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Inflammation, genetics, and longevity: further studies on the protective effects in men of IL-10-1082 promoter SNP and its interaction with TNF-α -308 promoter SNP

Ageing is associated with chronic, low grade inflammatory activity leading to long term tissue damage, and systemic chronic inflammation has been found to be related to mortality risk from all causes in older persons.1 Also, the genetic constitution of the organism interacting with systemic inflammation may cause defined organ specific illnesses. Thus, age related diseases such as Alzheimer’s disease (AD), Parkinson’s disease, atherosclerosis, type 2 diabetes, sarcopenia, and osteoporosis, are initiated or worsened by systemic inflammation, suggesting the critical importance of unregulated systemic inflammation in the shortening of survival in humans.1–3 Accordingly, proinflammatory cytokines are believed to play a pathogenetic role in age related diseases, and genetic variations located within their promoter regions have been shown to influence the susceptibility to age related diseases, by increasing gene transcription and therefore cytokine production.3,4 Conversely, genetic variations determining increased production of anti-inflammatory cytokines or decreased production of proinflammatory cytokines have been shown to be associated with successful ageing, suggesting a role for the control of the inflammatory state in the attainment of longevity. As recently reported, the distribution of +874T→A interferon(IFN)-γ,5 −174C→G IL-6,6 and −1082G→A interleukin(IL)-107 single nucleotide polymorphisms (SNPs) has been shown to be different in centenarians than in younger people.5–7 The +874T allele, involved in high production of the proinflammatory cytokine IFN-γ, was found less frequently in centenarian women than in control women.5 Also, the proportion of subjects homozygous for the G allele at the −174 IL-6 locus, characterised by high serum levels of the proinflammatory cytokine IL-6, was significantly decreased in centenarian men.6 Conversely, the presence of the −1082 GG genotype, suggested to be associated with high production of the anti-inflammatory cytokine IL-10, was significantly increased in centenarian men in comparison with younger male subjects.7 These …

Opposite effects of interleukin 10 common gene polymorphisms in cardiovascular diseases and in successful ageing: genetic background of male centenarians is protective against coronary heart disease

Centenarians escape, or at least have a delay in, age associated diseases that normally cause mortality at earlier ages. Considerable evidence supports the involvement of genetic components to longevity. Accordingly, the siblings of centenarians have a markedly increased probability of living to 100 years of age. A recent study showed that the offspring of centenarians had a markedly reduced prevalence of age associated diseases, particularly cardiovascular disease and cardiovascular risk factors. On the other hand, this is not unexpected in view of the fact that cardiovascular diseases account for about 50% of all deaths worldwide.1–3 ### Key points

Allele frequencies of +874T→A single nucleotide polymorphism at the first intron of interferon-γ gene in a group of Italian centenarians

Ageing is characterized by a pro-inflammatory status which could contribute to the onset of major age-related diseases such as cardiovascular diseases, neurodegeneration, osteoarthritis and osteoporosis, and diabetes. Thus, it can be hypothesized that genetic variations in pro- or anti-inflammatory cytokines might influence successful ageing and longevity. We have studied the distribution of +874T-->A interferon-gamma (IFN-gamma) polymorphisms in a large number of Italian centenarians to evaluate if the two alleles might be differently represented in people selected for longevity. DNA samples were obtained from 174 Italian centenarians (>99 years old, 142 women and 32 men) and from 248 <60-year-old control subjects (90 women and 158 men) matched for geographical distribution. Polymorphisms at +874 were identified by using amplification refractory mutational system methodology. The +874T allele was found less frequently in centenarian women than in centenarian men or in control women whereas no significant differences were observed in the distribution of the two alleles between male or female controls. Allele frequencies in centenarian men were not found significantly different from male controls. Possession of the +874A allele, known to be associated with low IFN-gamma production, significantly increases the possibility to achieve extended longevity, suggesting that the pro-inflammatory status characteristic of ageing may be detrimental for successful ageing. The datum that the allele was significantly increased in female but not male centenarians seems to strengthen the idea that gender may be a major variable in the biology of the ageing process. However, the present data add another piece of evidence to the complex puzzle of genetic and environmental factors involved in controlling life span expectancy in humans. Thus, studies on cytokine gene polymorphisms may promise to individuate a complex network of trans-interactive genes able to influence the type and strength of responses to environmental stressors and as a final result, thereby conditioning individual life expectancy.

