Analysis of polymorphisms Leiden Factor V G1691A and prothrombin G20210A as risk factors for acute myocardial infarction.

Thrombotic risk increases in elderly, therefore, the understanding of the genetic predisposition of hypercoagulability could make the difference in the prevention of venous and/or arterial thrombotic events. Laboratory evaluation of hyperfibrinogenemia, increased Factor VII levels, antiphospholipid antibodies presence and hyperhomocysteinemia are considered to have a consistent high predictivity for arterial thrombophilic diseases. Anyway, a large debate exists on the validity of testing Leiden Factor V (FV) G1691A and/or prothrombin (FII) G20210A polymorphisms in patients affected by arterial thrombotic diseases, despite of the several observations described. Here we report data strongly suggesting that at least the FII G20210A polymorphism might be considered an important risk factor for acute myocardial infarction in aged patients (55-80 years old). On the other hand, in spite of a not different genotypic and allelic distribution for the Leiden FV G1691A mutation, the presence of one or both the two polymorphisms is significantly higher among cases than in controls. In conclusion, our data suggest that FII G20210A and/or Leiden FV might be involved as risk factor for arterial disorders in about 5% of old subjects, justifying the opportunity of a genetic screening and an eventual preventive treatment, in particular in old subjects in which other and major risk factors, as hypertension and atherosclerosis, are detected

MIF rs755622 and IL6 rs1800795 Are Implied in Genetic Susceptibility to End-Stage Renal Disease (ESRD)

Chronic kidney disease (CKD) is characterized by an increased risk of kidney failure and end-stage renal disease (ESRD). Aging and comorbidities as cardiovascular diseases, metabolic disorders, infectious diseases, or tumors, might increase the risk of dialysis. In addition, genetic susceptibility factors might modulate kidney damage evolution. We have analyzed, in a group of ESRD patients and matched controls, a set of SNPs of genes (Klotho rs577912, rs564481, rs9536314; FGF23 rs7955866; IGF1 rs35767; TNFA rs1800629; IL6 rs1800795; MIF rs755622, rs1007888) chosen in relation to their possible involvement with renal disease and concomitant pathologies. Analysis of the raw data did indicate that IL6 rs180795 and MIF rs755622 SNPs might be markers of genetic susceptibility to ESRD. In particular, the C positive genotypes of MIF rs755622, (dominant model) seem to be an independent risk factor for ESDR patients (data adjusted for age, gender, and associated pathologies). Stratifying results according to age MIF rs755622 C positive genotype frequencies are increased in both the two age classes considered (<59 and ≥59-year-old subjects). Analyses of data according to gender allowed us to observe that ESRD women shoved a significantly reduced frequency of genotypes bearing IL6 rs180795 C allele. In addition, MIF rs755622 might interact with diabetes or hypercholesterolemia in increasing susceptibility to ESRD. In conclusion, our data indicate that some polymorphisms involved in the regulation of both renal function and inflammatory response can influence the evolution of chronic kidney disease and suggest that the modulation of the activities of these and other genes should also be considered as therapeutic targets on to intervene with innovative therapies

Cytokine serum profile in a group of Sicilian Nonagenarians

The aim of our study was to evaluate the possibility of using multiplex analysis of the cytokine profile as a marker for successful aging by comparing cytokine plasmatic levels of a group of Sicilian nonagenarians with those of young controls. We analyzed a panel of 17 cytokines, comprehensive of haematopoietic factors T helper 1 (Th1), Th2, inflammation regulatory cytokines, and chemokines. The assay was carried out using the Luminex system. Interleukin (IL)-6 levels (p = 0.01) were increased in nonagenarians, whereas no modifications of other proinflammatory cytokines and chemokines were observed. Interferon-gamma (IFN-gamma) and IL-2 levels are unmodified, suggesting a substantial maintenance of relevant T cell functions. In addition, a significant increase of IL-12 serum levels in nonagenarians versus young controls that might be related to the increase of natural killer (NK) cell functions characterizing aging processes was observed. The analysis of Th2 cytokines show an increase of IL-13 and a reduction of IL-4 levels mirroring the maintenance of some effector's mechanisms of the immunoresponse in advanced ages. Our results suggest that the multiplex analysis of cytokine levels might be useful in defining a successful aging profile

G-protein-coupled receptor kinase 5 polymorphism and Takotsubo cardiomyopathy.

