Lipoprotein genotype and conserved pathway for exceptional longevity in humans

Abstract

Alteration of single genes involved in nutrient and lipoprotein metabolism increases longevity in several animal models. Because exceptional longevity in humans is familial, it is likely that polymorphisms in genes favorably influence certain phenotypes and increase the likelihood of exceptional longevity. A group of Ashkenazi Jewish centenarians (n = 213), their offspring (n = 216), and an age-matched Ashkenazi control group (n = 258) were genotyped for 66 polymorphisms in 36 candidate genes related to cardiovascular disease (CVD). These genes were tested for association with serum lipoprotein levels and particle sizes, apolipoprotein A1, B, and C-3 levels and with outcomes of hypertension, insulin resistance, and mortality. The prevalence of homozygosity for the -641C allele in the APOC3 promoter (rs2542052) was higher in centenarians (25%) and their offspring (20%) than in controls (10%) (p = 0.0001 and p = 0.001, respectively). This genotype was associated with significantly lower serum levels of APOC3 and a favorable pattern of lipoprotein levels and sizes. We found a lower prevalence of hypertension and greater insulin sensitivity in the -641C homozygotes, suggesting a protective effect against CVD and the metabolic syndrome. Finally, in a prospectively studied cohort, a significant survival advantage was demonstrated in those with the favorable -641C homozygote (p < 0.0001). Homozygosity for the APOC3 -641C allele is associated with a favorable lipoprotein profile, cardiovascular health, insulin sensitivity, and longevity. Because modulation of lipoproteins is also seen in genetically altered longevity models, it may be a common pathway influencing lifespan from nematodes to humans.

Figure 1. Distribution of “Favorable” Gene Polymorphisms of APOC3, APOA4, and CETP in the Study Population

The genotype frequencies of the favorable gene polymorphisms of APOC3 C(− 641)A and CETP I405V were analyzed in controls and probands (60 to 100 y old). (Offspring were not included in this analysis due to the genotype dependency of this group on proband genotypes.) The frequency of these two variants was found to be higher among centenarians, with a monotonic increase with age. Other polymorphisms in these same genes ( APOC3 (−455) TT, APOA4 347 TT, and APOA4 360 EE) showed no differences in genotype frequency with age.

Figure 2. Haplotype Structure of APOC3 and APOA4 and CETP

Ordinal arrangement of 15 SNP associated with CVD and lipoprotein metabolism, according to their position on chromosomes with LD (number in boxes) where the highest rate is represented in red and no LD in lilac. Blocks define potential haplotypes between two clustered genes. (A) APOC3 and APOA4. (B) CETP.

Figure 3. Genotype Distribution of APOC3 C(−641)A and Serum APOC3 Concentrations

(A) APOC3 C(−641)A. (B) Serum APOC3. * p < 0.05, ** p = 0.001 versus control. CC, homozygous for (−641) C; AA, homozygous for (−641) A; CA, heterozygous for (−641) C/A.

Figure 4. Insulin Sensitivity and Hypertension according to APOC3 C(−641)A Genotype

All include offspring plus controls. (A) Insulin sensitivity. (B) Hypertension. * p = 0.05 CC, homozygous for (−641) C; CA/AA, homozygous and heterozygous for (−641) A.

Figure 5. Survival Analysis according to APOC3 Genotypes

Of the 381 participants we genotyped since 1998, 64 had the −641 CC genotype. To describe the relationship between genotype and death, we plotted the Kaplan–Meier survival function estimates of probands and controls by APOC3 genotype. Offspring were excluded in this analysis because all participants are currently alive and offspring genotype/phenotype is not independent of the probands. Log-Rank ( p = 0.0008); Wilcoxon ( p = 0.0007). CC, homozygous for (−641) C; CA/AA, homozygous and heterozygous for (−641) A.