Figure 1. Frequency Distribution of Lipoprotein Properties in Female Probands, Offspring, and Controls Female Probands 30 30 30 25 25 25 20 20 20 15 15 15 10 10 10 5 5 5 0 0 0 25 40 55 70 85 100 8.2 8.6 9.0 9.4 9.8 10.2 10.6 20.8 21.0 21.2 21.4 21.6 21.8 22.0 Female Offspring 30 30 30 25 25 25 20 20 20 15 15 15 10 10 10 5 5 5 0 0 0 25 40 55 70 85 100 8.2 8.6 9.0 9.4 9.8 10.2 10.6 20.8 21.0 21.2 21.4 21.6 21.8 22.0 Female Ashkenazi Controls 30 30 30 25 25 25 20 20 20 15 15 15 10 10 10 5 5 5 0 0 0 25 40 55 70 85 100 8.2 8.6 9.0 9.4 9.8 10.2 10.6 20.8 21.0 21.2 21.4 21.6 21.8 22.0 HDL Concentration, mg/dL HDL Particle Size, nm LDL Particle Size, nm noitalupoP ni %noitalupoP ni %noitalupoP ni %

Figure 1. Frequency Distribution of Lipoprotein Properties in Female Probands, Offspring, and Controls

The frequency distribution of plasma high-density lipoprotein (HDL) concentration levels and particle sizes, and low-density lipoprotein (LDL) particle sizes in female probands, their offspring, and an Ashkenazi control population. To convert HDL concentration to mmol/L, multiply by 0.0259. The solid lines represent the mean and the dotted lines represent 1 SD of control.

2034 JAMA, October 15, 2003—Vol 290, No. 15 (Reprinted)

we would expect probands to have a much higher frequency of the meta- bolic syndrome than the younger con- trol group. However, the frequency of themetabolicsyndromeinprobandswas

determined the frequency of metabolic syndrome according to the National Cholesterol Education Program III guidelines. Because the frequency of the metabolic syndrome increases with age,

Figure 2. Percentage of Large and Small HDL and LDL Particle Sizes in Long-Lived Probands, Offspring, and Ashkenazi and Framingham Controls

LDL and HDL Particles Size in Relationship to Hypertension, CVD, and the Metabolic

Offspring, and Ashkenazi and Framingham Controls Large HDL Particle Size Small HDL Particle Size 70 70 ∗ 60 60 ∗ 50 50 40 40 ∗ ∗ 30 30 20 20 10 10 0 0 ∗ Large LDL Particle Size Small LDL Particle Size ∗ 70 70 60 60 50 50 40 40 30 30 20 20 ∗ 10 10 ∗ 0 0 Probands Offspring Ashkenazi Framingham Probands Offspring Ashkenazi Framingham Controls Controls selcitraP LDH latoT fo %selcitraP LDL latoT fo selcitraP LDH latoT fo %selcitraP LDL latoT fo

Because lipoprotein concentrations and size are important CVD risk factors, we next examined the relationship be- tween lipoprotein particle size, hyper- tension, and the prevalence of CVD, de- fined as having a history of myocardial infarction, stroke, or transient ische- mic attack in the combined group of our Ashkenazi offspring and control (TABLE 2). The Framingham Off- spring Study and Einstein Aging Study were not included in this analysis be- cause clinical evaluation for these CVD traits was performed differently. Sig- nificantly higher percentage of large HDL particles, HDL particle size, per- centage of large LDL, and LDL par- ticle size where observed in healthy participants compared with those with hypertension. Moreover, significantly higher percentage of large HDL par- ticles, HDL particle size, percentage of large LDL, and LDL particle size were observed in healthy participants com- pared with those with CVD. Unexpect- edly, LDL levels were lower in the hy- pertension and CVD groups, probably accounted for by use of cholesterol- lowering drugs (18% in the healthy group, 38% in the hypertension group, and 60% in the CVD group). Signifi- cantly lower levels of HDL in hyper- tension and CVD groups were ob- served compared with the healthy group, but neither very LDL nor tri- glyceride levels were significantly dif- ferent between hypertension risk groups. In total, these findings sug- gest a possible link between the size of lipoprotein particles and age-related hy- pertension and CVD.

HDL indicates high-density lipoprotein; LDL, low-density lipoprotein. *P(cid:1).001 for probands vs Ashkenazi and Framingham controls and P(cid:1).001 for offspring vs Ashkenazi Framingham controls for both large and small HDL and LDL particle sizes.

Figure 3. HDL and LDL Particle Size as a Function of Age HDL Particle Size LDL Particle Size 9.8 21.6 Probands Offspring 9.6 21.4 Ashkenazi and Framingham Controls 9.4 21.2 9.2 21.0 9.0 20.8 8.8 20.6 8.6 20.4 60 65 70 75 80 85 90 95 100 60 65 70 75 80 85 90 95 100 Age, y Age, y

The metabolic syndrome (insulin re- sistance syndrome, syndrome X, dys- metabolic syndrome X)10 is a risk fac- tor for many causes of death.18 We

Cross-sectional data from probands with exceptional longevity aged 95 to 107 years (n=191), Ashkenazi and Framingham control groups combined aged 60 to 95 years (n=878), and their offspring aged 60 to 80 years (n=206). HDL indicates high-density lipoprotein; LDL, low-density lipoprotein.

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D442G in Ashkenazi control groups were 0.57 and 0, respectively. Neither allele or genotype frequencies of the –629 C/A variant differed signifi- cantly among probands, offspring, or Ashkenazi control groups, nor was this variant associated with lipoprotein lev- els or particle sizes. By contrast, allele frequencies of the I405V allele were 0.46, 0.43, and 0.29 in probands, off- spring, and Ashkenazi control groups, respectively. Strikingly, the frequency of homozygosity for the codon 405 va- line allele of CETP (VV genotype) was 24.8% in female and male probands compared with only 8.6% in Ash- kenazi control groups. These differ- ences were statistically significant in P<. both men and women (P .001 for both) (FIGURE 4).