4. Serum Upld Fractions in Finnish Centenarians In Relation to Their Apolipoprotein Genotype Combinations)

Genotype n* Cholesterol LDL-C HDL-C HDLj-C Triglyce ApoE e2/e2 + e2/e3 24 4.33±1.10 2.14±0.88 1.41 ±0.36 0.48±0.30+ 1.72±0.07 e1/e3+e3/e3 125 4.57±0.93 2.33±0.84 1.48±0.41 0.55±0.29+ 1.66+0.81 e3/e4 + e4/e4 30 4.82±0.90 2.57±0.75 1.60±0.41 0.67±0.30t 1.42±9.42 ApoB X1X1 S7 4.48±0.86 2.30±0.68 1.46±0.36 0.55±0.23 1.68±0.89 X1X2 M 4.62±0.99 2.40±0.78 1.48±0.40 0.55±0.31 1.70±0.74 m X2X2 4.73±1.04 2.53±0.98 1.58±0.49 0.62±0.35 1.38±0.49 ApoC-lll S1S1 130 4.60±0.92 2.40±0.75 1.49±0.42 0.55±0.30 1.64±0.79 S1S2 38 4.62±1.02 2.35±0.89 1.55±0.36 0.61 ±0.26 1.59±0.62 S2S2 3 4.63±1.84 2.62±1.31 1.20±0.37 0.31 ±0.32 1.78±1.19

LDL-C indicates low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; ApoE, apolipoprotein E; apolipoprotein B; and ApoC-lll, apolipoprotein C-lll. Values are mean±SD, expressed in millimoles per liter. *DNA samples for apoB and apoC-lll genotyping were available from 171 subjects only, tP<.05, statistical difference among three groups.

differences in the geographic origin of the subjects can have influenced our data. First, the youngest reference group was randomly selected from the national popula- tion register.1117 The middle-aged reference cohorts represented a random healthy population with full working ability.8'18 Second, earlier studies have shown that the distribution of the apoE phenotypes is very similar in southern,8 western,11 and eastern11 Finland. Third, the choice of subjects living in the Helsinki region as adult control subjects was based on the assumption that Finns living in the vicinity of the capital are representative of the whole Finnish population; in fact, previous studies on blood and polymorphic serum pro- tein markers are in harmony with this assumption.34

mmol/L) than those with the X1X1 genotype and E2 phenotype (3.43 mmol/L; P<S)5); subjects with other genotype/phenotype combinations had intermediate plasma cholesterol levels (Figure).

gene was not associated with significant variations in plasma cholesterol or triglyceride levels in the centenar- ians (Table 4). Neither did we find any significant association between the polymorphisms of the apolipo- protein genes examined and plasma phospholipid, apoA-I, apoA-II, or apoB concentrations (data not shown).

Discussion

The most striking finding of the present investigation was the significantly diminished prevalence of the apoE e4 allele in centenarians: the percentage frequency of this allele (8.4%) was less than half that found in middle-aged (22.7%) or young (19.4%) people. It is noteworthy that in the men aged older than 100 years the apoE e4 allele was almost absent (frequency, 3.6%; Table 3). Although our young and middle-aged control subjects were not fully matched with the centenarians regarding place of residence, it appears unlikely that

No conclusive explanation for the relative absence of the apoE e4 allele from the oldest age group can be provided. Although the following is not true of all populations examined,5'6 in Finland the apoE pheno- type E4 has been associated with an elevated serum LDL cholesterol level8 and is known to be more com- mon among patients with angiographically confirmed coronary disease than in the general population15 or in patients with cardiac disease who have normal coronary angiograms.35 In addition, the apoE e4 allele may promote accelerated atherosclerosis by mechanisms other than that operating via increased serum LDL cholesterol levels,3638 and some of these mechanisms may be important for life expectancy. Our data confirm the results of Davignon et al22 and Eggertsen et al,23 who both were able to show a decrease of the e4 allele frequency in elderly people compared with younger age groups. Thus, the frequency of the e4 allele in Canadian octogenarians (mean age, 85 years) was 8.7%, a figure significantly lower than the corresponding frequency (15.2%) in a population with a mean age of 36 years.22 The frequencies of the e4 allele in elderly (60 to 86 years) and younger (<40 years) Swedish people were 14.7% and 21.8%, respectively.23 Recently the apoE phenotype E4 has also been suggested as a genetic marker for increased risk to develop Alzheimer's dis-

E3/4 or E4/4 -^ E3/3 E2/2 or E2/3

Graph shows plasma cholesterol levels In Finnish centenarians in relation to their combined apolipoprotein E and B genotypes.

ease.3941 Whether these findings could partly explain the loss of the e4 allele from centenarians remains to be examined.

In conclusion, we show that, of the three common apolipoprotein polymorphisms previously recognized to be associated with high serum lipid levels and/or a higher than average risk of atherosclerotic cardiovascu- lar disease, apoE emerges as a factor in which genetic variation may affect life expectancy at the population level. Thus, among Finns the apoE phenotype E2/2 or E2/3 implies a fourfold greater likelihood of reaching the age of 100 years than the phenotype E3/4 or E4/4 (odds ratio, 4.0; 95% confidence interval, 1.9 to 8.3). However, because fewer than 0.01% of Finns with the E2 phenotype live longer than 100 years, it may be inadvisable to call the e2 allele a "longevity gene."