Study of age-association with cytokine gene polymorphisms in an aged Irish population
Introduction
Deterioration of the immune system with increasing age coupled with the associated increase in the susceptibility to infectious disease, cancer and autoimmune disorders (immunosenescence) has led to a great deal of gerontological attention being focussed on the immune function (Pawelec and Solana, 1997). Cytokines play a pivotal role in the regulation of the type and magnitude of the immune response in the elderly (Caruso et al., 1996, Ginaldi et al., 1999).
In several cytokine genes, polymorphism (mostly single nucleotide polymorphisms (SNPs) or microsatellites) located within the critical promoter or other regulatory regions, affects gene transcription resulting in inter-individual variation in levels of cytokine production. The polymorphism may either directly influence gene transcription or indirectly via tight linkage with other polymorphisms occurring elsewhere in the cytokine gene (Van Deventer, 2000). The polymorphic nature of the cytokine genes may confer flexibility on the immune response with certain alleles promoting differential production of cytokines that may influence the outcome of viral and bacterial infections or increase susceptibility/resistance to autoimmune disorders (Bidwell et al., 1999, Mira et al., 1999, Read et al., 2000, Van Deventer, 2000, Bidwell et al., 2001).
A number of the polymorphisms reported in cytokine genes are associated with variant levels of gene expression (Turner et al., 1997, Fishman et al., 1998, Awad et al., 1999, Pravica et al., 1999). Any qualitative or quantitative effect on cytokine production will ineluctably impinge upon the synthesis and secretion of other members of the cytokine cascade and may therefore alter the immune response. Previous studies have recorded conflicting polymorphic cytokine association data in aged populations of differing ethnic backgrounds (Bonafe et al., 2001, Wang et al., 2001, Lio et al., 2002a, Lio et al., 2002b, Olivieri et al., 2002). In the present study, a range of polymorphisms were chosen (Table 1) within the genes of cytokines (IL-2, IL-6, IL-8, IL-10, IL-12 and IFN-γ) that have been observed at different levels within the elderly (Mysliwska et al., 1998, Rink et al., 1998, Rea et al., 2000a, Bruunsgaard et al., 2001, Mariani et al., 2001). The frequency of these polymorphisms was analysed to investigate any potential age-related association in the Irish population.
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Subjects
One hundred control samples (59% female and 41% male with an age-range of 19–45 years; average age 29±6.4 years) were chosen at random from the DNA bank of normal healthy Caucasian individuals from the Northern Ireland population. These samples were stored within the Northern Ireland Histocompatibility and Immunogenetics Laboratory (NIHIL) of Belfast City Hospital. Some 93 aged consecutive samples (70% female, 30% male with an age range of 80–97 years; average age 90±3.2 years) from the Belfast
Results
The frequency of a cross-section of polymorphisms occurring within a number of cytokine genes were investigated in a healthy aged Irish cohort of subjects in comparison to a younger control group from the Irish population.
The genotype and allele frequencies observed for the polymorphic markers in the genes of IL-2, IL-8, IL-10 and IL-12 are displayed in Table 4. No obvious genotype frequency differences were observed when the entire cohort of aged subjects was compared to the young controls.
Discussion
Human longevity appears to be inextricably linked with optimal functioning of the immune system, suggesting that specific genetic determinants may reside in polymorphic loci in genes that regulate the immune response. In particular, the role of the cytokine network in immune function and in protection from, and susceptibility to, a variety of diseases may play a pivotal role in ageing and survival. Cytokine dysregulation is believed to play a key role in the proposed remodelling of the immune
Acknowledgements
The authors wish to acknowledge the European Union for support under the aegis of European Union Concerted Action on the Molecular Biology of Immunosenescence (EUCAMBIS; Biomed 1 contract CT94-1209); and Immunology and Ageing in Europe (IMAGINE; QLK6-CT-1999-O2031). O.A. Ross was a recipient of a CAST award jointly funded by the Department of Education and Learning (Northern Ireland) and the Northern Ireland Histocompatibility and Immunogenetics Charitable Trust Fund.
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