IL-10 and TNF-α polymorphisms and the recovery from HCV infection

Abstract Hepatitis C virus (HCV) infection becomes chronic in about 85% of infected individuals, whereas only 15% of infected people clear spontaneously the virus. It is conceivable that the host immunogenetic background influences the course of infection in term of recovery. Thus, in this study we have evaluated the effect of functionally relevant polymorphisms at tumor necrosis factor-α (TNFα, i.e., 2 biallelic polymorphisms at nt -863 and nt-308 of the promoter) and interleukin-10 (IL-10) loci (i.e., 1 biallelic polymorphism at nt -1082 of the promoter), on the clearance of HCV infection. To this purpose, we compared 18 Sicilian patients who had spontaneously recovered from previous HCV infection with 42 Sicilian patients with current HCV infection and 135 Sicilian healthy patients. The results demonstrate a decreased frequency of the -863CC TNF-α promoter genotype (involved in high production of this pro-inflammatory cytokine) and an increased frequency of the -1082GG IL-10 promoter genotype (involved in high production of this anti-inflammatory cytokine) in patients recovered from HCV infection. The evaluation of combined TNF-α and IL-10 genotypes revealed a significant increase of the “anti-inflammatory genotype” (low-TNF/high-IL-10 producers) in resolved HCV infection group compared with patients with persistent HCV infection. On the whole, our findings suggest that a genetically determined control of the HCV-induced inflammatory response may play a role in the resolution of HCV infection.

Association between longevity and cytokine gene polymorphisms. A study in Sardinian centenarians

Background and aims: Human longevity seems to be directly correlated with optimal functioning of the immune system, suggesting that some genetic determinants of longevity reside in those polymorphisms for the immune system genes which regulate immuneinflammatory responses, in particular cytokine gene polymorphisms. The frequency of − 174C single nucleotide polymorphism (SNP) in the promoter region of the interleukin(IL)-6 gene is increased in Italian male centenarians. Moreover, the frequency of − 1082G SNP at the 5′ flanking region of the IL-10 gene coding sequence is increased among male centenarians, and that of +874A SNP at the interferon (IFN)- γ gene was found more frequently in female centenarians. These findings indicate that different alleles at different cytokine gene codings for pro- (IL-6, IFN- γ) or anti-inflammatory (IL-10) cytokines may affect the individual life-span expectancy, influencing the type and intensity of immune-inflammatory responses against environmental stressors. Methods: In the present study, we analyzed these IL-6, IL-10 and IFN- γ gene polymorphisms in 112 (36 male, 76 female) centenarians from the island of Sardinia, whose population shows a genetic background quite different from that of mainland Italy, as well as in 137 sixty-year-old controls from the same geographic area. Results: No significant differences were observed on analyzing IL-6, IL-10 and IFN- γ polymorphism frequencies among centenarians and controls, either on the whole and when the data were analyzed according to gender. Conclusions: These data indicate that gene polymorphisms of cytokines playing a major regulatory role in the inflammatory response do not affect life expectancy in the Sardinian population. Thus, cytokine/longevity associations have a population-specific component, being affected by the population-specific gene pool as well as by gene-environment interactions, behaving as survival rather than longevity genes.

IL-10 and TNF-α polymorphisms in a sample of Sicilian patients affected by tuberculosis: implication for ageing and life span expectancy

Human longevity seems to be directly correlated with optimal functioning of the immune system, suggesting that some genetic determinants of longevity might reside in those polymorphisms for the immune system genes that regulate immune responses, in particular cytokine gene polymorphisms. In fact, modification of cytokine network is a constant report in studies on age related modification of immune response. Moreover cytokine polymorphisms studies are indicating their involvement in the reshaping of cytokines network as an integral part of the scenario related to a successful ageing. A particular role might be attributed to the influence of cytokine polymorphisms on the efficiency of immune response against infectious diseases that have been the principal selection in oldest old. Here are reported data on the evaluation of the frequency of the functional polymorphisms at genes coding for TNF-alpha (-308G-->A) and IL-10 (-1082G-->A), analysed by ARMS-PCR, in a group of Sicilian patients affected by chronic lung tuberculosis (TBC) compared to that from a group of healthy individuals living in the same region. Data obtained demonstrated a reduction of -308GG TNF homozygous individuals in TBC affected subject group. In the same group a reduction of IL-10 -1082A/* carriers was found. Our results seem to suggest that multiple genetic traits may affect the capacity to cope with an infectious agents and this might predispose to an overt disease. Moreover these data are in agreement with previous reports suggesting that a balanced interaction among pro- and anti-inflammatory molecules it is a key point for conditioning the life span expectancy.

