Study of age-association with cytokine gene polymorphisms in an aged Irish population.

The release of cytokines is of crucial importance in the regulation of the type and magnitude of the immune response in the elderly. A number of studies have shown different levels of cytokine production in the elderly. In the present study, a range of polymorphisms were chosen within the genes of cytokines (IL-2, IL-6, IL-8, IL-10, IL-12 and IFN-gamma) that have been observed at different levels within the elderly and analysed for age-association. No association was observed for the polymorphic cytokine markers and the healthy aged Irish population (or with respect to gender) examined in this study. These findings would suggest that polymorphism of cytokine genes may not play as crucial a role in healthy ageing as previously believed.

HLA haplotypes and TNF polymorphism do not associate with longevity in the Irish.

Polymorphism of the human leukocyte antigen has been implicated in a number of autoimmune disorders including ageing. In the course of the present study, no association of the human leukocyte antigen (HLA)-A1, B8, DR3 haplotype with a male Irish aged population, as previously reported, was observed. Two polymorphic nucleotides in the TNF cluster (G-308A TNF-alpha and G+252A TNF-beta), associated with increased TNF-alpha production, were shown to be in tight linkage disequilibrium with the class I and II HLA loci, generating HLA haplotypes with extended linkage disequilibrium. However, no age-related allele or genotype frequencies were observed for either polymorphic nucleotide.

Functional promoter region polymorphism of the proinflammatory chemokine IL-8 gene associates with Parkinson's disease in the Irish.

Parkinson's disease (PD) is one of the most prevalent neurodegenerative disorders and is characterized by the progressive loss of dopamine neurons in the substantia nigra. There is increasing evidence to suggest the inflammatory response of the brain contributes to the pathogenesis of PD. This study investigated the frequency of polymorphism located in the critical promoter region of the proinflammatory cytokine genes: interleukin (IL)-2, IL-6, IL-8, and tumor necrosis factor alpha (TNF-alpha) within a cohort of patients with PD in comparison to a group of healthy elderly individuals. No association was observed for single nucleotide polymorphism in the promoter regions of the IL-2, IL-6, and TNF-alpha genes. The single nucleotide polymorphism in the chemokine IL-8 gene was observed to associate with PD and appeared to be independent of age at onset. This association further supports the theory that the proinflammatory response in the brains of patients with PD plays a role in the pathogenesis of the disease and warrants further investigation into the role of chemokines in the brain, and a more detailed analysis of the genetics involved in the immune response of the brain.

Hypothetical soluble KIR2DS4 natural killer cell receptor molecule does not associate with successful ageing in the Irish.

The identification of immunogenetic longevity markers is a major area of molecular gerontological research. A number of genetic loci have been examined, e.g. the HLA and cytokine networks. This study investigated a genetic marker within the highly polymorphic KIR gene system with successful ageing in the Irish population. A 22 bp deletion was identified in the KIR2DS4 gene that predicts a truncated soluble KIR molecule with one intact Ig-like domain. The frequency of this variant was determined using a specific-primer PCR methodology. There was no observed association between this common polymorphic variation within this activatory KIR gene and the aged Irish population. This is the first study of KIR polymorphism in ageing and although no association was identified, the importance of the KIR network in the immune response and its polymorphic nature warrants more detailed analysis to ascertain its role in immunosenescence.

Investigation of KIR diversity in immunosenescence and longevity within the Irish population.

Natural killer (NK) cells play a pivotal role in the innate immune response. During the ageing process, variations occur in NK cell number and function. The cytolytic activity of NK cells is controlled by an array of activating and inhibitory cell surface receptors, including the killer cell immunoglobulin-like receptors (KIRs). In the present study, genetic diversity of the KIR loci was analysed with respect to successful ageing in the Irish population. A PCR-SSOP KIR gene identification system was employed to determine the frequency of the named KIR genes/pseudogenes and KIR genotypes within a healthy aged cohort and young control group. Although, two KIR genes (2DS3, 2DL5) displayed an initial increased frequency in the aged group, the significance of this association was lost when repeated in a second cohort. In view of the lack of studies to date, investigating the role of the KIR gene system in healthy ageing, further analysis of KIR diversity is required to fully elucidate it's role in respect to age-related disease and longevity.

Increased frequency of the 2437T allele of the heat shock protein 70-Hom gene in an aged Irish population.

The frequency of the functional polymorphism, T2437C transversion (Met-->Thr), in the HSP 70-Hom gene was investigated within a healthy aged Irish population using oligonucleotide probes. The 2437T polymorphic nucleotide was observed to increase in the elderly, although not attaining statistical significance. The TT genotype was observed to be significantly increased within the Irish aged population (p=0.03), while conversely the TC genotype was significantly decreased in the aged subjects (p=0.01). These findings would support the theory that the change from a Met (non-polar and hydrophobic) residue to a Thr (polar and neutral) residue may disrupt the peptide-binding specificity of HSP 70-Hom and have an effect on its functional efficiency. One postulates that the highly significant p-value obtained for the TC genotype may infer that the presence of both the T and the C allele (heterozygosity) resulting in the generation of two different HSP 70-Hom protein species may negatively influence longevity.

mt4216C variant in linkage with the mtDNA TJ cluster may confer a susceptibility to mitochondrial dysfunction resulting in an increased risk of Parkinson's disease in the Irish.

