We also performed stepwise multiple regression anal- ysis to evaluate independent contribution of heterozy- gous CETP deficiency and the Taq1B genotype, the LPL − − PvuII( / ) genotype and environmental factors to the

Table 7 Haplotype frequencies of 442D:G and Taq1B polymor- phisms of CETP gene in centenarians and controls. Data are pre- sented as observed number of cases and expected number of cases (parentheses) as calculated by the model of null hypothesis. In neither centenarians nor controls was Taq1B genotype and 442D:G mutation not in linkage disequilibrium (χ2=2.961, χ2=0.733, respectively)

C in centenarians. In contrast, sex was the strongest predictor of HDL-C in controls (r2=0.23, F =50.1, P<0.0001). Both CETP deficiency and the Taq1B geno- type were also independently associated with HDL-C; however, the LPL PvuII genotype had no significant ef- fect on their HDL-C in controls.

B1B1 B1B2 B2B2 Centenarians Wild type (n=238) 71 (67.8) 121 (122.8) 46 (47.4) 442D:G (n=16) 1 (4.6) 10 (8.3) 5 (3.2) Controls Wild type (n=174) 60 (59.2) 76 (76.5) 38 (37.2) 442D:G (n=13) 3 (5.4) 7 (7.0) 3 (3.4)

Discussion

deficiency and other genetic polymorphisms in RCT as a longevity factor for Japanese centenarians. The present study explored whether although heterozygous CETP de- ficiency is consistently associated with higher HDL-C concentrations both in centenarians and controls, this de- ficiency is not associated with longevity. In this point we agree with the results from the Omagari study reported by Hirano et al. [10]; however, our study provided no ev- idence that common CETP deficiency is disadvanta- geous for longevity. The allele frequencies of overall CETP deficiency in centenarians and controls were 0.035 and 0.042, respectively, which are similar to those of 0.042 in general population in Kanazawa [30] and 0.029 in Japanese-American men in the Honolulu Heart Study [6]. Although the number of centenarians with CETP deficiency was limited, we found no history of CAD or other atherosclerotic disease among those sub- groups. Neither was CETP deficiency associated with cognitive dysfunction or problems of activities of daily living in centenarians (data are not shown). To date much experimental and epidemiological data have been accumulated; however, the role of CETP on atherogene- sis is still in debating. Proatherogeneity of CETP defi- ciency is widely accepted to be caused by impairment of RCT. Results from the Honolulu Heart Study [6] indicate that a common CETP mutation could be a risk factor for CAD if it is combined with an HDL-C concentration be- tween 41–60 mg/dl. Hirano et al. [7] has reported that hyperalphalipoproteinemia caused by CETP gene defi- ciency can be associated with increased CAD when it combined with low HL activity. Hirano et al. [7] have also noted the interesting finding that CETP deficiency could not be susceptible for CAD if accompanied by higher LPL activity. These findings indicate that 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 antiatherogenic property of HDL parti- cle itself. In the study, however, there was no significant difference in demographics and biochemical parameters except HDL-C and CETP mass between centenarians with CETP deficiency and those with wild type. Neither did frequency of the C allele of the promoter polymor- phism in the HL gene, which may be associated with in- creased with 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 of

ed with lower CETP mass and with higher HDL-C con- centration in both centenarians and controls; however, we found no significant association with the allele and longevity. The result remained unchanged after exclud- ing the participants with CETP deficiency. Ordovas et al. [32] reported that the B2 allele is associated with higher HDL-C and with lower CAD risk only in men, not in women, in a population-based sample from the Framing- ham Offspring Study. In the present study even after re- striction 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 no associa- tion of two polymorphisms of CETP gene with longevity was unclear. Therefore we calculated haplotype frequen- cies of the 442D:G and Taq1B polymorphisms of CETP gene in centenarians and controls (Table 7). Despite the limited sample size we found extremely a lower frequen- cy of 442D:G and B1B1 haplotype than of 442D:G and χ B2B2 in centenarians (P=0.0328, 2). The frequency of the haplotype in centenarians seems to be lower than that χ in controls (P=0.2489, 2). The result indicated that the 442D:G and B1B1 haplotype in CETP gene could be disadvantageous for longevity. The findings should be investigated in a future study with large sample size.

− − a significant association between the LPL PvuII( / ) genotype and higher HDL-C concentration in centenari- ans 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 triglyceride, and lower HDL-C. Wang et al. [12] confirmed a similar effect of the LPL PvuII(+) allele on triglyceride but not on HDL-C concentrations in whites. Gerdes et al. [13] reported that a dose-dependent associations of the LPL HindIII H(+) allele with higher HDL-C, while no significant as- sociation 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