 1998; 338: 79-85.
    CrossrefPubMedGoogle Scholar
  • 6 Zito F, Di Castelnuovo A, Amore C, D’Orazio A, Donati MB, Iacoviello L. Bcl I polymorphism in the fibrinogen beta-chain gene is associated with the risk of familial myocardial infarction by increasing plasma fibrinogen levels. A case-control study in a sample of GISSI-2 patients. Arterioscler Thromb Vasc Biol 1997; 17: 3489-94.
    CrossrefPubMedGoogle Scholar
  • 7 De Maat MP, Kastelein JJ, Jukema JW, Zwinderman AH, Jansen H, Groenemeier B, Bruschke AV, Kluft C. -455G/A polymorphism of the beta-fibrinogen gene is associated with the progression of coronary atherosclerosis in symptomatic men: proposed role for an acute-phase reaction pattern of fibrinogen. Arterioscler Thromb Vasc Biol 1998; 18: 265-71.
    CrossrefPubMedGoogle Scholar
  • 8 Eriksson P, Kallin B, van’t Hooft FM, Bavenholm P, Hamsten A. Allele-specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad USA 1995; 92: 1851-5.
    CrossrefPubMedGoogle Scholar
  • 9 Van der Bom JG, de Knijff P, Haverkate F, Bots ML, Meijer P, de Jong PTVM, Hofman A, Kluft C, Grobbee DE. Tissue plasminogen activator and risk of myocardial infarction. The Rotterdam Study. Circulation 1997; 95: 2623-7.
    CrossrefPubMedGoogle Scholar
  • 10 Weiss EJ, Bray PF, Tayback M, Schulman SP, Kickler TS, Becker LC, Weiss JI, Gerstenblith G, Goldschmidt-Clermont PJ. A polymorphism of a platelet glycoprotein receptor as an inherited risk factor for coronary thrombosis. N Engl J Med 1996; 334: 1090-4.
    CrossrefPubMedGoogle Scholar
  • 11 Doggen CJM, Cats VM, Bertina RM, Rosendaal FR. Interaction of coagulation defects and cardiovascular risk factors. Increased risk of myocardial infarction associated with factor V Leiden and prothrombin 20210A. Circulation 1998; 97: 1037-41.
    CrossrefPubMedGoogle Scholar
  • 12 Arruda VR, von Zuben PM, Chiaparini LC, Annichino-Bizzacchi JM, Costa FF. The mutation Ala677R Val in the methylene tetrahydrofolate reductase gene: A risk factor for arterial disease and venous thrombosis. Thromb Haemost 1997; 77: 818-21.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Morita H, Taguchi J, Kurihara H, Kitaoka M, Kaneda H, Kurihara Y, Maemura K, Shindo T, Minamino T, Ohno M, Yamaoki K, Ogasawara K, Aizawa T, Suzuki S, Yazaki Y. Genetic polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR) as a risk factor for coronary heart disease. Circulation 1997; 95: 2032-6.
    CrossrefPubMedGoogle Scholar
  • 14 Cambien F, Poirier O, Lecerf L, Evans A, Cambou JP, Arvoiler D, Luc G, Bard JM, Bara L, Ricard S, Tiret L, Amouyel P, Alhenc-Gelas F, Soubrier F. Deletion polymorphism in the gene coding for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature 1992; 359: 641-4.
    CrossrefPubMedGoogle Scholar
  • 15 Nakai K, Itoh C, Miura Y, Hotta K, Musha T, Itoh T, Miyakawa T, Iwasaki R, Hiramori K. Deletion polymorphism of the angiotensin I-converting enzyme gene is associated with serum ACE concentrations and increased risk for CAD in the Japanese. Circulation 1994; 90: 2199-202.
    CrossrefPubMedGoogle Scholar
  • 16 Samani NJ, Thompson JR, O’Toole L, Channer K, Woods KL. A metaanalysis of the association of the deletion allele of the angiotensin-converting enzyme gene with myocardial infarction. Circulation 1996; 94: 708-12.
    CrossrefPubMedGoogle Scholar
  • 17 Evans AE, Poirier O, Kee F, Lecerf L, McCrum E, Falconer T, Crane J, O’Rourke DF, Cambien F. Polymorphisms of the angiotensin-converting-enzyme gene in subjects who die from coronary heart disease. Q J Med 1994; 87: 211-4.
