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The original version of this Article contained an error in the spelling of the author Robert Häsler, which was incorrectly given as Robert Häesler. This has now been corrected in both the PDF and HTML versions of the Article.

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.

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., (© 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

The role of superoxide dismutases (SODs) in aging and oxidative stress regulation has been widely studied and there is growing evidence that imbalances in these processes influence lifespan in several species. In humans, genetic polymorphisms in SOD genes may play an important role in the development of age-related diseases and genetic variation in SOD2 is thought to be associated with longevity. These observations prompted us to perform a case-control association study using a comprehensive haplotype tagging approach for the three SOD genes (SOD1, SOD2, SOD3) by testing a total of 19 SNPs in our extensive collection of 1,612 long-lived individuals (centenarians and nonagenarians) and 1,104 younger controls. Furthermore, we intended to replicate the previous association of the SOD2 SNP rs4880 with longevity observed in a Danish cohort. In our study, no association was detected between the tested SNPs and the longevity phenotype, neither in the entire long-lived sample set nor in the centenarian subgroup analysis. Our results suggest that there is no considerable influence of sequence variation in the SOD genes on human longevity in Germans.

Our study demonstrates that the genetic investigation of forkhead box O3A gene (FOXO3A), a validated human longevity gene, is greatly hampered by the fact that its exonic regions have 99% sequence homology with the FOXO3B pseudogene. If unaccounted for, this high degree of homology can cause serious genotyping or sequencing errors. Here, we present an experimental set-up that allows reliable data generation for the highly homologous regions and that can be used for the evaluation of assay specificity. Using this design, we exemplarily showed FOXO3A-specific results for two single-nucleotide polymorphisms (SNPs) (rs4945816 and rs4946936) that are significantly associated with longevity in our centenarian-control sample (P(each)=0.0008). Because both SNPs are located in the 3' untranslated region of FOXO3A, they could be of functional relevance for the longevity phenotype. Our experimental set-up can be used for reliable and reproducible data generation for further sequencing and genotyping studies of FOXO3A with the aim of discovering new SNPs of functional relevance.

New Zealand has one of the highest incidence rates of Crohn's Disease (CD), whilst the serum selenium status of New Zealanders is amongst the lowest in the world. A prospective case-control study in Auckland, New Zealand considered serum selenium as a potential CD risk factor. Serum selenium levels were significantly lower in CD patients compared to controls (101.8 ± 1.02 vs. 111.1 ± 1.01 ng/mL) (p = 5.91 × 10(-8)). Recent detailed studies in the United Kingdom have suggested an optimal serum level around 122 ng/mL, making the average CD patient in New Zealand selenium deficient. Of the 29 single nucleotide polymorphisms (SNPs) tested, 13 were found to significantly interact with serum selenium on CD. After adjustment for multiple testing, a significant interaction with serum selenium on CD was found for three SNPs, namely rs17529609 and rs7901303 in the gene SEPHS1, and rs1553153 in the gene SEPSECS. These three SNPs have not been reported elsewhere as being significantly associated with selenium or CD. It is unclear as to whether lower selenium levels are a cause or an effect of the disease.

Inflammatory bowel diseases (IBDs), Crohn's disease (CD), and ulcerative colitis (UC) are chronic inflammatory conditions, which are increasing in incidence, prevalence, and severity, in many countries. While there is genetic susceptibility to IBD, the probability of disease development is modified by diet, lifestyle, and endogenous factors, including the gut microbiota. For example, high intakes of mono- and disaccharides, and total fats consistently increases the risk developing both forms of IBD. High vegetable intake reduces the risk of UC, whereas increased fruit and/or dietary fiber intake appears protective against CD. Low levels of certain micronutrients, especially vitamin D, may increase the risk of both diseases. Dietary patterns may be even more important to disease susceptibility than the levels of individual foods or nutrients. Various dietary regimes may modify disease symptoms, in part through their actions on the host microbiota. Both probiotics and prebiotics may modulate the microflora, and reduce the likelihood of IBD regression. However, other dietary factors affect the microbiota in different ways. Distinguishing cause from effect, and characterizing the relative roles of human and microbial genes, diet, age of onset, gender, life style, smoking history, ethnic background, environmental exposures, and medications, will require innovative and internationally integrated approaches., (© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)