The expression of IL-10 is tightly regulated. Its levels are variable between individuals, and almost 70% of such intra-individual variation is heritable. In fact, IL-10 production is controlled by several polymorphic elements in the 5' flanking region of IL-10 gene on 1q32 locus, involving alleles at two microsatellite regions and several SNPs both in distal and proximal promoter region. However, in the proximal promoter region, three different inheritable haplotypes involving three biallelic polymorphisms at 1082 (G>A), 819 (C>T), and 592 (C>A) nucleotides of IL-10 promoter have been identified. One containing the 1082G allele (1082G/819C/592C) seems to be associated with high IL-10 production, and two containing the 1082A allele (1082A/819C/592C and 1082A/819T/592A) seem to be associated with lower cytokine production.

The prevalence of these polymorphisms was analyzed in a large number of Italian centenarians and compared to a group of younger control subjects. The three SNPs under study are in strong linkage. Thus, as observed in other Caucasian populations, only three out of eight possible haplotypes (GCC, ACC, and ATA) segregate in our population. The 1082G/819C/592C haplotype was the more represented haplotype in both the controls and centenarians (0.62±0.02 vs. 0.68±0.03), whereas the 1082A/819T/592A was the less frequent haplotype (0.16±0.01 vs. 0.13±0.02). The frequencies of the 1082A/819C/592C haplotype respectively were 0.21±0.01 and 0.19±0.02. No significant differences in haplotype distribution between centenarians and controls were observed by performing the analysis both on the whole and according to gender.

The positive significant association between 1082 IL-10 polymorphism and longevity was observed in centenarian men but not in women, in accord with previous observations on polymorphisms in Tyrosine Hydroxylase gene and mtDNA haplogroups. On the other hand, hemochromatosis and interferon (IFN)-γ gene polymorphisms have been shown to be associated with longevity in women but not in men. Altogether, these findings point out that gender is a major variable in the genetics of longevity and suggest as a working hypothesis that men and women follow different strategies to reach longevity.

The clean effect of a given gene is a function of the gene pair combination received from parents, and for 1082 SNP, a gene dosage-dependent effect on the IL-10 production has been suggested. Thus, we have evaluated the homo- and heterozygous frequency for the three SNPs under study in the two groups of subjects. The number of centenarians homozygous for 1082G genotype was increased in comparison with younger control subjects, but this increase attained significance only in men. Turner et al. showed not only that the 1082G allele is correlated with a high capability to produce IL-10 but also that this characteristicEffros RB, Caruso C, Remarque E, Barnett Y, Solana R. T cells and aging. Front Biosci; : D. 

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Subjects and IL-10 typing (9 DNA samples were obtained from 190 centenarians (99 years old, 159 women and 31 men) from north (n=58), centre (n=80) and south (n=52) Italy). Women outnumbered men with a ratio of about 5:1, similar to that expected from previous investigations. Age was verified by researching archival records in the City Hall and/or Church registries, paying attention to the concordance between reported age and personal chronologies (age of marriage and of military service for men, age of first and last pregnancy for women, age of children among others). DNAs from 260 (99 women and 161 men) 60 years old controls matched for geographical origin were also collected. Written informed consent for enrolling in the study and for personal data management was obtained from all the subjects according to Italian laws. Blood specimens were collected in tripotassium EDTA sterile tubes and immediately stored at -70 C. Genomic DNA extraction was carried out according to Miller et al and stored at -20 C for the IL-10 gene analysis. Three different biallelic polymorphisms at 1082 (G>A), 819 (C>T) and 592 (C>A) nucleotides, were identified using the oligotyping hybridisation methodology of Turner et al as previously described. Statistical analysis IL-10 allele frequencies were evaluated by gene count and haplotype frequencies calculated by a maximum likelihood algorithm (Arlequin Software, University of Geneva). The data were tested for the goodness-of-fit and between the observed and expected genotype values (chi-square test) and their fit to Hardy-Weinberg equilibrium. Analysis of statistical differences between haplotype frequencies in centenarians and controls were evaluated by...

13 http://www.pam.bris.ac.uk./services/GAI/cytokine4.htm.

14 Bhojak TJ, DeKosky ST, Ganguli M, Kamboh MI. Genetic polymorphisms in the cathespin D and interleukin-1 genes and the risk of Alzheimer's disease. Neurosci Lett; : .

Grimaldi LM, Casadei VM, Ferri C et al. Association of early-onset Alzheimer's disease with an interleukin-1α gene polymorphism. Ann Neurol; : .

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