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.

Fig. 1

Study setting. Associations between variables are depicted by bold arrows. A dashed arrow is used to indicate that the association between FOXO3A and longevity may be due partially to confounding by lung cancer. Smoking serves as a proxy for lung cancer. Note that cases and controls differ by both their life expectancy and generation membership

Fig. 2

FOXO3A odds ratios for attaining old age, with and without adjustment for smoking. Odds ratios were obtained by logistic regression analyses of longevity and FOXO3A SNP genotype, with (vertical axis) and without smoking adjustment (horizontal axis). Circles German sample; diamonds Danish sample. Significant associations are marked by filled symbols. All analyses were adjusted for APOE genotype