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

D Lio1, L Scola1, A Crivello1, G Colonna-Romano1, G Candore1, M Bonafè2, L Cavallone3, C Franceschi2,3 and C Caruso1

1 Dipartimento di Biopatologia e Metodologie Biomediche, Università di Palermo, Palermo, Italy; 
2 Dipartimento di Patologia Sperimentale, Università di Bologna, Bologna, Italy; 
3 Istituto Nazionale di Riposo e Cura per Anziani di Ancona, Ancona, Italy 

Ageing is characterized by a pro-inflammatory status that 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 the IL-10 gene on 1q32 locus, involving alleles at two microsatellite regions and several polymorphisms in the promoter region. We analyzed 190 Italian centenarians (≥99 years old), 159 women and 31 men and 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 biallelic polymorphisms were determined by sequence-specific probes. The 1082G homozygous genotype was increased in centenarians (P ≤ 0.025) but not in centenarian women. No difference was found between centenarians and control subjects for the other two polymorphisms. The presence of the 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 gender is a major variable in the genetics of longevity, suggesting that men and women use different strategies to reach longevity. Concerning the biological significance of this association, we have not found functional proof 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 men. However, recent data on IL-6 and IFN-γ genes suggest 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 high IL-10 production, is significantly increased in centenarians.

Keywords: IL-10; longevity; inflammation; centenarians; immunogenetics

Introduction

Survival from 80 to more than 100 years of age suggests that genetics plays a role in longevity. Indeed, there is some evidence that extreme longevity clusters in some families and preliminary results from several studies suggest a modest recurrent risk for exceptional longevity. Therefore, the role of genetics in longevity might be much higher than predicted. Current evidence, based primarily on Scandinavian Twin Registries, suggests that about a quarter of the variation in adult lifespan can be attributed to genetic factors; i.e., the heritability of lifespan is about 25%. It is not known, however, how important genetic factors are in explaining survival from 80 to more than 100 years of age.

A dysregulation of both immune and inflammatory responses occurring with increasing age is believed to substantially contribute to morbidity and mortality in humans. Conversely, human longevity seems to be directly correlated with optimal functioning of the immune system, suggesting that some genetic determinants of successful ageing might reside in those polymorphisms for the immune system genes that regulate immune responses.

Correspondence: Prof. C Caruso, Laboratorio di Immunopatologia, Dipartimento di Biopatologia e Metodologie Biomediche, Corso Tukory 211, 90134 Palermo, Italy. E-mail: marcoc@unipa.it

These studies have been supported by grants from MURST, Rome (ex 40%, Immunogenetics of Longevity, coordinated by Professor Calogero Caruso, to CC and DL), ex 60% to CC and DL., from Ministry of Health Projects Immunological parameters age-related and Pharmacogenomics of Alzheimer's Disease, from Sicilian Government Breast Cancer and Immune Response and by a cooperation contract between the Dipartimento di Biopatologia e Metodologie Biomediche dell'Università di Palermo and theTargets for transcription regulating factors have been described, even if conflicting results have been reported on which of these may influence, alone or in reciprocal linkage, the transcription of IL-10. However, a biallelic polymorphism at 1082 (G>A) has been described in the proximal region of the promoter, and the homozygous genotype for the SNP allele 1082*G seems to be associated with higher IL-10 production compared to G/A heterozygous and A/A homozygous. The effects of this allelic promoter region difference (relative to the transcription start site) on IL-10 gene activation have been confirmed in reporter gene assays. On the other hand, it should be taken into account that different effects may be observed in different cells with different stimuli. However, this SNP seems to be functionally relevant. In fact, 1082A carriers (i.e., IL-10 low producers) have been shown to be more likely to develop inflammatory diseases (or to be affected by more severe clinical patterns), such as rheumatoid arthritis. Conversely, it can be hypothesized that anti-inflammatory cytokines might be involved in successful aging and longevity. The cytokine IL-10 seems to be an appropriate candidate from this point of view. In fact, IL-10 was recognized for its ability to inhibit activation and effector function of T cells, monocytes and macrophages. Its principal routine function appears to be to limit and ultimately terminate inflammatory responses.