Gender-specific association between −1082 IL-10 promoter polymorphism and longevity

Abstract

Ageing is characterized by a pro-inflammatory status, which could contribute to the onset of major age-related diseases. Thus, genetic variations in pro- or anti-inflammatory cytokines might influence successful ageing and longevity. IL-10 is an appropriate candidate because it exerts powerful inhibitory effects on pro-inflammatory function. 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 polymorphisms in promoter region. We analysed in 190 Italian centenarians (>99 years old, 159 women and 31 men) and in 260 <60 years old control subjects (99 women and 161 men), matched for geographical distribution, genotype frequencies for −1082GA, −819CT and −592CA IL-10 proximal promoter gene biallelic polymorphisms by sequence specific probes. −1082G homozygous genotype was increased in centenarian men (P < 0.025) but not in centenarian women. No difference was found between centenarians and control subjects regarding the other two polymorphisms. The presence of −1082GG genotype, suggested to be associated with high IL-10 production, significantly increases the possibility to reach the extreme limit of human lifespan in men. Together with previous data on other polymorphic loci (Tyrosine Hydroxylase, mitochondrial DNA, IL-6, haemochromatosis, IFN-γ), this finding points out that that gender is a major variable in the genetics of longevity, suggesting that men and women follow different strategies to reach longevity. Concerning the biological significance of this association, we have not searched for functional proves that IL-10 is involved. Thus, we should conclude that our data only suggest that a marker on 1q32 genomic region may be involved in successful ageing in man. However, recent data on IL-6 and IFN-γ genes suggest that longevity is negatively associated with genotypes coding for a pro-inflammatory profile. Thus, it is intriguing that the possession of −1082G genotype, suggested to be associated with IL-10 high production, is significantly increased in centenarians.