Rare and common variants in the Apolipoprotein E gene in healthy oldest old
Abstract
Apolipoprotein E (APOE) alleles are associated with longevity in genome-wide scans, with ε4 correlated with shorter life, and ε2 with longer life, than ε3. We hypothesized that rare APOE variants with large individual effects might also contribute to long-term good health. The APOE exons and promoter were resequenced in DNA samples from 376 healthy oldest old aged ≥ 85 yrs with no self-reported history of cancer, cardiovascular disease, diabetes, major pulmonary disease or Alzheimer disease ("Super-Seniors") and 376 population-based controls aged 41-54. Forty variants were observed: 32 were rare (minor allele frequency <2%); 9 were nonsynonymous. Controls were more likely to have an ε4 allele (Pearson χ(2) = 6.61, p = 0.04). Among the Super-Seniors, APOE allele status was not associated with body mass index or Mini Mental State Examination score. There was no excess of rare APOE variants in healthy oldest old compared with midlife controls, or vice-versa; however, this does not rule out an effect of some variants on ApoE function. Our findings were consistent with ε4 being a risk factor for early mortality.
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A resequencing study of 376 healthy individuals ≥85 years of age and 376 controls 41 to 54 years of age found no excess of rare variants in the 85+ year olds.
“A resequencing study of 376 healthy individuals ≥85 years of age and 376 controls 41 to 54 years of age found no excess of rare variants in the 85+ year olds. 38”
From <i>APOE</i> and dementia – resequencing and genotyping in 105,597 individuals (2020) · cites this paper as [38]
Cites
A method and server for predicting damaging missense mutations.
Adzhubei, I. A., Schmidt, S., Peshkin, L., Ramensky, V. E., Gerasimova, A., Bork, P., Kondrashov, A. S., & Sunyaev, S. R. (2010) · Nature Methods · doi:10.1038/nmeth0410-248 · Cited by 13,194 · see citing works
Predicting Deleterious Amino Acid SubstitutionsPreprint
Ng, P. C., & Henikoff, S. (2001) · Genome Research · doi:10.1101/gr.176601 · Cited by 2,667 · see citing works
Multiple Rare Alleles Contribute to Low Plasma Levels of HDL Cholesterol
Cohen, J. C., Kiss, R. S., Pertsemlidis, A., Marcel, Y. L., McPherson, R., & Hobbs, H. H. (2004) · Science · doi:10.1126/science.1099870 · Cited by 1,108 · see citing works
Genetic associations with human longevity at the APOE and ACE loci
Schächter, F., Faure-Delanef, L., Guénot, F., Rouger, H., Froguel, P., Lesueur-Ginot, L., & Cohen, D. (1994) · Nature Genetics · doi:10.1038/ng0194-29 · Cited by 1,095 · see citing works
Genetic signatures of exceptional longevity in humans
Sebastiani, P., Solovieff, N., DeWan, A. T., Walsh, K. M., Puca, A., Hartley, S. W., Melista, E., Andersen, S., Dworkis, D. A., Wilk, J. B., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0029848 · Cited by 464 · see citing works
Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia
Johansen, C. T., Wang, J., Lanktree, M. B., Cao, H., McIntyre, A. D., Ban, M. R., Martins, R. A., Kennedy, B. A., Hassell, R. G., Visser, M. E., et al. (2010) · Nature Genetics · doi:10.1038/ng.628 · Cited by 437 · see citing works
Brooks-Wilson, A. R., Kaurah, P., Suriano, G., Leach, S., Senz, J., Grehan, N., Butterfield, Y. S. N., Jeyes, J., Schinas, J., Bacani, J., et al. (2004) · Journal of Medical Genetics · doi:10.1136/jmg.2004.018275 · Cited by 359 · see citing works
Self-citationDeelen, J., Beekman, M., Uh, H., Helmer, Q., Kuningas, M., Christiansen, L., Kremer, D., van der Breggen, R., Suchiman, H. E. D., Lakenberg, N., et al. (2011) · Aging Cell · doi:10.1111/j.1474-9726.2011.00705.x · Cited by 280 · see citing works
Nebel, A., Kleindorp, R., Caliebe, A., Nothnagel, M., Blanché, H., Junge, O., Wittig, M., Ellinghaus, D., Flachsbart, F., Wichmann, H. ‐., et al. (2011) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2011.06.008 · Cited by 201 · see citing works
Yu, C., Seltman, H. J., Peskind, E. R., Galloway, N. M., Zhou, P. X., Rosenthal, E. A., Wijsman, E. M., Tsuang, D. W., Devlin, B., & Schellenberg, G. D. (2007) · Genomics · doi:10.1016/j.ygeno.2007.02.002 · Cited by 155 · see citing works