BACKGROUND: Takotsubo cardiomyopathy (TTC) is an increasingly reported clinical syndrome that mimics acute myocardial infarction without obstructive coronary artery disease and is characterized by transient systolic dysfunction of the apical and/or mid-segments of the left ventricle. The syndrome mainly occurs in postmenopausal women with high adrenergic state conditions. Nowadays, the pathophysiology of TTC is not yet known and the possibility of a genetic predisposition is controversial. AIMS: The purpose of this study was to assess the genetic susceptibility to TTC through analysis of the L41Q polymorphism of the G-protein-coupled receptor kinase 5 (GRK5). METHODS AND RESULTS: In a cohort of 20 patients enrolled in two tertiary Italian centers with diagnosis of TTC, accordingly to the commonly accepted Mayo Clinic criteria and in 22 healthy individuals (control) we have evaluated the polymorphism in GRK5 gene. The TTC patients had a mean age of 65 ± 9 years and 19 of 20 were women. The presence of one or two L41 alleles of GRK5 was significantly more frequent in TTC group than in the control group (40 vs. 8%, P = 0.0372). CONCLUSION: In our study, we have found a significant difference in the frequency of GRK5 polymorphism between TTC patients and controls, supporting a genetic predisposition to this cardiac syndrome

Relevance of gamma interferon, tumor necrosis factor alpha, and interleukin-10 gene polymorphisms to susceptibility to Mediterranean spotted fever.

The acute phase of Mediterranean spotted fever (MSF) is characterized by dramatic changes in cytokine production patterns, clearly indicating their role in the immunomodulation of the response against the microorganism, and the differences in cytokine production seem to influence the extent and severity of the disease. In this study, the single nucleotide polymorphisms (SNPs) of tumor necrosis factor alpha (TNF-α) -308G/A (rs1800629) and interleukin-10 (IL-10) -1087G/A (rs1800896), -824C/T (rs1800871), and -597C/A (rs1800872) and the gamma interferon (IFN-γ) T/A SNP at position +874 (rs2430561) were typed in 80 Sicilian patients affected by MSF and in 288 control subjects matched for age, gender, and geographic origin. No significant differences in TNF-α -308G/A genotype frequencies were observed. The +874TT genotype, associated with an increased production of IFN-γ, was found to be significantly less frequent in MSF patients than in the control group (odds ratio [OR], 0.18; 95% confidence interval [95% CI], 0.06 to 0.51; P corrected for the number of genotypes [Pc], 0.0021). In addition, when evaluating the IFN-γ and IL-10 genotype interaction, a significant increase of +874AA/-597CA (OR, 5.31; 95% CI, 2.37 to 11.88; Pc, 0.0027) combined genotypes was observed. In conclusion, our data strongly suggest that finely genetically tuned cytokine production may play a crucial role in the regulation of the immune response against rickettsial infection, therefore influencing the disease outcomes, ranging from nonapparent or subclinical condition to overt or fatal disease

Genetics of longevity. Data from the studies on Sicilian centenarians

The demographic and social changes of the past decades have determined improvements in public health and longevity. So, the number of centenarians is increasing as a worldwide phenomenon. Scientists have focused their attention on centenarians as optimal model to address the biological mechanisms of “successful and unsuccessful ageing”. They are equipped to reach the extreme limits of human life span and, most importantly, to show relatively good health, being able to perform their routine daily life and to escape fatal age-related diseases, such as cardiovascular diseases and cancer. Thus, particular attention has been centered on their genetic background and immune system. In this review, we report our data gathered for over 10 years in Sicilian centenarians. Based on results obtained, we suggest longevity as the result of an optimal performance of immune system and an overexpression of anti-inflammatory sequence variants of immune/inflammatory genes. However, as well known, genetic, epigenetic, stochastic and environmental factors seem to have a crucial role in ageing and longevity. Epigenetics is associated with ageing, as demonstrated in many studies. In particular, ageing is associated with a global loss of methylation state. Thus, the aim of future studies will be to analyze the weight of epigenetic changes in ageing and longevity

Role of prothrombotic polymorphisms in successful or unsuccessful aging

The study of the genetic profile of centenarians aims to identify the genes and allelic variants which may influence a greater life expectancy and that can be considered as predisposing factors associated to the aging diseases, such as Alzheimer. Centenarians, that represent a cohort of selected survivors, show an hypercoagulability state characterised by striking signs of high coagulation enzyme activity, as directly assessed by the tested higher plasma level of some important factors involved in the haemostasis balance. Anyway, these individuals seem to have a reduced susceptibility to dementia, as well as to cardiovascular events. In this study we analyze the frequencies of Leiden Factor V polymorphism (G1691A), and G20210A of prothrombin (FII) in three cohorts of subjects: patients with Alzheimer\u2019s disease (unsuccessful aging), nonagenarians (successful aging) and young healthy controls, to assess whether allelic variants associated to the modification of haemostatic system function, may play a role in the protection or susceptibility to Alzheimer disease, as well as to reach a successful aging. No significant differences were observed in the frequencies of the three groups studied. These results indicate that the presence or absence of the gene variants examined did not influence the achievement of advanced age and are not risk factors for Alzheimer\u2019s disease. The state of hypercoagulability and the possession of these risk alleles appear to be compatible with the achievement of longevity and are not implied as risk factors in Alzheimer disease development