2032 JAMA, October 15, 2003—Vol 290, No. 15 (Reprinted)

much higher proportion of total HDL and LDL than in the control groups, whereas the relative amounts of small HDL and LDL were much less than in control groups. Similar trends were ob- served in the offspring.

ingly different distribution of LDL par- ticle size in offspring of probands compared with control groups. These distributions suggest that only a sub- set of offspring carry the high HDL trait, which may have been inherited in these individuals. Additionally, this distri- bution could represent a survival effect. Trends for men were similar, al- though mean HDL and LDL particles size were lower than in women (data not shown).

and P = .001 in women and men, respectively). As in their parents, off- spring of exceptional longevity pro- bands had significantly larger sizes of their LDL and HDL particles com- pared with their age-matched controls AinP<. (P .001 for both), although the dif- ference in HDL particle size was not as high in men.

Examining the relationship tween lipoprotein particle sizes and in our sample, we found that both and HDL particle sizes are larger for spring of probands than in the group across all ages (FIGURE 3). The same relationship apparent when men and women considered separately. Lipoprotein ticle sizes were relatively constant til 80 to 85 years, after which sizes increased dramatically. This gests more survival to older ages in

The plasma HDL frequency distri- bution was approximately normal in women (FIGURE 1) and men. How- ever, offspring of probands had a skewed distribution in which 46% of the female offspring and 42% of male offspring had plasma HDL levels that were 1 SD above the mean. Similarly, we found a bimodal frequency distri- bution of HDL particle size with strik-

Differences among the probands, off- spring, and control groups in the pro- portions of total LDL and HDL contrib- uted to by the large and small subclasses of these lipoproteins are shown in FIGURE 2. In probands, the large HDL and LDL subclasses accounted for a

Table 1. Lipoprotein Properties in Families With Exceptional Longevity

P Value Mean (SD) Proband vs Proband vs Offspring vs Offspring vs Ashkenazi Framingham* Ashkenazi Framingham Ashkenazi Framingham Proband Offspring Control Control Control Control Control Control Women No. of participants 157 122 147 276 Body mass index† 22.7 (3.3) 24.9 (3.7) 24.7 (3.3) 26.7 (5.1) .001 .001 .75 .001 Lipoprotein levels, mg/dL Total cholesterol 204 (40) 227 (37) 222 (37) .006 .22 LDL 117 (35) 128 (35) 132 (35) .02 .27 ApoB 96 (22) 104 (24) 100 (24.6) .35 .34 HDL 56 (15) 70 (17) 59 (17) .17 .001 ApoA1 151 (29) 186 (27) 172 (31) .001 .001 VLDL, mg/dL 73 (38) 75 (47) 79 (41) 78 (42) .21 .22 .50 .51 Lipoprotein particle size, nm LDL 21.5 (0.5) 21.5 (0.5) 21.0 (0.73) 21.0 (0.5) .001 .001 .001 .001 HDL 9.55 (0.47) 9.38 (0.46) 9.18 (0.51) 9.35 (0.43) .001 .001 .001 .56 LDL particle concentration, nmol/L 1079 (341) 1190 (390) 1135 (416) 1576 (432) .41 .001 .40 .001 Men No. of participants 56 94 111 309 Body mass index† 23.3 (2.6) 26.7 (3.3) 25.8 (3.1) 26.9 (4.5) .001 .001 .21 .80 Lipoprotein levels, mg/dL Total cholesterol 183 (36) 196 (36) 187 (33) .43 .03 LDL 105 (29) 112 (32) 107 (27) .61 .20 ApoB 91 (19) 95 (21) 88 (17) .41 .06 HDL 50 (17) 53 (15) 47 (14) .28 (cid:1).001 ApoA1 131 (24) 148 (29) 143 (29) .04 .37 VLDL 71 (37) 77 (45) 74 (31) 93 (49) .60 .001 .59 .01 Lipoprotein particle size, nm LDL 21.3 (0.6) 21.1 (0.78) 20.9 (0.59) 20.7 (0.5) .001 .001 .01 .001 HDL 9.39 (0.57) 9.09 (0.47) 8.88 (0.35) 9.04 (0.38) .001 .001 .05 .26 LDL particle concentration, nmol/L 1019 (246) 1077 (336) 949 (247) 1589 (385) .22 .001 .02 .001

Abbreviations: Apo, apolipoprotein; HDL, high-density lipoprotein; LDL, low-density lipoprotein; VLDL, very low-density lipoprotein. SI conversion factors: To convert cholesterol, HDL, LDL, and VLDL levels to mmol/L, multiply by 0.0259. *The measurements of the Framingham Offspring Study were not obtained at the same laboratory as the other groups and thus were not used for comparison. †Calculated as weight in kilograms divided by the square of height in meters.

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ship as the dependent variable, and the 4 lipid variables as independent vari- ables. Direct comparison of the regres- sion coefficients is not meaningful be- cause the independent variables are measured in different units. The corre- sponding z scores, however, are dimen- sionless and commensurable. The z scores (associated P values) for the 4 lipid values were –1.48 (P=.14) for LDL ae ISP<. cholesterol, 4.52 (P .001) for LDL size, ANP<. –4.68(P .001)forHDLcholesterol,and A.P<. 5.77 (P .001) for HDL size. The z sta- tisticsrankHDLsizeasthestrongestand LDL size as the next strongest determi-

nant of group membership. High- density lipoprotein cholesterol also pro- vided strong ordinal discrimination among the groups, but in the opposite direction, and LDL cholesterol pro- vided weak nonsignificant discrimina- tion in the opposite direction as well.

To further examine the differences in lipidvaluedistributionsamongthestudy groups, we performed a multivariate analysis to examine the effect of each lipid variable while controlling for the effects of the others. Study group mem- bership is an ordinal-level variable, with controlshavingtheleast,offspringanin- termediate amount, and probands the highest frequency of genes and pheno- types that promote longevity. There- fore, we performed an ordered logistic regression with study group member-

Finally,becauseprobandvariancewas equal between sexes, although the off- spring variance was not equal between sexes, heritability of lipoprotein traits was performed in the 2 offspring sexes separately. The h2 of HDL size is 0.32 (SD, 0.16) in female and 0.70 (SD, 0.22) in male offspring (P=.01 and P=.004,