Genetic Variants in PVRL2-TOMM40-APOE Region Are Associated with Human Longevity in a Han Chinese Population

Abstract

PurposeHuman longevity results from a number of factors, including genetic background, favorable environmental, social factors and chance. In this study, we aimed to elucidate the association of human longevity with genetic variations in several major candidate genes in a Han Chinese population.MethodsA case-control association study of 1015 long-lived individuals (aged 90 years or older) and 1725 younger controls (30–70 years old) was undertaken. Rs2075650 in TOMM40 was firstly genotyped using the ABI SNaPshot method in an initial cohort consisted of 597 unrelated long-lived individuals and 1275 younger controls enrolled from Sichuan. Secondly, eighteen tag single-nucleotide polymorphisms (SNPs) in the PVRL2-TOMM40-APOE locus were genotyped for extensive study in the same cohort. Finally, 5 associated SNPs were genotyped in a replication cohort including 418 older individuals and 450 younger controls. The genotype and allele frequencies were evaluated using the χ2 tests. The linkage disequilibrium (LD) block structure was examined using the program Haploview.ResultsThe case-control study of rs2075650 in TOMM40 showed significant difference in allele frequencies between cases and controls (P = 0.006) in an initial study. Of the 18 SNPs genotyped, rs405509 in APOE and another three SNPs (rs12978931, rs519825 and rs395908) in the PVRL2 gene also showed significant association with human longevity in extensive study in the same cohort. Rs2075650 in TOMM40, rs405509 in APOE and rs519825 in PVRL2 showed a significant association with human longevity in a replication cohort.ConclusionThese results suggested that PVRL2, TOMM40 and APOE might be associated with human longevity. However, further research is needed to identify the causal variants and determine which of these genes are involved in the progress of human longevity.

APOEAlleles and Extreme Human Longevity

“…Several genome-wide association studies have associated tag SNPs in the cluster of genes PVRL2, TOMM40, APOE, and APOC1 in chromosome 19 to EL (40,(46)(47)(48), and some investigators have hypothesized that these variants may be important for EL independently of the APOE alleles ε ε ε…”

“…, , . For example, Lu et al used haplotype analysis of SNPs tagging this region to conjecture that PVRL2, TOMM40, in addition to APOE, may be important for EL (48). In a recent meta-analysis of four genome-wide association studies of EL (37), we identified a large cluster of SNPs in this region that was significantly associated with EL and, by examining their patterns of linkage disequilibrium, we identified two most significantly associated SNPs with EL (Supplementary Figure 6A).…”

Genetic landscape of APOE in human longevity revealed by high-throughput sequencing

“…Interestingly, Poolseq with target region including regulatory region such as proximal upstream and intronic region identified longevity-associated common variants, rs405509 and rs769449 that were previously associated with longevity and other aging-related disease phenotypes (Lu et al, 2014; Soerensen et al, 2013). They are also predicted (Supplementary Figure 2) and experimentally proved (Supplementary Table 3) to be functional, implicating the potential role of regulatory variants in a longevity-association.…”

Living long and ageing well: is epigenomics the missing link between nature and nurture?

“…Davies et al (2015) using the large subject number and meta-analysis, also demonstrated a significant and increased correlation between general cognitive function with increased cohort age, compared to the youngest age groups, with the cognitive effect size being related to rs10119, the most major SNP located in the ApoE/TOMM40 region. Roses et al (2010) and Lu et al (2014) have further shown that TOMM40 gene has long and short variants, combinations of which appear to contribute to earlier presentation and shorter life expectancy with late onset of Alzheimers disease (LOAD), and although the mechanisms involved have not to date been elucidated, the earlier presenting variants are considered to be more closely associated with its lipidassociated effects (Yu et al 2013;Bekris et al 2012).…”