Lipid & Longevity Variants (APOE, FOXO3) - References

Lipid & Longevity Variants (APOE, FOXO3) — Literature Dossier

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• Backed Topic Note: Lipid & Longevity Variants (APOE, FOXO3)
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Landmark Peer-Reviewed Studies

1. Willcox et al. (2008) — FOXO3A Genotype and Extreme Human Longevity

• Citation: Willcox, B. J., Donlon, T. A., He, Q., Chen, R., Grove, J. S., Yano, K., … & Curb, J. D. (2008). FOXO3A genotype is strongly associated with human longevity. Proceedings of the National Academy of Sciences, 105(37), 13987–13992.
• Identifiers: DOI: 10.1073/pnas.0801030105 (DOI · SciDB · Scholar) | PMID: 18765803 (PubMed · Europe PMC) | PMCID: PMC2544566 (PMC Full Text)
• Study Design & Cohort: Prospective nested case-control study within the Kuakini Honolulu Heart Program ($N=615$ long-lived men aged $\ge 95$ vs. average-lived controls).
• Quantitative Findings & Diagnostic Thresholds:
  • For FOXO3A rs2802292: Heterozygotes (G/T) had an Odds Ratio of $1.91$ ($p=0.0003$) and homozygotes (G/G) had an Odds Ratio of $2.75$ ($95\%\text{ CI }1.51–5.02$, $p=0.0007$) for surviving to $\ge 95\text{ years}$.
  • G-allele carriers exhibited significantly lower fasting insulin ($p<0.05$), lower HOMA-IR, and markedly lower prevalence of coronary heart disease and cancer.

2. Deelen et al. (2019) — Meta-Analysis of Genome-Wide Association Studies of Human Longevity

• Citation: Deelen, J., Evans, D. S., Arking, D. E., Tesi, N., Nygaard, M., Liu, X., … & Slagboom, P. E. (2019). A meta-analysis of genome-wide association studies identifies multiple longevity genes. Nature Communications, 10(1), 3669.
• Identifiers: DOI: 10.1038/s41467-019-11558-2 (DOI · SciDB · Scholar) | PMID: 31413261 (PubMed · Europe PMC) | PMCID: PMC6694108 (PMC Full Text)
• Study Design & Cohort: International multi-consortium GWAS meta-analysis ($N=11,262$ cases surviving at or beyond the 90th and 99th survival percentile vs. $25,483$ controls across 20 cohorts).
• Quantitative Findings & Diagnostic Thresholds:
  • APOE $\epsilon 4$ (rs429358): Strongly reduced odds of surviving to the 90th percentile ($\text{OR }0.64$, $p=1.9\times 10^{-44}$) and 99th percentile ($\text{OR }0.48$, $p=1.1\times 10^{-29}$).
  • APOE $\epsilon 2$ (rs7412): Significantly increased odds of surviving to the 90th percentile ($\text{OR }1.28$) and 99th percentile ($\text{OR }1.59$, $p=1.7\times 10^{-17}$).

3. Belloy et al. (2020) — Klotho KL-VS Heterozygosity Attenuates APOE4 Alzheimer’s Risk

• Citation: Belloy, M. E., Napolioni, V., Han, S. S., Le Guen, Y., Greicius, M. D., & Alzheimer’s Disease Neuroimaging Initiative. (2020). Association of Klotho-VS Heterozygosity With Risk of Alzheimer Disease in Individuals Who Carry APOE4. JAMA Neurology, 77(7), 849–862.
• Identifiers: DOI: 10.1001/jamaneurol.2020.0414 (DOI · SciDB · Scholar) | PMID: 32282020 (PubMed · Europe PMC) | PMCID: PMC7154955 (PMC Full Text)
• Study Design & Cohort: Case-control and longitudinal survival/PET-amyloid meta-analysis across 25 cohorts ($N=22,748$ non-Hispanic white participants aged $\ge 60$).
• Quantitative Findings & Diagnostic Thresholds:
  • Among APOE4 carriers aged $60–80$, KL-VS heterozygosity (rs9536314 F/V) reduced the risk of conversion to mild cognitive impairment or Alzheimer’s disease by 31% ($\text{HR }0.69$, $95\%\text{ CI }0.61–0.79$, $p=3.6\times 10^{-8}$) and completely abrogated APOE4-associated CSF and PET amyloid-$\beta$ pathology ($p=0.003$).

4. Cohen et al. (2006) — PCSK9 Sequence Variations, Lifelong Low LDL-C, and Protection from CHD

• Citation: Cohen, J. C., Boerwinkle, E., Mosley Jr, T. H., & Hobbs, H. H. (2006). Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. New England Journal of Medicine, 354(12), 1264–1272.
• Identifiers: DOI: 10.1056/NEJMoa054013 (DOI · SciDB · Scholar) | PMID: 16554528 (PubMed · Europe PMC)
• Study Design & Cohort: Prospective 15-year follow-up in the Atherosclerosis Risk in Communities (ARIC) cohort ($N=12,887$).
• Quantitative Findings & Diagnostic Thresholds:
  • Carriers of PCSK9 R46L (rs11591147) had a lifelong $15\%$ reduction in LDL-C and a 47% reduction in coronary heart disease ($\text{HR }0.53$, $p=0.003$); carriers of nonsense mutations (Y142X or C679X) had a $28\%$ lifelong reduction in LDL-C and an 88% reduction in CHD ($\text{HR }0.12$, $p=0.008$), validating early lifelong ApoB suppression.