Genotype Number (%) IL-10 (cid:1)819 C/C 48 (9.6) C/T 226 (45.2) T/T 226 (45.2) IL-10 (cid:1)592 C/C 48 (9.6) C/A 226 (45.2) A/A 226 (45.2) IL-10 (cid:1)1082 G/G 3 (0.6) G/A 41 (8.2) A/A 456 (91.2)

a Japanese population. Our present data also suggested a possible association of TNF-a (cid:1)1031 T/C with age and of IL-18 (cid:1)607 A/C and MMP-3 (cid:1)1171 5A/6A with gender. However, multiple testing may cause a false-positive result. When our data in Table 2 were evaluated by Bonferroni correction, only an association of IL-10 (cid:1)819 T/T with age attained statistical significance. However, it may be possible that the Bonferroni correction overcorrects for the inflated false-positive rate and thereby throws away valid informa- tion in the sample (23). A weak association should be regarded as a borderline statistical association at the present time and subjected to further investigations. Although the association of TNF-a (cid:1)1031 T/C with age and that of IL-18 (cid:1)607 A/C with gender are our new findings, the association of MMP-3 (cid:1)1171 5A/6A with gender was previously pointed out in coronary heart disease (24,25).

control participants 25–53 years old, indicating an increased or decreased frequency of the genotype GCC/GCC or ACC/ ATA, respectively, in an elderly group. These reports suggested the importance of the G allele of (cid:1)1082 A/G. However, no significant association of (cid:1)1082 A/G with longevity was observed in Finnish nonagenarians (14), an aged Irish population (15), or Sardinian centenarians (14). As one possible explanation for such discrepancies, Pes and colleagues (17) suggested that cytokine–longevity associa- tions have a population-specific component, being affected by the population-specific gene pool as well as by gene– environment interactions.

people (mean age, 82.3 years; range, 64–100 years) with mild chronic disorders except for malignancy; these 163 people made up 65.7% of the 248 participants (cid:2)64 years old. However, when considering that 63.2% of Japanese people aged (cid:2)65 years are receiving regular outpatient treatment due to some disease (based on the data in the Official Web Site of Ministry of Health, Labour and Welfare in Japan, http://www.mhlw.go.jp/), this percentage of patients with chronic disorders in our population could correspond to that in the entire Japanese population. We also compared the genotype distribution of all the SNPs tested between 163 elderly patients from the hospital setting and healthy controls aged (cid:2)64 years (n ¼ 85; mean age, 77.9 years; range, 64–98 years). None of the SNPs showed a significant difference of genotype distribution between these 2 groups (data not shown). Furthermore, there was no significant difference of genotype distribution and allele frequency on IL-10 (cid:1)819 T/C between our population and other Japanese populations previously reported (26,27), suggesting the absence of remarkable genetic heterogeneity in our population.

We showed that the genotype distribution of IL-10 (cid:1)1082 A/G is different from that of (cid:1)819 T/C or (cid:1)592 A/C in the Japanese population used in this study. This result was consistent with previous findings in a Japanese population (29), but differed from those in Caucasian populations (8,14), which revealed that these 3 polymorphisms were strongly linked, and only 3 of 8 possible haplotypes (GCC, ACC, ATA) segregated in Caucasian populations (8,22). In our population, IL-10 (cid:1)819 T/C was in perfect linkage disequilibrium with (cid:1)592 A/C, whereas it was not with (cid:1)1031 A/G [linkage disequilibrium was calculated as described previously (30); data not shown]. It was thus considered that there is little significance of this haplotype analysis in our population. The genotype distribution of these 3 polymorphisms was also quite different between our population and a Caucasian population (14). These findings clearly indicate a populational difference of the IL-10 promoter polymorphisms.

The effect of (cid:1)1082 A/G on IL-10 gene transcription or protein production seems to be controversial at the present time (31). In contrast, Temple and colleagues (32) reported the (cid:1)819 TT/(cid:1)592 AA haplotype as a determinant of high IL-10 transcription when peripheral blood mononuclear cells were stimulated with lipopolysaccharide or heat-killed Streptococcus pneumoniae, and IL-10 messenger RNA was measured by reverse transcriptase–PCR, although it is still not clear whether the haplotype affects IL-10 production at the protein level. This finding might be supported by a recent association study showing that the IL-10 (cid:1)592 A/A genotype was associated with a decreased risk of grade III or IV acute graft-versus-host disease and death in remission in 933 recipients after hematopoietic cell transplantation (33). Further studies on different populations, and functional

Association of IL-10 promoter polymorphisms with longevity was previously shown in two studies. Lio and colleagues (8) first reported that the frequency of the IL-10 (cid:1)1082 G/G genotype was increased in centenarian men, but not in centenarian women, compared with control partic- ipants ,60 years old. No difference was found between centenarians and controls for the (cid:1)819 T/C and (cid:1)592 A/C genotype distributions. As several functional studies suggested a relation between IL-10 (cid:1)1082 GG and AG genotypes with a higher production of IL-10 (28), the data indicated that IL-10, a major anti-inflammatory cytokine, could be involved in successful aging. In another study (9), haplotypes (GCC, ACC, ATA) were compared between elderly people in 10 families with longevity members and

Further studies on different populations, and functional analyses of IL-10 (cid:1)819 and (cid:1)592 regions, are required to confirm the association of (cid:1)819 T/C and (cid:1)592 A/C with

Cavallone L, Bonafe M, Olivieri F, et al. The role of IL-