Analysis of polymorphisms in 59 potential candidate genes for association with human longevity

Morris BJ1,2,3, Donlon TA1,4,5, Chen R1, Masaki KH1,2, Allsopp RC6,7, Willcox DC1,2,8, Elliott A1 and Willcox BJ1,2

  1. Department of Research, Honolulu Heart Program/Honolulu-Asia Aging Study, Kuakini Medical Center, Honolulu, Hawaii, USA.
  2. Department of Geriatric Medicine, John A Burns School of Medicine, University of Hawaii, Honolulu, Hawaii.
  3. School of Medical Sciences and Bosch Institute, University of Sydney, NSW.
  4. Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA.
  5. Department of Pathology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA.
  6. Institute of Biogenesis Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii.
  7. Cancer Center, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii.
  8. Department of Human Welfare, Okinawa International University, Okinawa, Japan.

This study tested single nucleotide polymorphisms (SNPs) in genes differentially expressed during caloric restriction in mice for association with human longevity. Subjects were American men of Japanese ancestry recruited in the mid-1960s for the Honolulu Heart Program and followed until the present or death as the Honolulu-Asia Aging Study. The longevity group comprised 440 men who survived to age ≥ 95 years and 374 men who had an average lifespan. Using leukocyte DNA from blood collected in 1991 to 1993, we tested 459 SNPs in the human homologues of 46 genes found to be differentially expressed in calorically-restricted mice (Estep et al. PLoS One 2009;4:e5242), 4 that were differentially expressed, but not significantly so, and 8 other genes of interest, for association with human longevity. All SNPs chosen had a minor allele frequency ≥ 5%. SNPs were genotyped at the University of Hawaii Cancer Center on the Illumina GoldenGate platform, which performs high-throughput SNP genotyping on universal bead arrays. Based on a dominant model of inheritance, an association with longevity at the P ≤ 0.05 level was seen for SNPs in 13 of the genes. Testing by all possible models increased the number of genes to 16. After correction for multiple testing, SNPs in 4 genes retained significance, namely, MAP3K5 (P=0.00004), SIRT7 (P=0.00004), SIRT5 (P=0.0007), and PIK3R1 (P=0.01). In a dominant model, association with longevity was seen for multiple adjacent SNPs within two of these genes (MAP3K5 and PIK3R1), as well as in FLT1, consistent with linkage disequilibrium with a causative variant in the vicinity of each respective SNP set. Haplotypes of MAP3K5 and FLT1 were associated with longevity. In conclusion, the present study implicates variation in MAP3K5, FLT1, PIK3R1, SIRT7 and SIRT5 in human longevity. These findings may merit further study in other populations and age-related conditions.