44%, similar to a frequency of 39% in the much younger control group. Off- spring had a significantly lower fre- quencyofthemetabolicsyndrome(26%, P=.03vscontrol),althoughthesegroups were well matched for BMI and age. We further tested whether the participants without the metabolic syndrome have also larger lipoprotein sizes (Table 2). Indeed, larger HDL and LDL particle sizes were apparent when age-matched participants with and without the meta- bolic syndrome were compared. This effect was not noted for LDL levels, be- cause of the widespread use of statin therapy. Because reduced HDL level is one of the criteria for having the meta- bolic syndrome and is associated with HDLparticlesize,werepeatedtheanaly- sis with participants whose metabolic syndrome was redefined by 3 criteria other than plasma HDL levels. Lipopro- tein particle sizes were still signifi-

cantly larger in those without the meta- bolic syndrome. These findings suggest a lower frequency of metabolic syn- drome–related traits in participants ge- netically predisposed to longevity.

in CETP Gene

Polymorphism in CETP and Phenotype of Exceptional Longevity

Exceptional Longevity

Cholesteryl ester transfer protein has been shown to modulate HDL and LDL levels and sizes.19-22 To determine if ge- netic variation in CETP might influ- ence lipoprotein particle size or lon- gevity, we analyzed several common single nucleotide polymorphisms of CETP. All of the single nucleotide poly- morphisms examined were in Hardy- Weinberg equilibrium in probands, their offspring, and the Ashkenazi con- trol groups (Framingham Offspring Study samples were not genotyped). The allele frequencies of –629 C/A and

The offspring of probands had a VV genotype frequency of 20.7% in women and men combined, intermediate be-

Table 2. Lipoproteins and Their Particle Sizes in Relation to Age-Related Diseases

Mean (SE) P Value Offspring and Spouse Cardiovascular Healthy vs Healthy vs of Offspring* Healthy Hypertension Disease Hypertension Cardiovascular Disease No. of participants 209 64 20 HDL Concentration, mg/dL 64.5 (0.09) 57.1 (0.3) 50.8 (0.9) .004 .003 Large particle size, % of total 54.5 (0.07) 46.8 (0.3) 41.3 (1.1) .002 .001 Particle size, nm 9.32 (0.01) 9.07 (0.06) 8.96 (0.03) .001 .001 LDL Concentration, mg/dL 120.3 (2.6) 116.9 (3.6) 104.1 (3.9) .20 .03 Large particle size, % of total 66.5 (2.2) 57.6 (2.5) 43.3 (4.5) .02 .001 Particle size, nm 21.4 (0.03) 21.1 (0.04) 20.8 (0.05) .008 .001 VLDL concentration, mg/dL 80.2 (3.4) 93.7 (5.3) 114 (6.5) .10 .05 P Value Mean (SE) Healthy vs Offspring and Spouse The Metabolic The Metabolic Syndrome Healthy vs The Metabolic Syndrome of Offspring† Healthy Syndrome (Excluding HDL Criteria) The Metabolic Syndrome (Excluding HDL Criteria) No. of participants 221 47 25 HDL Concentration, mg/dL 63.2 (1.14) 46.6 (1.75) 46.8 (4.98) (cid:1).001 .002 Large particle size, % of total 66.9 (1.58) 42 (3.94) 40.89 (2.9) (cid:1).001 (cid:1).001 Particle size, nm 9.28 (0.03) 8.88 (0.05) 8.95 (0.07) (cid:1).001 .001 LDL Concentration, mg/dL 122 (2.14) 112.9 (5.4) 114.9 (6.43) .09 .32 Large particle size, % of total 56.5 (0.9) 39.7 (2.06) 51.3 (2.23) (cid:1).001 (cid:1).001 Particle size, nm 21.33 (0.04) 20.76 (0.11) 20.97 (0.13) (cid:1).001 .01 VLDL concentration, mg/dL 66.8 (2.5) 106.4 (6.3) 108 (7.2) (cid:1).001 (cid:1).001 Abbreviations: HDL, high-density lipoprotein; LDL, low-density lipoprotein; VLDL, very low-density lipoprotein.

Abbreviations: HDL, high-density lipoprotein; LDL, low-density lipoprotein; VLDL, very low-density lipoprotein. SI conversion factor: To convert HDL, LDL, and VLDL concentrations to mmol/L, multiply by 0.0259. *Healthy, hypertension ((cid:2)130/85 mm Hg or treatment for hypertension), or history of cardiovascular disease (history of either myocardial infarction or stroke/transient ischemic

†Healthy, the metabolic syndrome (by National Cholesterol Education Program [Adult Treatment Panel III] criteria11), and the metabolic syndrome by 3 criteria excluding HDL.

2036 JAMA, October 15, 2003—Vol 290, No. 15 (Reprinted)

their offspring compared with appro- priately age-matched control groups, supporting a functional role for lipo- proteins in promoting survival to very old age. The pattern of distribution of lipoprotein sizes, their marked herita- bility in the offspring, and the mark- edly increased frequency of homozy- gosity for the codon 405 valine CETP allele support a genetic component to this phenotype and exceptional lon- gevity.

eases, including CVD, dementia, infec- tions, and cancer. The longevity phenotype is likely to be one that in- volves diverse biological processes and protects from a number of age-related diseases, and these processes may be different than suggested from studies of other species.23 This study demon- strates to our knowledge the first time that families with exceptional longev- ity have markedly larger particle sizes of HDL and LDL, which are largely in- dependent of the absolute levels of li- poproteins and apolipoproteins. This particular phenotype is associated with a lower prevalence of hypertension and CVD and the metabolic syndrome in

tween probands and control groups and also significantly higher than in con- trol groups (P=.004).

In principle, one cannot calculate the attributable risk of VV genotype for lon- gevity from a case-control study be- cause it is derived from incidence rates. However, a reasonable approximation can be calculated by using the estima- tion formula:

Does lipoprotein particle size play a direct biological role in successful ag- ing and the longevity phenotype, or are these measures simply markers of the longevity phenotype? Although our