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Genetic associations with human longevity at the APOE and ACE loci

Abstract

In an effort to dissect the genetic components of longevity, we have undertaken case–control studies of populations of centenarians (n=338) and adults aged 20–70 years at several polymorphic candidate gene loci. Here we report results on two genes, chosen for their impact on cardiovascular risk, encoding apolipoprotein E (ApoE), angiotensin–converting enzyme (ACE). We find that the ε4 allele of APOE, which promotes premature atherosclerosis, is significantly less frequent in centenarians than in controls (p<0.001), while the frequency of the ε2 allele, associated previously with type III and IV hyperlipidemia, is significantly increased (p<0.01). A variant of ACE which predisposes to coronary heart disease is surprisingly more frequent in centenarians, with a significant increase of the homozygous genotype (p<0.01). These associations provide examples of genetic influences on differential survival and may point to pleiotropic age–dependent effects on longevity.

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References

  1. Abbott, M.H., Murphy, E.A., Bolling, D.R. & Abbey, H. The familial component in longevity, a study of the offspring of nonagenarians II. Preliminary analysis of the completed study. Johns Hopkins med. J. 134, 1–16 (1974).

    CAS  PubMed  Google Scholar 

  2. Finch, C.E. Genetic influences on lifespan, mortality rates, and age-related diseases. In Longevity, senescence and the genome, p. 298–352 (University of Chicago Press, Chicago, 1990).

    Google Scholar 

  3. Schächter, F. & Cohen, D. Longevity: a new field for human genetics. Lifespan 4, 1–3 (1993).

    Google Scholar 

  4. Schächter, F., Cohen, D. & Kirkwood, T.B.L. Prospects for the genetics of human longevity.Human Genetics 91, 519–526 (1993).

    Article  PubMed  Google Scholar 

  5. Proust, J. et al. HLA and longevity. Tissue Antigens 19, 168–173 (1982).

    CAS  Article  PubMed  Google Scholar 

  6. Takata, H., Ishii, T., Suzuki, M., Sekiguchi, S. & Iri, H. Influence of major histocompatibllity complex region genes on human longevity among Okinawan-Japanese centenarians and nonagenarians. Lancet ii, 824–826 (1987).

    Article  Google Scholar 

  7. Hatton, F. & Michel, E. Les causes de mortalité en 1990. Insee première 196, mai 1992.

  8. Zannis, I. et al. Proposed nomenclature of apoE isoproteins, apoE genotypes and phenotypes. J. lipid Res. 23, 911–914 (1982).

    CAS  PubMed  Google Scholar 

  9. Davignon, J., Gregg, R.E. & Sing, C.F. Apolipoprotein E polymorphism and atherosclerosis. Arteriosclerosis 8, 1–21 (1988).

    CAS  Article  PubMed  Google Scholar 

  10. Van Bockxmeer, F.M. & Mamotte, C.D.S. Apolipoprotein ε4 homozygosity in young men with coronary heart disease. Lancet 340, 879–880 (1992).

    CAS  Article  PubMed  Google Scholar 

  11. Eto, M., Watanabe, K. & Makino, I. Increased frequencies of apolipoprotein ε2 and ε4 alleles In patients with ischemic heart disease. Clin. Genet. 36, 183–188 (1989).

    CAS  Article  PubMed  Google Scholar 

  12. Tiret, L. et al. Evidence, from combined segregation and linkage anylysis, that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels. Am. J. hum. Genet. 51, 197–205 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Cambien, F. et al. Deletion polymorphism in the gene coding for angiotensin-oonverting enzyme is a potent risk factor for myocardial infarction. Nature 359, 641–644 (1992).

    CAS  Article  PubMed  Google Scholar 

  14. Tiret, L. et al. Deletion polymorphism in angiotensin-converting enzyme gene associated with parental history of myocardial infarction. Lancet 341, 991–992 (1993).

    CAS  Article  PubMed  Google Scholar 

  15. Hixson, J.E. & Vernier, D.T. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J. lipid Res. 31, 545–548 (1990).

    CAS  PubMed  Google Scholar 

  16. Rigat, B., Hubert, C., Corvol, P. & Soubrier, F. PCR detection of the insertion/deletion polymorphism of the human angiotensin converting enzyme gene. Nucl. Acids Res. 20, 1433 (1992).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Bailleul, S. et al. Direct phenotyping of human apolipoprotein E in plasma: application to population frequency distribution in Paris (France). Hum. Hered. 43, 159–165 (1993).

    CAS  Article  PubMed  Google Scholar 

  18. Boerwinkle, E., Lee, S.S., Butler, R., Schumaker, V.N. & Chan, L. Rapid typing of apolipoprotein BDNA polymorphisms by DNA amplification. Atherosclerosis 81, 225 (1990).

