LPL PvuII P(/) 20 18/2 18.7±3.1 3.6±0.5 163±38 88±30 61±18* 71±23* 3.3±1.2 P(/+) 101 77/24 19.0±3.6 3.5±0.4 163±32 95±28 50±12* 92±42* 3.0±0.9 P(+/+) 135 95/40 19.4±3.7 3.6±0.4 162±31 With an HDL-C concentration between 41-60 mg/dl, Hirano et al. [7] reported that hyperalphalipoproteinemia caused by CETP gene deficiency can be associated with increased CAD when combined with low HL activity. Hirano et al. [7] also noted the interesting finding that CETP deficiency may not be susceptible to CAD if accompanied by higher LPL activity. These findings indicate that the pro-atherogeneity of CETP deficiency may be compensated by other genetic and circumstantial factors, such as key enzymes synergistically involved in reverse cholesterol transport and/or the antiatherogenic property of HDL particles themselves. However, in the study, there was no significant difference in demographics and biochemical parameters except HDL-C and CETP mass between centenarians with CETP deficiency and those with the wild type. Neither did the frequency of the C allele of the promoter polymorphism in the HL gene, which may be associated with an increased risk of CAD, differ between the two groups (0.500, 0.504, P=0.961, respectively). Compatible with results from several epidemiological studies [8, 9, 31], we demonstrated that the B2 allele is associated with lower CETP mass and higher HDL-C concentration in both centenarians and controls; however, we found no significant association of the allele with longevity. The result remained unchanged after excluding the participants with CETP deficiency. Ordovas et al. [32] reported that the B2 allele is associated with higher HDL-C and lower CAD risk only in men, not in women, in a population-based sample from the Framingham Offspring Study. In the present study, even after restriction to men, there was no difference in frequencies of B2 alleles among centenarians and controls (0.400, 0.443, P=0.472, respectively). The reason for the lack of association of two polymorphisms of CETP gene with longevity was unclear. Therefore, we calculated haplotype frequencies of the 442D:G and Taq1B polymorphisms of the CETP gene in centenarians and controls (Table 7). Despite the limited sample size, we found an extremely lower frequency of 442D:G and B1B1 haplotype than of 442D:G and B2B2 in centenarians (P=0.0328, 2). The frequency of the haplotype in centenarians seems to be lower than that in controls (P=0.2489, 2). The result indicated that the 442D:G and B1B1 haplotype in the CETP gene could be disadvantageous for longevity. The findings should be investigated in a future study with a large sample size.

We found a significant association between the LPL PvuII( / ) genotype and higher HDL-C concentration in centenarians but not in controls. Results from epidemiological studies on the association between the LPL genotype and serum lipid have been conflicting. Chamberlain et al. [11] reported significant associations between the LPL PvuII(+/+) genotype and higher triglycerides and lower HDL-C. Wang et al. [12] confirmed a similar effect of the LPL PvuII(+) allele on triglycerides but not on HDL-C concentrations in whites. Gerdes et al. [13] reported that dose-dependent associations of the LPL HindIII H(+) allele with higher HDL-C, while no significant association between the LPL PvuII genotype and any lipid variables in middle-aged Danish men. The inconsistency of those results could be due not only to ethnicity but also to confounding factors such as abdominal adiposity and other cardiovascular risk factors which may affect the significance of the LPL genotype. In the present study, multiple regression analysis revealed that the determinants of HDL-C concentration are quite different between centenarians and controls, suggesting that the relationship between LPL polymorphisms and lipid levels could be modulated by environmental factors as previously described by Wang et al. [12]. It is possible that the LPL genotype has a dual function on lipid metabolism in relation to middle or old age. Methods in evaluating the overall efficacy of reverse cholesterol transport are required to investigate which combination of candidate gene polymorphisms could be optimum for human longevity.