    PubMedGoogle Scholar
  • 18 Katsuya T, Koike G, Yee TW, Sharpe N, Jackson R, Norton R, Horiuchi M, Pratt RE, Dzau VJ, MacMahon S. Association of angiotensinogen gene T235 variant with increased risk of coronary heart disease. Lancet 1995; 345: 1600-3.
    CrossrefPubMedGoogle Scholar
  • 19 Ridker PM, Baker MT, Charles HH, Stampfer MJ, Vaughan DE. Alu-repeat polymorphism in the gene coding for tissue-type plasminogen activator (t-PA) and risks of myocardial infarction among middle-aged men. Arterioscler Thromb Vasc Biol 1997; 17: 1687-90.
    PubMedGoogle Scholar
  • 20 Lindpaintner K, Pfeffer MA, Kreutz R, Stampfer MJ, Grodstein F, LaMotte F, Buring J, Hennekens CH. A prospective evaluation of an angiotensin-converting-enzyme gene polymorphism and the risk of ischaemic heart disease. N Engl J Med 1995; 332: 706-11.
    CrossrefPubMedGoogle Scholar
  • 21 Agerholm-Larsen B, Nordestgaard BG, Steffensen R, Sørensen TIA, Jensen G, Tybjærg-Hansen A. ACE gene polymorphism: Ischaemic heart disease and longevity in 10150 individuals. A case-referent and retrospective cohort study based on the Copenhagen City Heart Study. Circulation 1997; 95: 2358-67.
    CrossrefPubMedGoogle Scholar
  • 22 Ridker PM, Hennekens CH, Schmidtz C, Stampfer MJ, Lindpainter K. PlA1/A2 polymorphism of platelet glycoprotein llla and risks of myocardial infarction, stroke, and venous thrombosis. Lancet 1997; 349: 385-8.
    CrossrefPubMedGoogle Scholar
  • 23 Lane A, Green F, Scarabin PY, Nicaud V, Bara L, Humphries S, Evans A, Luc G, Cambou JP, Arveiler D, Cambien F. Factor VII Arg/Gln353 polymorphism determines factor VII coagulant activity in patients with myocardial infarction (MI) and control subjects in Belfast and in France but is not a strong indicator of MI risk in the ECTIM study. Atherosclerosis 1996; 119: 119-27.
    CrossrefPubMedGoogle Scholar
  • 24 Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Miletich JP. Arterial and venous thrombosis is not associated with the 4G/5G polymorphism in the promoter of the plasminogen activator inhibitor gene in a large cohort of US men. Circulation 1997; 95: 59-62.
    CrossrefPubMedGoogle Scholar
  • 25 Ye S, Green FR, Scarabin PY, Nicaud V, Bara L, Dawson SJ, Humphries SE, Evans A, Luc G, Cambou JP, Arveiler D, Henney AM, Cambien F. The 4G/5G genetic polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene is associated with differences in plasma PAI-1 activity but not with risk of myocardial infarction in the ECTIM Study. Thromb Haemost 1995; 74: 837-41.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Ma J, Stampfer MJ, Hennekens CH, Frosst P, Selhub J, Horsford J, Malinow R, Willett WC, Rozen R. Methylenetetrahydrofolate reductase polymorphism, plasma folate, homocysteine, and risk of myocardial infarction in US physicians. Circulation 1996; 94: 2410-6.
    CrossrefPubMedGoogle Scholar
  • 27 Tybjærg-Hansen A, Agerholm-Larsen B, Humphries SE, Abildgaard S, Schnohr P, Nordestgaard BG. A common mutation (G-455R A) in the β-fibrinogen promoter is an independent predictor of plasma fibrinogen, but not of ischaemic heart disease. J Clin Invest 1997; 99: 3034-9.
    CrossrefPubMedGoogle Scholar
  • 28 Doggen CJM, Manger Cats V, Bertina RM, Reitsma PH, Vandenbroucke JP, Rosendaal FR. A genetic propensity to high factor VII is not associated with the risk of myocardial infarction in men. Thromb Haemost 1998; 80: 281-5.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 De Maat MPM, Green F, de Knijff P, Jespersen J, Kluft C. Factor VII polymorphisms in populations with different risks of cardiovascular disease. Arterioscler Thromb Vasc Biol 1997; 17: 1918-23.
