See the HEALES presentation.
It’s a very involved installation (I wonder if latch.bio could help)_
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^see my report on the bottom
I supposedly have PRS of 92% for CRP but my CRP is 0.03. Also my cardiovascular disease risk is definitely not that high, given that no one in my family has had a history of it or had any issues with it (other than an uncle who unexpectedly/suddenly died of a heart attack). My grandparents tend to die of “weird things” (one was smoking-related to that says nothing, one was autoimmune disease related)
FOXO3 genotypes are associated with the risk of death from coronary artery disease (CAD) in the elderly. The longevity-associated G allele of FOXO3 SNP rs2802292 is protective against CAD mortality (117). The plasma TNF-α levels of G allele carriers were lower than that of non-carriers, implying that FOXO3-mediated inflammation inhibition is a protective mediator of CAD death risk (117). LDL-cholesterol is an important risk factor for CVD. FOXO3 and SIRT6 regulate LDL cholesterol homeostasis by regulating the PCSK9 gene expression, which lowers LDL levels by inhibiting LDL receptor degradation (118).
Here we describe the role of FOXO3 and its single-nucleotide polymorphisms (SNPs) in healthy aging, with a focus on the enhancer region encompassing the SNP rs2802292, which upregulates FOXO3 expression and can promote the activity of the aging hub in response to different stress stimuli. FOXO3 protective effect on lifespan may be due to the accessibility of this region to transcription factors promoting its expression. This could in part explain the differences in FOXO3 association with longevity between genders, as its activity in females may be modulated by estrogens through estrogen receptor response elements located in the rs2802292-encompassing region. Altogether, the molecular mechanisms described here may help establish whether the rs2802292 SNP can be taken advantage of in predictive medicine and define the potential of targeting FOXO3 for age-related diseases.
^I have G/G on this
The rs2802292, rs2764264 and rs13217795 variants of FOXO3 have been associated with extreme longevity in multiple human populations, but the mechanisms underpinning this remain unclear. We aimed to characterise potential effects of longevity-associated variation on the expression and mRNA processing of the FOXO3 gene. We performed a comprehensive assessment of FOXO3 isoform usage across a wide variety of human tissues and carried out a bioinformatic analysis of the potential for longevity-associated variants to disrupt regulatory regions involved in isoform choice. We then related the expression of full length and 5′ truncated FOXO3 isoforms to rs13217795 genotype in peripheral blood and skeletal muscle from individuals of different rs13217795 genotypes. FOXO3 isoforms displayed considerable tissue specificity. We determined that rs13231195 and its tightly aligned proxy variant rs9400239 may lie in regulatory regions involved in isoform choice. The longevity allele at rs13217795 was associated with increased levels of full length FOXO3 isoforms in peripheral blood and a decrease in truncated FOXO3 isoforms in skeletal muscle RNA. We suggest that the longevity effect of FOXO3 SNPs may in part derive from a shift in isoform usage in skeletal muscle away from the production of 5′ truncated FOXO3 isoforms lacking a complete forkhead DNA binding domain, which may have compromised functionality.
Moreover, our results suggested that CDKN2A-CDKN2B rs4977756 polymorphism was associated with a notable increased risk of glioma in Europeans. However, in Asians, we could not come to a conclusion because of lack of studies
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from the J. Deelen et al 2019 paper (which does not focus on FOXO3 and is thus a more “neutral”/less “motivated” paper)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694136/table/Tab4/
We were able to detect significant genetic associations at two previously identified longevity/lifespan-related loci, FOXO3 and CDKN2A/B. For the other loci, we did not find evidence for replication (P > 7.8 × 10−4), despite having adequate power (≥ 0.8) for replication of all but one of the examined genetic variants (rs28926173) associated with the discrete longevity phenotypes. We were not able to calculate our power to replicate the variants associated with the continuous lifespan-related phenotypes, although we should have had adequate power to replicate variants with a minor allele frequency (MAF) > 12% and an OR > 1.1 (based on the 90th percentile versus all controls analysis). However, several of the variants associated with parental lifespan show a directionally consistent and nominal significant association with our phenotypes, indicating they may also be relevant for longevity. The failure to replicate previously reported loci could be due to the use of a different longevity phenotype then what was used in previous studies, the small effect size of some of the variants associated with parental lifespan, and the modest power of our study. The fact that we detect significant associations of variants in the FOXO3 locus is not surprising, since this locus was previously reported in the longevity GWA study from the CHARGE consortium7, from which many cohorts are included in these meta-analyses. So far, three functional longevity-associated variants have been identified at the FOXO3 locus (rs2802292, rs12206094, and rs4946935). For all of them, an allele-specific response to cellular stress was observed. Consistently, the longevity-associated alleles of all three variants were shown to induce FOXO3 expression38,39. The CDKN2A/B locus has previously been associated with parental lifespan and parents’ attained age in the UK Biobank as well as a diversity of age-related diseases13,20,40. The longevity-associated allele of the most significant variant at this locus (rs1556516) has also been associated with lower odds of developing CAD41. Although the molecular mechanism behind this association is still unclear, it is known that genes encoded at the CDKN2A/B locus are involved in cellular senescence42, a known hallmark of ageing in animal models43.
OakVar shows no results on the latter two variants of the FOXO3 locus…
Here is my VCF file: NB723PB4.vcf.gz - Google Drive
OakVar report: All my lab results here (Alex K. Chen) - General Health and Longevity - CR Society Forum
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