Cytokine Genotyping (TNF and IL-10) in Patients With Celiac Disease and Selective IgA Deficiency

OBJECTIVE:Selective IgA deficiency (IgAD) and celiac disease (CD) are frequently associated and share the ancestral haplotype human leukocyte antigen (HLA)-8.1, which is characterized by a peculiar cytokine profile. The aim of this study was to evaluate the role of tumor necrosis factor (TNF) and interleukin (IL)-10 alleles in CD and CD-IgAD.METHODS:The distribution of some biallelic polymorphisms of both cytokine promoters (−308G→A and −863C→A at TNF promoter sequence and −1082G→A, −819C→A, and −592C→T at IL-10 promoter) were typed using biotilinated specific probes in 32 celiac patients, in 34 CD-IgAD patients, and in 96 healthy controls.RESULTS:In CD and CD-IgAD, the −308A allele was significantly more frequent than in controls, whereas no significant differences were observed for the biallelic polymorphisms at the −863 and for the three IL-10 promoter polymorphisms. The evaluation of combined TNF and IL-10 genotypes showed in CD-IgAD a significant reduction of −308G/−1082G homozygous subjects and both in CD and CD-IgAD groups an increase of 308AA/1082GG. Accordingly, CD-IgAD patients positive both for −308A TNF and −1082A IL-10 showed an increase of TNF-α and a reduction of IL-10 serum levels.CONCLUSIONS:Genetically determined increased production of TNF-α and reduction of IL-10 may be relevant for susceptibility to CD, mainly in IgAD, as the different allele expression at TNF and IL-10 loci seems to influence cytokine production profile.

Plasma cytokine profiles in patients with celiac disease and selective IgA deficiency

Celiac disease (CD) and selective IgA deficiency (IgAD) are frequently associated, and share the same genetic background. The aim of the present study was to evaluate both Type 1 and 2 plasma cytokine levels in CD and in CD‐IgAD. IL‐2, TNF‐α, IL‐10, IL‐4 and IL‐13 plasma levels were measured both at diagnosis and after a gluten‐free diet (GFD) in 32 CD patients, in 27 CD‐IgAD patients and in 30 healthy controls. IFN‐γ levels were significantly higher in CD and CD‐IgAD than in controls, TNF‐α displayed significantly higher levels in CD‐IgAD when compared both with controls and with CD, and IL‐2 was in CD‐IgAD significantly increased respect to controls. Kinetics of the Type 1 cytokine plasma levels did not show a clear relationship with the GFD in both groups of CD patients, and particularly in those with IgAD. IL‐4 and IL‐13, both at diagnosis and after a GFD, were not significantly different in controls and in celiac patients (with and without IgAD). IL‐10, whose production is stimulated by the TNF‐α, had significantly higher plasma levels in CD‐IgAD, but not in CD patients, with a significant decrease after a GFD. CD and especially CD‐IgAD patients display persistently higher pro‐inflammatory cytokine levels, suggesting a persistent state of activation of pro‐phlogistic signals in CD, particularly when IgAD coexists. Serial measurement of serum IL‐10 may be an adjunctive evaluating criterion in the follow‐up of CD‐IgAD patients.

Search for Genetic Factors Associated with Susceptibility to Multiple Sclerosis

Abstract:  Multiple sclerosis (MS) is a cell‐mediated autoimmune disease characterized by type‐1 cytokine production. Environmental and individual genetic background might influence this response particularly in cytokine gene polymorphisms. We evaluated whether polymorphisms of interleukin (IL)‐10, IL‐12, and tumor necrosis factor (TNF)‐α genes, which might play a role in MS pathogenesis, are associated with MS susceptibility. Genotype frequencies for all the analyzed polymorphisms were not differently distributed between cases and controls. It is reasonable to suppose that the cytokine single‐nucleotide polymorphisms (SNPs) studied must be considered against a larger genetic background involving other functional SNPs of Th1 regulator elements such as IL‐21 and IL‐23.

Analysis of HLA-DRB1,DQA1,DQB1 haplotypes in Sardinian centenarians

Some genetic determinants of longevity might reside in those polymorphisms for the immune system genes that regulate immune responses. Many longevity association studies focused their attention on HLA (the human MHC) polymorphisms, but discordant results have been obtained. Sardinians are a relatively isolate population and represent a suitable population for association studies. Some HLA-DR and DQ alleles form very stable haplotypes with a strong linkage disequilibrium. In a previous study on Sardinian centenarians we have suggested that HLA-DRB1 *15 allele might be marginally associated to longevity. HLA-DR,DQ haplotypes are in strong linkage disequilibrium and well conserved playing a role in the association to diseases. Hence, we have evaluated, by amplification refractory mutation system/polymerase chain reaction (ARMS-PCR) the HLADQA1 and HLA-DQB1 allele frequencies in 123 centenarians and 92 controls from Sardinia to assess whether the association to HLA-DRB1 *15 allele may be due to the other genes involved in the HLA-DR,DQ haplotypes. The frequencies of HLA-DQA1, DQB1 haplotypes were not significantly modified in centenarians. Nevertheless by evaluating the frequency of DRB1 *15 linked haplotypes, we observed a not significant increase in centenarians of HLA-DQA1 *01, DQB1 *05 and HLA-DQA1 *01,DQB1 *06 haplotypes. These data suggest that these haplotypes might have a role in determining life span expectancy and longevity.