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Huebbe, P., Nebel, A., Siegert, S., Moehring, J., Boesch, C., Most, E., Pallauf, J., Egert, S., Müller, M. J., Schreiber, S., et al. (2011) · The FASEB Journal · doi:10.1096/fj.11-180935 · Cited by 83 · see citing works
Longevity and the 2 Allele of Apolipoprotein E: The Finnish Centenarians Study
Frisoni, G. B., Louhija, J., Geroldi, C., & Trabucchi, M. (2001) · The Journals of Gerontology Series A · doi:10.1093/gerona/56.2.m75 · Cited by 78 · see citing works
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Halaschek-Wiener, J., Vulto, I. M., Fornika, D., Collins, J. A., Connors, J. M., Le, N. D., Lansdorp, P. M., & Brooks-Wilson, A. R. (2008) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2008.07.004 · Cited by 70 · see citing works
Self-citationBelbin, O., Dunn, J. L., Ling, Y., Morgan, L., Chappell, S., Beaumont, H., Warden, D. R., Smith, D. A., Kalsheker, N. A., & Morgan, K. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddm171 · Cited by 59 · see citing works
Apolipoprotein E and familial longevity
Schupf, N., Barral, S., Perls, T. T., Newman, A. B., Christensen, K., Thyagarajan, B., Province, M. A., Rossi, W. K., & Mayeux, R. P. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.08.019 · Cited by 47 · see citing works
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Halaschek-Wiener, J., Amirabbasi-Beik, M., Monfared, N., Pieczyk, M., Sailer, C., Kollar, A., Thomas, R. E., Agalaridis, G., Yamada, S., Oliveira, L., et al. (2009) · PLoS ONE · doi:10.1371/journal.pone.0006641 · Cited by 47 · see citing works
Self-citationMaloney, B., Ge, Y., Petersen, R. C., Hardy, J., Rogers, J. T., Pérez‐Tur, J., & Lahiri, D. K. (2009) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30973 · Cited by 44 · see citing works
Parra‐Bonilla, G., Arboleda, G., Yunis, J. J., Solano, E., Pardo, R., Arango, G. J., Hedmont, D., & Arboleda, H. (2003) · Neuroscience Letters · doi:10.1016/s0304-3940(03)00816-4 · Cited by 17 · see citing works
Maloney, B., Ge, Y., Petersen, R. C., Hardy, J., Rogers, R., Pérez‐Tur, J., & Lahiri, D. K. (2010) · UCL Discovery (University College London) · Cited by 2 · see citing works
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Lü, F., Guan, H., Gong, B., Liu, X., Zhu, R., Wang, Y., Qian, J., Zhou, T., Lan, X., Wang, P., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0099580 · Cited by 36 · see citing works
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Sena, G. G. S., Camporez, D., dos Santos, L. R., Silva, A. S. D., Pimassoni, L. H. S., Tieppo, A., Batitucci, M. D. C. P., Morelato, R. L., & Paula, F. (2018) · Genetics and Molecular Biology · doi:10.1590/1678-4685-gmb-2017-0169 · Cited by 14 · see citing works
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Rebhun, R. B., York, D. S., Graaf, F. M. D. D., Yoon, P., Batcher, K., Luker, M. E., Ryan, S., Peyton, J. L., Kent, M. S., Stern, J. A., et al. (2023) · GeroScience · doi:10.1007/s11357-023-00968-2 · Cited by 4 · see citing works
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Self-citation
- Authors
- Tindale, L. C., Leach, S., Ushey, K., Daley, D., & Brooks-Wilson, A. R.
- Affiliations
- BC Cancer Agency (CA)
- University of British Columbia (CA)
- Corresponding author
- Brooks-Wilson, Angela R.
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2014-03
- Volume
- 35
- Issue
- 3
- Pages
- 727.e1-727.e3
- ISSN
- 0197-4580 (ISSN-L)
- OpenAlex
- W1988522492
- Cited by
- 14
- References
- 19
- Citations by year
- 2023: 1 · 2022: 1 · 2020: 3 · 2019: 2 · 2018: 2 · 2017: 1 · 2016: 1 · 2015: 1 · 2014: 2
- FWCI
- 0.93
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- apolipoprotein E, rare variants, oldest old, longevity, APOE ε4, APOE ε2, APOE ε3, non-synonymous mutations, body mass index, cognitive function, mortality risk
- MeSH terms
- Adult, Aged, 80 and over, Alleles, Apolipoproteins E, Female, Gene Frequency, Humans, Longevity, Male, Middle Aged, Risk Factors, Genetic Variation, Apolipoprotein E3, Apolipoprotein E2, Genome-Wide Association Study
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