cluster polymorphisms are devoid of any functional significance in this respect; alternatively, the second is that IL-1 polymorphisms have a functional value, but they do not impinge upon longevity at the population level due to their limited impact on whole population mortality. In fact, the relationship between IL-1 gene cluster parameters and susceptibility to or severity of a variety of immunologically mediated diseases (Clay et al., 1994; Crusius et al., 1995; Heresbach et al., 1997; Hurme et al., 1998; Nemetz et al., 1999) as well as age- related diseases such as Alzheimer’s (Grimaldi et al., 2000; Licastro et al., 2000) and coronary single vessel disease (Francis et al., 1999), has been widely acknowl- edged. However, both the present work and the paper on Finnish nonagenarians suggest that the overall increase in the susceptibility to various diseases due to particular genotypes at the IL-1 cluster is likely to be small at the population level, indicating that even if these polymorphisms affect the progression of common age-related diseases, their importance is slight. In this regard, a number of genetic risk factors associated with major age-related diseases have been found to be under- represented in centenarians. This is the case for APOE

were consistent with those predicted by the HWE (P  / 0.05). No significant difference in the genotype fre- quency distributions was observed, neither when the sexes were analysed together (Table 1) nor separately (data not shown). The analysis of the difference in the three groups of allele frequency distributions was also not significant (Table 2) even when the sexes were analysed separately (data not shown). The frequency distribution of the three loci haplotypes was estimated in the three age groups by means of maximum likelihood estimation algorithm (Table 3). Again, no significant differences were detected.

3.2. IL-1Ra and IL-1b plasma levels during aging

IL-1Ra plasma levels were assessed in a group of 130 unrelated randomly selected subjects (71 females and 59 males) ranging from 20 to 102 years of age. Fig. 1 shows that IL-1Ra plasma levels showed a significant age-

Table 1

Genotype frequency distributions of IL-1Ra, IL-1a and IL-1b polymorphism in 688 young subjects, 309 elderly subjects and 134 centenarian subjects from Northern and Central Italy

19(cid:1)64 years (n(cid:5)688, %9S.D.) 65(cid:1)99 years (n(cid:5)309, %9S.D.) 100 years (n(cid:5)134, %9S.D.) / / / / / / / / IL-1Ra VNTRa 11 356 (0.5290.02) 170 (0.5590.03) 70 (0.5290.04) / / / 12 243 (0.3590.02) 94 (0.3090.03) 52 (0.3990.04) / / / 13 23 (0.0390.01) 13 (0.0490.01) 4 (0.0390.01) / / / 22 57 (0.0890.01) 28 (0.0990.02) 7 (0.0590.02) / / / 23 9 (0.0190.01) 4 (0.0190.01) 1 (0.0190.01) / / / IL-1a (cid:2)889b / CC 337 (0.4990.02) 137 (0.4490.03) 71 (0.5390.04) / / / CT 287 (0.4290.02) 142 (0.4690.03) 51 (0.3890.04) / / / TT 64 (0.0990.01) 30 (0.1090.02) 12 (0.0990.02) / / / IL-1b (cid:2)511c / CC 288 (0.4290.02) 129 (0.4290.03) 58 (0.4390.04) / / / CT 318 (0.4690.02) 141 (0.4690.03) 61 (0.4690.04) / / / TT 82 (0.1290.01) 39 (0.1290.02) 15 (0.1190.03) / / /

All groups were in HWE (P (cid:1)0.05). x2-tests for comparison of genotype distribution was performed by Monte-Carlo algorithm implemented in / SPSS. No significant different distributions of IL-1 cluster alleles were observed between the three groups of subjects. a x2(cid:5)5.407; d.f.(cid:5)8; P(cid:5)0.72. / / / b x2(cid:5)3.337; d.f.(cid:5)4; P(cid:5)0.51. / / / c x2(cid:5)0.258; d.f.(cid:5)4; P(cid:5)0.99. / / /

polymorphism, a major risk factor for Alzheimer’s and cardiovascular diseases (Gerdes et al., 2000), and for IL- 6-174C/G polymorphism which is associated with sus- ceptibility to a variety of cardiovascular diseases (Basso et al., 2002). This latter finding is of particular im- portance since it concerns an inflammatory cytokine, and it recalls other data indicating that even IL-10 and

Thus, the current data suggest that IL-1 cluster polymorphisms, in contrast to the genetic variation at other proinflammatory/anti-inflammatory cytokines, have a negligible impact on human longevity. Moreover, we suggest that the age-related changes in the plasma

Table 2

Allele frequency distributions of IL-1Ra, IL-1a and IL-1b polymorphisms in 688 young subjects, 309 elderly subjects and 134 centenarian subjects from Northern and Central Italy

19(cid:1)64 years (n(cid:5)1376, %9S.D.) 65(cid:1)99 years (n(cid:5)618, %9S.D.) 100 years (n(cid:5)268, %9S.D.) / / / / / / / / IL-1Ra VNTRa 1 978 (0.7190.01) 447 (0.7290.02) 196 (0.7390.03) / / / 2 365 (0.2690.01) 153 (0.2590.02) 67 (0.2590.03) / / / 3 33 (0.0290.00) 18 (0.0390.01) 5 (0.0290.01) / / / IL-1a (cid:2)889b / C 961 (0.7090.01) 416 (0.6790.02) 193 (0.7290.03) / / / T 415 (0.3090.01) 202 (0.3390.02) 75 (0.2890.03) / / / IL-1b (cid:2)511c / C 894 (0.6590.01) 399 (0.6590.02) 177 (0.6690.03) / / / T 482 (0.3590.01) 219 (0.3590.02) 91 (0.3490.03) / / /

x2-tests for comparison of allelic distribution was performed by use of Monte-Carlo algorithms implemented in SPSS. No significant different distributions of IL-1 cluster alleles were observed between the three groups of subjects. a x2(cid:5)1.702; d.f.(cid:5)4; P(cid:5)0.79. / / / b x2(cid:5)2.255; d.f.(cid:5)2; P(cid:5)0.33. / / / c x2(cid:5)0.181; d.f.(cid:5)2; P(cid:5)0.92. / / /

x2-tests for comparison of allelic distribution was performed by use of Monte-Carlo algorithms implemented in SPSS. No significant different distributions of IL-1 cluster alleles were observed between the three groups of subjects.

Table 3

Haplotype frequency distributions of IL-1 gene cluster in 688 young subjects, 309 elderly subjects and 134 centenarian subjects from Northern and Central Italy