unclear, recent studies have suggested that gene polymorphisms for diabetes mellitus, disease, and cancer may be associated in Koreans. This study aimed to identify susceptibility variants controlling longevity by performing a high-throughput candidate gene study using 137 Koreans over 90 years old and 213 young healthy Koreans. The researchers evaluated 463 informative markers located in 176 candidate genes mostly associated with diabetes mellitus, cardiovascular disease, and cancer under five genetic models. They estimated odds ratios for each allele, genotype, haplotype, and gene-gene interaction using logistic regression analysis.

The study revealed associations between 13 genes and longevity at a P-value less than 0.01. Notably, the rs671 (A) allele of the aldehyde dehydrogenase 2 family (mitochondrial) (ALDH2) gene was associated with longevity only in men (odds ratio [OR] 2.11, P = 0.008). Four genes, proprotein convertase subtilisin/kexin type 1 (PCSK1, P = 0.008), epidermal growth factor receptor (EGFR, P = 0.003), paired box 4 (PAX4, P = 0.008), and V-yes-1 Yamaguchi sarcoma viral related oncogene homolog (LYN, P = 0.002), consistently yielded statistical evidence for association with longevity.

The findings of this study may provide a starting point for future research to unravel genetic factors related to longevity in Koreans.association with lifespan among nonagenarian women (P < 0.05) (data not shown). Among these, 26 SNPs of 22 genes showed a significant genotypic OR and 7 genes had a P value less than 0.01 (Table 2A). The genotypic effects of the rs2075650 (Thr241Met) in the PON1 and the rs1800795 (Asp299Gly) in the Toll-like receptor 4 (TLR4) were stronger than the allelic effects in either direction. On the other hand, the allelic effect of the rs1042522 (Arg72Pro) in the TP53 was stronger than the genotypic effect. In addition, 86 SNPs located in 52 genes were statistically associated with one or more age/gender groups using regression models for five modes of inheritance (P < 0.05) (data not shown). Among these, the genotypic ORs of 70 SNPs located in 47 genes were nominally significant in at least one age/gender group and 10 genes had a P value less than 0.01 (Table 2B). The genotypic effect of the rs2075650 (Thr241Met) in the PON1 was also stronger than its allelic effect among nonagenarian women. In addition, the genotypic effect of the rs1800795 (Asp299Gly) in TLR4 was significant among nonagenarian women under a dominant model.Associations were analyzed between genes and lifespan in two age groups of women: those over 90 years old and centenarian women. The EGFR and PPP1R14C genes had lower allelic P values in the group of centenarians, but IL12RB2 was significant only in the younger group with more subjects. However, the rare T allele of rs2030071 was not common enough to determine the genetic model. A total of 27 SNPs located in 25 genes showed evidence for association with lifespan in both gender groups. Although the allelic effects of MGP and TNFSF11 were insignificant, these genes showed notable genotypic effects in the overdominant model. TG heterozygotes of rs1054016 were observed at lower frequencies among the old age group compared to the young age group. All 27 genes consistently showed evidence for association with lifespan in both allele- and genotype-based analyses, with six genes showing significant association attracting considerable attention as candidate genes affecting lifespan in Koreans: ADCY2, PPP1R1A, LYN, PAX4, ALDH2, and IL12RB2.

There were significant gender differences in genetic associations with longevity. Among the 69 genes that showed significant genotypic association, we found significant association with longevity in 12 genes by using tagSNPs for 32 genes with at least three genotyped SNPs. Among nine genes that consistently yielded significant evidence of allelic, genotypic, and haplotypic associations with longevity (i.e. HK2, ERBB4, PCSK1, ITK, EGFR, PAX4, LPL, LYN, and CDK10), only PCSK1, EGFR, PAX4, and LYN remained significant after the Bonferroni correction for multiple testing of haplotypes in each gene.

Figure 1 summarizes the -log (P value) obtained from three different analyses of association for these four genes. The presence of the G allele of rs155979 in the CGA haplotype of PCSK1 decreased lifespan among the group of nonagenarian men adjusted by sex. The G allele of rs712700 increased lifespan. A total of 43 SNPs located in 31 genes including four missense mutations located in each of eukaryotic elongation factor 2 kinase, NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 7 (NDUFA7), TNFSF11, and LYN showed evidence for association with longevity among nonagenarian men.rs2030071 is an intron C/T located at positions 159/3 and 156/16. The table presents results from haplotype-based analyses for candidate genes that show evidence of association with longevity. The best fitting mode of inheritance was determined using only SNPs with a significant genotypic OR from the most significant regression model (P < 0.01) for the gene. The table shows gene, SNPs, haplotypes, frequency, OR, 95% CI, and P value for each haplotype using a general linear model (GLM). The paper reports the first evidence associating the PCSK1, PAX4, EGFR, and LYN genes with human longevity.