    CAS  Article  PubMed  Google Scholar 

  19. Peacock, R. et al. Apolipoprotein B gene polymorphisms, lipoproteins and coronary atherosclerosis: A study of young myocardial infarction survivors and healthy population-based individuals. Atherosclerosis 92, 151–164 (1992).

    CAS  Article  PubMed  Google Scholar 

  20. Andrew, S. et al. Nonrandom association between Huntington disease and two loci separated by about 3 Mb on 4p16.3. Genomics 13, 301–311 (1992).

    CAS  Article  PubMed  Google Scholar 

  21. Weber, J.L. & May, P.E. Abundant class of human DNA polymorphisms which can be typed using the polymerase chain reaction. Am. J. hum. Genet. 44, 388–396 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Fries, J.F. Aging, natural death and the compression of morbidity. New Engl. J. Med. 303, 130 (1980).

    CAS  Article  PubMed  Google Scholar 

  23. Ordovas, J.M., Litwack-Klein, L., Wilson, P.W.F., Schaefer, M.M. & Schaefer, E.J. Apolipoprotein E isoform phenotyping methodology and population frequency with identification of apoE1 and apoE5 isoforms. J. lipid Res. 28, 371–380 (1987).

    CAS  PubMed  Google Scholar 

  24. Utermann, G., Steinmetz, A. & Weber, W. Genetic control of human apolipoprotein E polymorphism: comparison one- and two-dimensionai techniques of isoprotein analysis. Hum. Genet. 60, 344–351 (1982).

    CAS  Article  PubMed  Google Scholar 

  25. Boemi, M. et al. Gender differences in a type 2 (non-insulin-dependent) diabetic population with respect to apolipoprotein E phenotype frequencies. Diabetologia 36, 229–233 (1993).

    CAS  Article  PubMed  Google Scholar 

  26. Jeunemaître, X., Lifton, R.P., Hunt, S.C., Williams, R.R. & Lalouel, J.M. Absence of linkage between the angiotensin converting enzyme locus and human essential hypertension. Nature Genet. 1, 72–75 (1992).

    Article  PubMed  Google Scholar 

  27. Ehlers, M.R.W. & Riordan, J.F. Angiotensin-converting enzyme: new concepts concerning its biological role. Biochemistry 28, 5311–5313 (1989).

    CAS  Article  PubMed  Google Scholar 

  28. Costerousse, O., Jaspard, E., Wei, L., Corvol, P. & Alhene-Gelas, F. The angiotensin I-converting enzyme (kininase II): molecular organization and regulation of its expression in humans. J. cardiovasc. Pharmacol. 20 (suppl. 9), S10–S15 (1992).

    CAS  Article  PubMed  Google Scholar 

  29. McGeer, E.G. & Singh, E.A. Angiotensin-converting enzyme in cortical tissue in Alzheimer's and some other neurological diseases. Dementia 3, 299–303 (1992).

    Google Scholar 

  30. Eisenlohr, L.C., Bacik, I., Bennink, J.R., Bernstein, K. & Yewdell, J.W. Expression of a membrane protease enhances presentation of endogenous antigens to MHC class I-restricted T lymphocytes. Cell 71, 963–972 (1992).

    CAS  Article  PubMed  Google Scholar 

  31. Jorgensen, J.O.L. & Christiansen, J.S. Brave new senescence: GH therapy in adults. Lancet 341, 1247 (1993).

    CAS  Article  PubMed  Google Scholar 

  32. Donald, J.A. et al. Linkage relationships of the gene for apolipoprotein CII with loci on chromosome 19. Hum. Genet. 69, 39–43 (1985).

    CAS  Article  PubMed  Google Scholar 

  33. Strittmatter, W.J. et al. Apolipoprotein E: high avidity binding to β-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc. natn Acad. Sci. U.S.A. 90, 1977–1981 (1993).

    CAS  Article  Google Scholar 

  34. Corder, E.H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261, 921–923 (1993).

    CAS  Article  PubMed  Google Scholar 

  35. Skoog, I., Nilsson, L., Palmertz, B., Andreasson, L.A., Svanborg, A. A population-based study of dementia in 85-year-olds. New Engl. J. Med. 328, 153–158 (1993).

    CAS  Article  PubMed  Google Scholar 

  36. Kirkwood, T.B.L. & Rose, M.R. Evolution of senescence: late survival sacrificed for reproduction. Phil. Trans. R. Soc. Lond. B 332: 15–24 (1991).

    CAS  Article  Google Scholar 

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Schächter, F., Faure-Delanef, L., Guénot, F. et al. Genetic associations with human longevity at the APOE and ACE loci. Nat Genet 6, 29–32 (1994). https://doi.org/10.1038/ng0194-29

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