Genetic associations with human longevity at the APOE and ACE loci

Schächter, François; Faure-Delanef, Laurence; Guénot, Frédérique; Rouger, H.; Froguel, Philippe; Lesueur‐Ginot, Laurence; Cohen, Daniel

doi:10.1038/ng0194-29

Cited by 1,007 publications

(561 citation statements)

References 29 publications

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“…ACE polymorphisms have been associated with cardiovascular disease as well as longevity. 33 It is therefore not surprising that some of the SNPs in a gene associated with both depression and cardiovascular disease would be out of HWE in a group of individuals with a low prevalence of both disorders.…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms in the angiotensin-converting enzyme gene are associated with unipolar depression, ACE activity and hypercortisolism

et al. 2006

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Angiotensin-converting enzyme (ACE) is assumed to influence the activity of the hypothalamic-pituitary-adrenocortical (HPA) system, which shows hyperactivity in the majority of patients with major depression. The ACE gene, known to be associated with cardiovascular disorders, which in turn are accompanied with an increased susceptibility for depression, is therefore a promising candidate gene for affective disorders. We investigated the genetic association between 35 single-nucleotide polymorphisms (SNPs) and an insertion/deletion (I/D)-polymorphism in the ACE gene and the susceptibility for unipolar major depression together with the genetic association with ACE serum activity and functional parameters of the HPA system. Two independent case/control samples with a total of 843 unrelated unipolar depressed patients and 1479 healthy controls were investigated. A case/control sample was screened to detect genetic associations with unipolar major depression. In addition, a replication sample was used to confirm the detected associations and to further investigate functional consequences of the genetic variants associated with depression. In the screening sample, two SNPs within the ACE gene were significantly associated with unipolar major depression. The association with unipolar major depression of one SNP (rs4291) located in the promoter region of the ACE gene was confirmed in our replication sample. The T-allele of this SNP was associated with depression and depressed T-allele carriers showed higher ACE serum activity and HPA-axis hyperactivity. Variants of the ACE gene such as SNP rs4291 are suggested susceptibility factors for unipolar major depression. We could show that SNP rs4291 influences ACE activity and HPA-axis hyperactivity and might therefore represent a common pathophysiologic link for unipolar depression and cardiovascular disease.

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Section: Discussionmentioning

confidence: 99%

Polymorphisms in the angiotensin-converting enzyme gene are associated with unipolar depression, ACE activity and hypercortisolism

et al. 2006

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“…Overall the apoE e4 genotype is associated with increased morbidity and mortality in the elderly and the allele frequency is significantly declining from 85 years of age (35,36) . The influence of the e4 allele on mortality is even increasing in advanced age (92-103 years) (37) .…”

Section: Proceedings Of the Nutrition Societymentioning

confidence: 99%

ApoE genotype: from geographic distribution to function and responsiveness to dietary factors

2012

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ApoE is a key protein in lipid metabolism with three major isoforms. ApoE allele frequencies show non-random global distribution especially in Europe with high apoE e3 frequency in the Mediterranean area, whereas the apoE e4 genotype is enriched in Northern Europe. The apoE e4 genotype is one of the most important genetic risk factors for age-dependent chronic diseases, including CVD and Alzheimer's disease (AD). The apoE polymorphism has been shown to impact on blood lipids, biomarkers of oxidative stress and chronic inflammation, which all may contribute to the isoform-dependent disease risk. Studies in mice and human subjects indicate that the apoE e3 but not the apoE e4 genotype may significantly benefit from dietary flavonoids (e.g. quercetin) and n-3 fatty acids. Metabolism of lipid soluble vitamins E and D is likewise differentially affected by the apoE genotype. Epidemiological and experimental evidence suggest a better vitamin D status in apoE e4 than e3 subjects indicating a certain advantage of e4 over e3. The present review aims at evaluation of current data available on interactions between apoE polymorphism and dietary responsiveness to flavonoids, fat soluble vitamins and n-3 fatty acids. Likewise, distinct geographic distribution and chronic disease risk of the different apoE isoforms are addressed.

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“…Despite more than 20 years of research into the genetic basis of human longevity, only alleles in the APOE and FOXO3 genes have repeatedly been shown to be associated with survival to very advanced ages (Schächter et al ., 1994; Willcox et al ., 2008; Flachsbart et al ., 2009; Soerensen et al ., 2010; Deelen et al ., 2013). APOE and FOXO3 were initially detected in candidate‐driven case–control investigations, but APOE has since then been confirmed in a number of genome‐wide association studies (GWAS).…”

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confidence: 99%

“…aSNP rs2075650 was not considered for replication in this study, because the association at 19q31.32 was already established in the French sample (Schächter et al ., 1994) and parts of the Danish sample (Soerensen et al ., 2010). …”

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confidence: 99%

Immunochip analysis identifies association of the RAD 50/ IL 13 region with human longevity

et al. 2016

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SummaryHuman longevity is characterized by a remarkable lack of confirmed genetic associations. Here, we report on the identification of a novel locus for longevity in the RAD50/IL13 region on chromosome 5q31.1 using a combined European sample of 3208 long‐lived individuals (LLI) and 8919 younger controls. First, we performed a large‐scale association study on 1458 German LLI (mean age 99.0 years) and 6368 controls (mean age 57.2 years) by targeting known immune‐associated loci covered by the Immunochip. The analysis of 142 136 autosomal single nucleotide polymorphisms (SNPs) revealed an Immunochip‐wide significant signal (PI mmunochip = 7.01 × 10–9) for the SNP rs2075650 in the TOMM40/APOE region, which has been previously described in the context of human longevity. To identify novel susceptibility loci, we selected 15 markers with PI mmunochip < 5 × 10–4 for replication in two samples from France (1257 LLI, mean age 102.4 years; 1811 controls, mean age 49.1 years) and Denmark (493 LLI, mean age 96.2 years; 740 controls, mean age 63.1 years). The association at SNP rs2706372 replicated in the French study collection and showed a similar trend in the Danish participants and was also significant in a meta‐analysis of the combined French and Danish data after adjusting for multiple testing. In a meta‐analysis of all three samples, rs2706372 reached a P‐value of PI mmunochip+Repl = 5.42 × 10−7 (OR = 1.20; 95% CI = 1.12–1.28). SNP rs2706372 is located in the extended RAD50/IL13 region. RAD50 seems a plausible longevity candidate due to its involvement in DNA repair and inflammation. Further studies are needed to identify the functional variant(s) that predispose(s) to a long and healthy life.

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Genetic associations with human longevity at the APOE and ACE loci

Cited by 1,007 publications

References 29 publications

Polymorphisms in the angiotensin-converting enzyme gene are associated with unipolar depression, ACE activity and hypercortisolism

Polymorphisms in the angiotensin-converting enzyme gene are associated with unipolar depression, ACE activity and hypercortisolism

ApoE genotype: from geographic distribution to function and responsiveness to dietary factors

Immunochip analysis identifies association of the RAD 50/ IL 13 region with human longevity

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