by the concordance of the present data with the analogous data reported for the HLA-DR locus, which is in linkage disequilibrium with the (A/C)−110 poly- morphism (Cascino et al. 1993a,b). Indeed, a female- specific association has been reported between some alleles of the HLA-DR locus and longevity (Ivanova et al. 1998). These results clearly indicate that the chromosomal region surrounding HLA-DR and HSP70-1 loci harbors variants which can affect human longevity. The (A/C)−110 polymorphism of HSP70- 1 may be one of the variants that play this role in the above chromosomal region. The (A/C)−110 marker lies in HSF1-HSE binding domain of HSP70-1 (Abravayata et al. 1991). Although this polymorphism was reported not to affect either HSE-HSF binding or hsp70 protein synthesis (Favatier et al. 1999), the possibility that allele (A)−110 and allele (C)−110 may have slightly different binding efficiency in very old organisms is a reasonable hypothesis. In fact, from a biological point of view, aging is a stressful condi- tion which implies a profound reshaping of most physiological functions (Franceschi et al. 2000c). Allele (A)−110 may have a lower efficiency than allele (C)−110 in coping with such a stressful condi- tion which is also accompanied by the physiological age-related decline of the HSE-HSF binding activity (Gutsmann-Conrad et al. 1998). This would explain the age-related frequency decrease of allele (A)−110 in the healthy aging population. In vitro experiments on (A/C)−110 allele-specific expression in cells from very

As for males (Table 1b), no significant age-related modification of the (A/C)−110 genotypic/allele pool was observed. In fact the (A)−110 allele frequency was independent of the age of the sample group (b = 1 0.0003, 95% c.i. [–0.0018, 0.0023]). In agreement, no difference was present between ‘cases’ and ‘controls’ as defined above (χ 12 = 0.432, P = 0.511 for alleles; χ 22 = 0.547, P = 0.761 for genotypes).

Discussion

Association studies with candidate genes are powerful tools for dissecting the genetics of complex traits.

Table 1. Genotypic and allelic counts of the (A/C)−110 polymorphism in females (a) and males (b) of different Relative frequencies (× 100 ± standard error) are given in parentheses.

Age class (years) Genotypes Alleles AA AC CC A C 18–29 40 (46.0 ± 5.3) 39 (44.8 ± 5.3) 8 (9.2 ± 3.1) 119 (68.4 ± 3.5) 55 (31.6 ± 3.5) 30–49 29 (49.2 ± 6.5) 26 (44.1 ± 6.5) 4 (6.8 ± 3.3) 84 (71.2 ± 4.2) 34 (28.8 ± 4.2) 50–69 22 (36.7 ± 6.2) 30 (50.0 ± 6.5) 8 (13.3 ± 4.4) 74 (61.7 ± 4.4) 46 (38.3 ± 4.4) 70–89 12 (35.3 ± 8.2) 17 (50.0 ± 8.6) 5 (14.7 ± 6.1) 41 (60.3 ± 5.9) 27 (39.7 ± 5.9) 90–109 28 (31.8 ± 5.0) 44 (50.0 ± 5.3) 16 (18.2 ± 4.1) 100 (56.8 ± 3.7) 76 (43.2 ± 3.7) b) Males Age class (years) Genotypes Alleles AA AC CC A C 18–29 11 (45.8 ± 10.2) 9 (37.5 ± 9.9) 4 (16.7 ± 7.6) 31 (64.6 ± 6.9) 17 (35.4 ± 6.9) 30–49 24 (32.9 ± 5.5) 31 (42.5 ± 5.8) 18 (24.7 ± 5.0) 79 (54.1 ± 4.1) 67 (45.9 ± 4.1) 50–69 32 (40.0 ± 5.5) 39 (48.8 ± 5.6) 9 (11.2 ± 3.5) 103 (64.4 ± 3.8) 57 (35.6 ± 3.8)           

AA AC CC A C 18–29 11 (45.8 ± 10.2) 9 (37.5 ± 9.9) 4 (16.7 ± 7.6) 31 (64.6 ± 6.9) 17 (35.4 ± 6.9) 30–49 24 (32.9 ± 5.5) 31 (42.5 ± 5.8) 18 (24.7 ± 5.0) 79 (54.1 ± 4.1) 67 (45.9 ± 4.1) 50–69 32 (40.0 ± 5.5) 39 (48.8 ± 5.6) 9 (11.2 ± 3.5) 103 (64.4 ± 3.8) 57 (35.6 ± 3.8) 70–89 20 (44.4 ± 7.4) 19 (42.2 ± 7.4) 6 (13.3 ± 5.1) 59 (65.6 ± 5.0) 31 (34.4 ± 5.0) 90–106 16 (39.0 ± 7.6) 18 (43.9 ± 7.8) 7 (17.1 ± 5.9) 50 (61.0 ± 5.4) 32 (39.0 ± 5.4)     

rel. freq.oo200 400 @ obs. freqtrajectory+ + + + upper envelope———— lower envelope1200600 800age (years)

Figure 1. Age-related frequency trajectory of the (A)−110 allele of the HSP70-1 gene analysed in females (subjects aged 18–29; 30–49; 50–69; 70–89; 90–109 years). The observed frequencies of the allele in the five age groups, the fitting straight line (least squares method) and the lower and upper envelopes of 10,000 simulated trajectories are shown.

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