Polymorphism of the mtDNA genome has been implicated as playing a role in the development and pathogenesis of Parkinson's disease (PD). A PCR-RFLP methodology was employed to generate genetic haplotypes for a cohort of 90 PD sufferers. No association was observed between the various mtDNA haplotypes observed and PD in comparison to healthy aged controls. The longevity-associated European J haplogroup and T haplogroup were identified and were both found to be in tight linkage with the mt4216C polymorphism. The mt4216C variant was observed at a significantly increased frequency in the PD cases (28%) in comparison to the healthy aged controls (15%; p=0.014). However, when the frequency of the mt4216C variant was examined in a cohort of 200 young controls (18-45 years) a similar frequency to the PD cases (25%) was observed. The frequencies obtained for the two branches of the J haplogroup (J1 and J2) and the T haplogroup in the cohort of PD subjects also reflected those observed for the young controls used in the previous longevity study. These findings lead one to postulate that the mt4216C variant, in linkage with the mtDNA TJ cluster, may influence mitochondrial dysfunction, resulting in an increased risk of PD.

A novel polymorphic triplet repeat in intron five of the alpha-synuclein gene: no evidence of expansion or allelic association with idiopathic Parkinson's disease in the Irish.

The recent discovery of two mutations associated with autosomal dominant Parkinson's disease (PD) has led to the hypothesis that the alpha-synuclein gene plays a role in the pathogenesis of PD. Here we report a novel triplet CAA repeat within the unusually large intron 5 sequence of the alpha-synuclein gene. Microsatellite analysis revealed a high degree of polymorphism within the Irish population with seven alleles detected, ranging from eight to 17 CAA repeats. Analysis of the allele/genotype frequency differences observed between an Irish idiopathic PD cohort (eta = 98) and a healthy aged control group ( eta= 92) revealed no strong association with either group. All PD subjects displaying homozygous profiles were examined for expansion of the trinucleotide repeat, but no expansion was observed. These results would suggest that polymorphism of the alpha-synuclein gene may not play as significant a role in the pathogenesis of idiopathic PD as previously hypothesised.

Blood pressure and TNF-α act synergistically to increase leucocyte CD11b adhesion molecule expression in the BELFAST study: implications for better blood pressure control in ageing.

Hypertension, a key risk factor for stroke, cardiovascular disease and dementia, is associated with chronic vascular inflammation, and although poorly understood, putative mechanisms include pro-inflammatory responses induced by mechanical stretching, with cytokine release and associated up-regulated expression of adhesion molecules. Because blood pressure increases with age, we measured baseline and tumour necrosis alpha (TNF-α)-stimulated CD11b/CD18 adhesion molecule expression on leucocytes to assess any association between the two. In 38 subjects (mean age 85 years), consecutively enrolled from Belfast Elderly Longitudinal Free-Living Aging Study (BELFAST), baseline and TNF-α-stimulated CD11b/CD18 expression on separated monocytes and neutrophils increased with systolic blood pressure >120 mmHg (p = 0.05) and for lymphocytes, with diastolic blood pressure >80 mmHg (p < 0.05).These findings show increased potential stickiness of intravascular cells with increasing blood pressure which is accentuated by TNF-α, and suggest mechanistic reasons why better hypertension control is important.

Nature or nurture; BMI and blood pressure at 90. Findings from the Belfast Elderly Longitudinal Free-living Aging STudy (BELFAST).

Hypertension is a key risk factor for stroke, cardiovascular disease and dementia. Although the link between weight, sodium and hypertension is established in younger people, little is known about their inter-relationship in people beyond 80 years of age. Associations between blood pressure, anthropometric indices and sodium were investigated in 495 apparently healthy, community-living participants (age 90, SD 4.8; range 80­106), from the cross-sectional Belfast Elderly Longitudinal Free-living Aging STudy (BELFAST) study. In age-sex-adjusted logistic regression models, blood pressure ≥140/90 mmHg significantly associated with body mass index (BMI) [odds ratio (OR) = 1.28/ kg/m2], with weight (OR = 1.22/kg) approaching significance (P = 0.07). In further age-sex-adjusted models, blood pressure above the 120/80 mmHg normotensive reference value significantly associated with BMI (OR = 1.44/kg/m2), weight (OR = 1.36/kg), skin-fold-thickness (OR = 1.33/mm) and serum sodium (OR = 1.37 mmol/l). In BELFAST participants over 80 years old, blood pressure ≥140/90 mmHg is associated with BMI, in apparently similar ways to younger groups.

ABCB1 (MDR1) rs1045642 is associated with increased overall survival in plasma cell myeloma.

Multi-drug resistance (MDR) may compromise the successful management of haematological malignancies, impairing the effectiveness of chemotherapy. The P-glycoprotein (P-gp) drug efflux pump, encoded by the gene ABCB1 (MDR1), is the most widely studied component in MDR. A single nucleotide polymorphism (SNP) has been identified within ABCB1, rs1045642 (C3435T), which may alter P-gp substrate specificity and have an impact on the effectiveness of treatment, and hence overall survival (OS). We estimated the frequency of this SNP in the Northern Irish population and investigated its impact on the OS of patients with plasma cell myeloma (PCM). There was no significant difference in the frequency of rs1045642 between the PCM cohort and an age- and gender-matched control population. Findings within the PCM cohort suggest that rs1045642 genotype influences OS (p = 2 x 10(-2)). If confirmed in larger studies, these results suggest that genotyping rs1045642 may be a useful predictor of outcome in PCM and could indicate modified treatment modalities in certain individuals.