Search

Cytochrome P450 enzymes, especially the CYP2C subfamily, are involved in the generation of reactive oxygen species and are regarded as susceptibility factors for age-related diseases. Furthermore, the CYP2C-encoding genes are known to be highly polymorphic, with a number of variants leading to changes in enzyme activity. These observations prompted us to investigate whether allelic variation in the CYP2C-encoding genes was associated with human longevity. In a comprehensive haplotype tagging approach, we genotyped 56 single nucleotide polymorphisms located in the CYP2C gene family (CYP2C8, CYP2C9, CYP2C18, and CYP2C19) in our extensive collection of 1,384 long-lived individuals (centenarians and nonagenarians) and 945 younger controls. None of the tested single nucleotide polymorphisms showed a significant association with the longevity phenotype at the allele, genotype, or haplotype level. These results suggest that there is no notable influence of sequence variation in the CYP2C genes on longevity in the examined German population

FOXO3 is consistently annotated as a human longevity gene. However, functional variants and underlying mechanisms for the association remain unknown. Here, we perform resequencing of the FOXO3 locus and single-nucleotide variant (SNV) genotyping in three European populations. We find two FOXO3 SNVs, rs12206094 and rs4946935, to be most significantly associated with longevity and further characterize them functionally. We experimentally validate the in silico predicted allele-dependent binding of transcription factors (CTCF, SRF) to the SNVs. Specifically, in luciferase reporter assays, the longevity alleles of both variants show considerable enhancer activities that are reversed by IGF-1 treatment. An eQTL database search reveals that the alleles are also associated with higher FOXO3 mRNA expression in various human tissues, which is in line with observations in long-lived model organisms. In summary, we present experimental evidence for a functional link between common intronic variants in FOXO3 and human longevity., FOXO3 is one of the few established longevity genes. Here, the authors fine-map the FOXO3-longevity association to two intronic SNPs and, using luciferase assays and EMSAs, show that these SNPs affect binding of transcription factors CTCF and SRF and associate with FOXO3 expression.

Human 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. Human 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.

Die Variation in der Lebensspanne wird beim Menschen bis zu 30% durch genetische Faktoren beinflusst, während ca. 70% dieser Variation auf Umweltbedingungen zurückzuführen ist. Bisher zeigen nur Einzelbasenvariationen (SNVs) in den Genen Apolipoprotein E (APOE) und Forkhead-Box-Protein O3A (FOXO3A) eine konsistente Assoziation mit Langlebigkeit beim Menschen in verschiedenen Populationen. Ziel der vorliegenden Studie war es daher, über Kandidatengenstudien und mittels ImmunochipTechnologie neue Suszeptibilitätsfaktoren und funktionell relevante Varianten in der deutschen Population zu identifizieren. Kandidatengenstudien wurden jeweils für die Superoxiddismutasen (SODs), das Cholesterinester-Transferprotein (CETP) und die FOXO3A-Genregion durchgeführt. Die SNV-Auswahl für die SODs und CETP erfolgte über einen umfassenden haplotype tagging Ansatz, während für die FOXO3A-Genregion drei verschiedene Sequenzierungs-Technologien (SOLiD, Illumina und Sanger) genutzt wurden, um potentielle funktionell relevante Varianten zu detektieren. In einem weiteren Ansatz sind mittels Immunochip-Technologie ca. 200.000 SNVs getestet worden. Der Immunochip umfasst genetische Varianten, die potentiell für immunvermittelte und altersbedingte Erkrankungen relevant sind. ... Up to 30% of variation in human lifespan is influenced by genetic factors, whereas 70% is attributed to environmental factors. However, thus far, only single nucleotide variants (SNVs) in the Apolipoprotein E and Forkhead box protein O3 (FOXO3A) genes have been consistently associated with human longevity in many populations. The aim of the current study was, therefore, to identify new susceptibility loci and functional relevant variants for human longevity in a German population by candidate gene studies and immunochip technology. Individual candidate gene studies were performed for the superoxide dismutases (SODs), the cholesterol ester transfer protein (CETP), and the FOXO3A gene regions. Selection of SNVs for SODs and CETP was conducted using a comprehensive haplotype tagging approach while for the FOXO3A gene region, three different sequencing technologies (SOLiD, Illumina, and Sanger) were applied to detect potentially functional relevant variants. In a parallel approach, about 200,000 SNVs were tested using immunochip technology. The immunochip contains genetic variants that are thought to be relevant for immune mediated and age-related diseases....