Adjustment for smoking does not alter the FOXO3A association with longevity

Abstract

Human longevity is a multifactorial phenotype influenced by both genetic and environmental factors. Despite its heritability of 25-32 %, the genetic background of longevity is as yet largely unexplained. Apart from APOE status, variation in the FOXO3A gene is the only confirmed genetic contributor to survival into old age. On the other hand, FOXO3A activity is known to be downregulated in various cancers, and the gene was recently identified as a novel deletion hotspot in human lung adenocarcinoma. In view of the strong association between smoking and lung cancer, we set out to explore whether smoking modifies the known association between FOXO3A variation and longevity. To this end, we conducted a case-control study in two different populations, drawing upon extensive collections of old-aged individuals and younger controls available to us (1,613 German centenarians/nonagenarians and 1,104 controls; 1,088 Danish nonagenarians and 736 controls). In the German sample, 21 single nucleotide polymorphisms (SNPs) from the FOXO3A gene region were genotyped, whereas 15 FOXO3A SNPs were analyzed in the Danish sample. Eight SNPs were typed in both populations. Logistic regression analysis revealed that adjustment for smoking does not systematically alter the association between FOXO3A variation and longevity in neither population. Our analysis therefore suggests that the said association is not largely due to the confounding effects of lung cancer.

Specific suppression of insulin sensitivity in growth hormone receptor gene‐disrupted (GHR‐KO) mice attenuates phenotypic features of slow aging

“…One major branch of this pathway extends through the Forkhead box class O 3A (FoxO3A) transcription factor. In multiple studies of unrelated human populations, Foxo3a variants have been associated with increased survivorship more extensively than polymorphisms for any other gene or locus (Willcox et al ., 2008; Anselmi et al ., 2009; Flachsbart et al ., 2009; Li et al ., 2009; Pawlikowska et al ., 2009; Soerensen et al ., 2010; Ziv & Hu, 2011; Däumer et al ., 2014). (The predominance of these single nucleotide polymorphisms in noncoding regions is reviewed in Donlon et al ., 2012; Flachsbart et al ., 2013.)…”

Longevity-Associated Forkhead Box O3 (FOXO3) Single Nucleotide Polymorphisms are Associated with Type 2 Diabetes Mellitus in Chinese Elderly Women

“…Of the 12 FOXO3 SNPs (rs2764264, rs2802292, rs12206094, rs7762395, rs9400239, rs479744, rs1935949, rs4946935, rs13217795, rs2802288, rs2153960, and rs13220810) reported to be associated with longevity, 9 SNPs (rs2764264, rs2802292, rs7762395, rs9400239, rs479744, rs13217795, rs2802288, rs2153960, and rs13220810) were included in this study and 3 SNPs (rs12206094, rs1935949, and rs4946935) were not included as only 1 study was available. The top 3 longevity-associated FOXO3 variants polymorphism (rs13217795, rs2764264, and rs2802292) and rs13220810 as a control were selected [18,22–26,29,32–36].…”

Genetic Association Analysis of Common Variants in FOXO3 Related to Longevity in a Chinese Population

“…In 2014, a meta-analysis performed in four independent studies showed absence of association between SNP 10 and longevity [28]. However, later, SNP 10 was found to be significantly associated with longevity [29, 30] and bone fracture [31], one of aging phenotypes, in Caucasians.…”