    CrossrefPubMedGoogle Scholar
  • 30 Green F, Kelleher C, Wilkes H, Temple A, Meade T, Humphries S. A common genetic polymorphism associated with lower coagulation factor VII levels in healthy individuals. Arterioscler Thromb 1991; 11: 540-6.
    CrossrefPubMedGoogle Scholar
  • 31 Humphries S, Temple A, Lane A, Green F, Cooper J, Miller G. Low plasma levels of factor VIIc and antigen are more strongly associated with the 10 base pair promoter (-323) insertion than the glutamine 353 variant. Thromb Haemost 1996; 75: 567-72.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 32 Marchetti G, Gemmati D, Patracchini P, Pinotti M, Bernardi F. PCR detection of a repeat polymorphism within the F7 gene. Nucleic Acid Res 1991; 19: 4570.
    PubMedGoogle Scholar
  • 33 Thomas AE, Green FR, Kelleher CH, Wilkes HC, Brennan PJ, Meade TW, Humphries SE. Variation in the promoter region of the ß fibrinogen gene is associated with plasma fibrinogen levels in smokers and non-smokers. Thromb Haemost 1991; 65: 487-90.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 34 Mansfield MW, Stickland MH, Grant P. Environmental and genetic factors in relation to elevated circulating levels of plasminogen activator inhibitor-1 in Caucasian patients with non-insulin-dependent diabetes mellitus. Thromb Haemost 1995; 74: 842-7.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 35 Ludwig M, Wohn K-D, Schleuning W-D, Olek K. Allelic dimorphism in the human tissue-type plasminogen activator (TPA) gene as a result of an Alu insertion/deletion event. Hum Genet 1992; 88: 388-92.
    CrossrefPubMedGoogle Scholar
  • 36 Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88: 3698-703.
    PubMedGoogle Scholar
  • 37 Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJH, den Heijer M, Kluijtmans LAJ, van den Heuvel LP, Rozen R. A candidate genetic risk factor for cardiovascular disease: a common mutation in methylenetetrahydrofolate reductase. Nature Genetics 1995; 10: 111-3.
    CrossrefPubMedGoogle Scholar
  • 38 Rees DC, Liu YT, Cox MJ, Elliott P, Wainscoat JS. Factor V Leiden and thermolabile methylenetetrahydrofolate reductase in extreme old age. Thromb Haemost 1997; 78: 1357-9
    Article in Thieme ConnectPubMedGoogle Scholar
  • 39 Heijmans BT, Kluft C, Knook DL, Westendorp RGJ, Slagboom PE. Association studies of the 4G/5G polymorphism in the promoter of the plasminogen activator inhibitor gene with mortality. Proteolysis 1999; 13: 53.
    PubMedGoogle Scholar
  • 40 Mannucci PM, Mari D, Merati G, Payvandi F, Tagliabue L, Sacchi E, Taioli E, Sansoni P, Bertolini S, Franceschi C. Gene polymorphisms predicting high plasma levels of coagulation and fibrinolysis proteins. Arterioscler Thromb Vasc Biol 1997; 17: 755-9.
    CrossrefPubMedGoogle Scholar
  • 41 Olsen H, Jeune B, Andersen-Ranberg K. Centenarians in a county of Denmark. Morbidity and functional capacity. Ugeskr Læger 1996; 158: 7397-401.
    PubMedGoogle Scholar
  • 42 Mari D, Mannucci PM, Coppola R, Bottasso B, Bauer KA, Rosenberg RD. Hypercoagulability in centenarians: the paradox of successful aging. Blood 1995; 85: 3144-9.
    PubMedGoogle Scholar
  • 43 Coppola R, Cristilli P, Cugno M, Ariens RA, Mari D, Mannucci PM. Measurement of activated FXII in health and disease. Blood Coagul Fibrinolysis 1996; 7: 530-5.
    CrossrefPubMedGoogle Scholar
  • 44 Weverling-Rijnsburger AWE, Blauw GJ, Lagaay AM, Knook DL, Meinders AE, Westendorp RGJ. Total cholesterol and risk of mortality in the oldest old. Lancet 1997; 350: 1119-23.
    CrossrefPubMedGoogle Scholar