Evidence from case–control and longitudinal studies supports associations of genetic variation in APOE, CETP, and IL6 with human longevity

Soerensen, Mette; Dato, Serena; Tan, Qihua; Thinggaard, Mikael; Kleindorp, Rabea; Beekman, Marian; Suchiman, H. Eka D.; Jacobsen, Ramunė; McGue, Matt; Stevnsner, Tinna; Bohr, Vilhelm A.; Craen, Anton J. M. de; Westendorp, Rudi G.J.; Schreiber, Stefan; Slagboom, P. Eline; Nebel, Almut; Vaupel, James W.; Christensen, Kaare; Christiansen, Lene

doi:10.1007/s11357-011-9373-7

Cited by 81 publications

(57 citation statements)

References 77 publications

(78 reference statements)

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“…A post hoc analysis of the APOE epsilon variants and the remaining phenotypes of the present study did not show significance when considering the number of variants tested (data not shown). Moreover, APOE -rs769449, which was associated with longevity in the discovery cohort in our previous study (Soerensen et al, 2013), and was found to be in modest LD (R 2 =0.55) with the APOE ε4 defining variant rs429358 (Soerensen et al, 2013), displayed no significant associations in the present study when considering correction for multiple testing (see Supplementary Table 2). Hence, the lack of association to the aging phenotypes of the present study could imply that rs769449 and the APOE epsilon variants mediate their effects on longevity via other aging related phenotypes than those investigated in the present study, or it could indicate that the effect sizes are too modest to display significance.…”

Section: Discussioncontrasting

confidence: 55%

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No Association between Variation in Longevity Candidate Genes and Aging-related Phenotypes in Oldest-old Danes

Soerensen

Nygaard

Debrabant

et al. 2016

Experimental Gerontology

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In this study we explored the association between aging-related phenotypes previously reported to predict survival in old age and variation in 77 genes from the DNA repair pathway, 32 genes from the growth hormone 1/insulin-like growth factor 1/insulin (GH/IGF-1/INS) signalling pathway and 16 additional genes repeatedly considered as candidates for human longevity: APOE, APOA4, APOC3, ACE, CETP, HFE, IL6, IL6R, MTHFR, TGFB1, SIRTs 1, 3, 6; and HSPAs 1A, 1L, 14. Altogether, 1,049 single nucleotide polymorphisms (SNPs) were genotyped in 1,088 oldest-old (age 92–93 years) Danes and analysed with phenotype data on physical functioning (hand grip strength), cognitive functioning (mini mental state examination and a cognitive composite score), activity of daily living and self-rated health. Five SNPs showed association to one of the phenotypes; however, none of these SNPs were associated with a change in the relevant phenotype over time (7 years of follow-up) and none of the SNPs could be confirmed in a replication sample of 1,281 oldest-old Danes (age 94–100). Hence, our study does not support association between common variation in the investigated longevity candidate genes and aging-related phenotypes consistently shown to predict survival. It is possible that larger sample sizes are needed to robustly reveal associations with small effect sizes.

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Section: Discussioncontrasting

confidence: 55%

“…The selection of genes and gene variants, and the generation of genotype data in the discovery sample are described in detail in (Soerensen et al, 2012, Soerensen et al, 2013 and Supplementary Information). The SNPs were primarily chosen to be tagging SNPs with an R 2 >0.8.…”

Section: Methodsmentioning

confidence: 99%

No Association between Variation in Longevity Candidate Genes and Aging-related Phenotypes in Oldest-old Danes

Soerensen

Nygaard

Debrabant

et al. 2016

Experimental Gerontology

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“…Investigations of both monogenic CETP deficiency and polymorphisms in the CETP gene provided controversial evidence. Some studies reported reduced cardiovascular disease risk and prolonged life expectancy in individuals with CETP mutants, [193][194][195][196] others did not find any impact or even increased cardiovascular risk. 197,198 Previous meta-analyses of genetic studies, provided compelling evidence that polymorphisms that are associated with reduced CETP activity and increased HDL-cholesterol levels are also associated with reduced cardiovascular risk.…”

Section: Fibratesmentioning

confidence: 98%

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

Annema

Eckardstein

2016

Translational Research

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Low plasma levels of high-density lipoprotein (HDL) cholesterol are associated with increased risks of coronary heart disease. HDL mediates cholesterol efflux from macrophages for reverse transport to the liver and elicits many anti-inflammatory and anti-oxidative activities which are potentially antiatherogenic. Nevertheless, HDL has not been successfully targeted by drugs for prevention or treatment of cardiovascular diseases. One potential reason is the targeting of HDL cholesterol which does not capture the structural and functional complexity of HDL particles. Hundreds of lipid species and dozens of proteins as well as several microRNAs have been identified in HDL. This physiological heterogeneity is further increased in pathologic conditions due to additional quantitative and qualitative molecular changes of HDL components which have been associated with both loss of physiological function and gain of pathologic dysfunction. This structural and functional complexity of HDL has prevented clear assignments of molecules to the functions of normal HDL and dysfunctions of pathologic HDL. Systematic analyses of structure-function relationships of HDL-associated molecules and their modifications are needed to test the different components and functions of HDL for their relative contribution in the pathogenesis of atherosclerosis. The derived biomarkers and targets may eventually help to exploit HDL for treatment and diagnostics of cardiovascular diseases.

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“…Interestingly, Poolseq with target region including regulatory region such as proximal upstream and intronic region identified longevity-associated common variants, rs405509 and rs769449 that were previously associated with longevity and other aging-related disease phenotypes (Lu et al, 2014; Soerensen et al, 2013). They are also predicted (Supplementary Figure 2) and experimentally proved (Supplementary Table 3) to be functional, implicating the potential role of regulatory variants in a longevity-association.…”

Section: Descriptionmentioning

confidence: 99%

Genetic landscape of APOE in human longevity revealed by high-throughput sequencing

Ryu

Atzmon

Barzilai

et al. 2016

Mechanisms of Ageing and Development

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Apolipoprotein E (APOE) gene has been the most replicated longevity-associated gene in humans. Two common APOE alleles are either significantly depleted (ε4 allele) or enriched (ε2 allele) in long-lived individuals as compared to controls. We performed high-throughput sequencing analysis of exons and 2 kb proximal promoter of APOE in 450 centenarians and 500 controls of Ashkenazi Jewish decent. We found two common regulatory variants, rs405509 (p=0.006) and rs769449 (p=0.036), that were significantly depleted in centenarians. Genotyping analysis of rs7412 and rs429358 showed significant enrichment of ε2 allele (p=0.003) and ε2/ε3 genotype (p= 0.005), and significant depletion of ε3/ε4 genotype (p=0.005) in centenarians. Our findings support the hypothesis that variants in both coding and regulatory regions of APOE may contribute to longevity in humans.

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Evidence from case–control and longitudinal studies supports associations of genetic variation in APOE, CETP, and IL6 with human longevity

Cited by 81 publications

References 77 publications

No Association between Variation in Longevity Candidate Genes and Aging-related Phenotypes in Oldest-old Danes

No Association between Variation in Longevity Candidate Genes and Aging-related Phenotypes in Oldest-old Danes

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

Genetic landscape of APOE in human longevity revealed by high-throughput sequencing

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