Discussion: APOC3 is a major component of very low-density lipoproteins and chylomicron remnants; it is also a minor component of HDL [8]. In vitro, it has been shown to inhibit the activity of lipoprotein lipase, resulting in delayed TG clearance from plasma [12]. Several studies have shown that various polymorphisms of the APOC3 gene either within the promoter region, in particular the T-455C variant polymorphism in the insulin response element, or in the gene, are associated with elevated TG levels but not with significant change in APOC3 levels [13-17]. Previous studies have also associated high levels of APOC3 with macrovascular and microvascular disease and their risks. Increased APOC3 levels were a significant indicator of coronary risk in men and in patients with metabolic syndrome. In particular, those with vascular disease and metabolic syndrome had a markedly increased probability of coronary heart disease in an allele. In addition to showing statistical associations of the APOC3 genotype with exceptional longevity, we found significant associations between this genotype and several intermediate longevity-associated traits directly related to lipoproteins.

Surviving (%) 3wD a3APOC CC APOC3 CA YAA os 65T 80T 85 90 Age (years) 95T 100 105 110 HOMA Percentage of Hypertension 50 40 30 20 10 H4poc3 cc Dlapoc3 CA/AA AllMi apoc3 cc [L] APOC3 CA/AA 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. 

These findings suggest that the APOC3 genotype may have favorable pleiotropic effects on a number of cardiovascular traits and mortality. Interestingly, while a recent study found that the phenotypic effects of APOC3 polymorphisms are modified by dietary polyunsaturated fatty acids [22], the interactions of APOC3 levels with exercise, body mass index or other environmental effect have not been well studied. Our population by genotype had similar body mass index, suggesting that body weight is not strongly modulated by genotype. The APOC3 gene is located on the long arm of Chromosome 11q23, in tandem with the apolipoprotein A1 and A4 genes [8,26]. The APO A1-C3-A4-A5 gene cluster has been studied extensively in relation to lipoproteins and CVD, and most recently in the oldest old [8,27,28]. Given LD within this gene cluster, we cannot rule outOverrepresented in our centenarians, a finding that was confirmed in oldest old Italians [32]. Low CETP levels, which were explained in part by this CETP variant, were observed in our study [6] and in Japanese centenarians [31]. Sequence variants in another lipoprotein gene, the microsomal transfer protein gene, were implicated in another study of centenarians [7]. This study adds APOC3 to the list of lipoprotein genes that may influence exceptional longevity. Interestingly, all these genes are involved in different steps of lipoprotein metabolism and could potentially be additive in their effects.

Materials and Methods

Study design and participants. In this case-control study, Ashkenazi Jews were recruited as described elsewhere [5,6]. The Ashkenazi population is believed to have descended from a small group of founders based on both historical records and modern genetic evidence. The advantage of using founder populations is that the genetic determinants of a particular disease may be more homogeneous and easier to define, and false positive results due to population stratification are less likely [39]. Indeed, specific mutations in a number of disease genes (e.g., breast cancer gene 1, breast cancer gene 2, adenomatosis polyposis coli gene, hereditary prostate cancer gene) have been initially identified in the Ashkenazi population at prevalence rates consistent with a founder effect [40-44]. Stratification in these studies has not been required, and indeed these genes were later implicated in other populations too [45,46].

Two hundred and thirteen probands with exceptional longevity (157 females and 56 males, age 98.2 (0.36) y [mean (SE)], range 95-107 y; 48% over the age of 100 y) were recruited to participate in the study. The participants' ages were defined by birth certificates or dates of birth as stated on passports. Probands were required to have been living independently when they were 95 y of age as a reflection of good health, although at the time of recruitment, they could be at any level of dependency. In addition, probands were required to have a child who was willing to participate in the study. The offspring group consisted of 122 females and 94 males (age 68.3 [0.45] y, range 51-89 y). The control group included 258 participants derived from two sources: Ashkenazi Jews from the general population recruited by the Einstein Aging Study and spouses of the recruited offspring. The study sample included 183 participants with mean age 71.3 (0.67) y, 57% female [47]. Spouses of offspring included 75 participants with mean age 70.2 (1.17) y, 53% female. These controls as a comparison group similar in age to the offspring are important to overcome the limitation of a cross-sectional sample because the effects of age on genotype, phenotype (APOC3 levels, lipids, etc.), and outcomes (hypertension and longevity) are minimized. Written informed consent was obtained, and the study was approved by the Committee on Clinical Investigations of the Albert Einstein College of Medicine.