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1.
Medicina (Kaunas) ; 60(2)2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38399542

RESUMO

Background and Objectives. Retinitis pigmentosa (RP) is the most common inherited rod-cone dystrophy (RCD), resulting in nyctalopia, progressive visual field, and visual acuity decay in the late stages. The autosomal dominant form (ADRP) accounts for about 20% of RPs. Among the over 30 genes found to date related to ADRP, RP1 pathogenic variants have been identified in 5-10% of cases. In a cohort of RCD patients from the Palermo province on the island of Sicily, we identified a prevalent nonsense variant in RP1, which was associated with ADRP. The objective of our study was to analyse the clinical and molecular data of this patient cohort and to evaluate the potential presence of a founder effect. Materials and Methods. From 2005 to January 2023, 84 probands originating from Western Sicily (Italy) with a diagnosis of RCD or RP and their relatives underwent deep phenotyping, which was performed in various Italian clinical institutions. Molecular characterisation of patients and familial segregation of pathogenic variants were carried out in different laboratories using Sanger and/or next-generation sequencing (NGS). Results. Among 84 probands with RCD/RP, we found 28 heterozygotes for the RP1 variant c.2219C>G, p.Ser740* ((NM_006269.2)*, which was therefore significantly prevalent in this patient cohort. After a careful interview process, we ascertained that some of these patients shared the same pedigree. Therefore, we were ultimately able to define 20 independent family groups with no traceable consanguinity. Lastly, analysis of clinical data showed, in our patients, that the p.Ser740* nonsense variant was often associated with a late-onset and relatively mild phenotype. Conclusions. The high prevalence of the p.Ser740* variant in ADRP patients from Western Sicily suggests the presence of a founder effect, which has useful implications for the molecular diagnosis of RCD in patients coming from this Italian region. This variant can be primarily searched for in RP-affected subjects displaying compatible modes of transmission and phenotypes, with an advantage in terms of the required costs and time for analysis. Moreover, given its high prevalence, the RP1 p.Ser740* variant could represent a potential candidate for the development of therapeutic strategies based on gene editing or translational read-through therapy for suppression of nonsense variants.


Assuntos
Distrofias de Cones e Bastonetes , Retinose Pigmentar , Humanos , Distrofias de Cones e Bastonetes/genética , Sicília/epidemiologia , Efeito Fundador , Proteínas do Olho , Retinose Pigmentar/genética , Retinose Pigmentar/diagnóstico , Fenótipo , Linhagem , Mutação , Análise Mutacional de DNA , Proteínas Associadas aos Microtúbulos/genética
2.
Hemoglobin ; 42(2): 103-107, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30200835

RESUMO

The hemoglobinopathies, as ß-thalassemia (ß-thal) and sickle cell disease, are the most common hereditary hemolytic anemias. The increase of fetal hemoglobin (Hb F) levels can ameliorate the symptoms of hemoglobinopathies. There are several transcription factors such as MYB and SOX-6, which are involved in the regulation of Hb F. There are not enough studies investigating the association between single nucleotide polymorphisms (SNPs) of the SOX-6 and MYB genes and the variation of Hb F levels in patients affected by sickle cell disease and ß-thal. We therefore decided to analyze the role of four missense variants of MYB and SOX-6 genes in the regulation of Hb F levels. In order to do so, we examinated 30 Sicilian patients affected by sickle cell disease and ß-thal, to understand if these variants could also have an influence in our populations. Comparing two groups of patients with low and high levels of Hb F, we found no significant differences in the genetic distribution and allelic frequency of MYB and SOX-6 gene polymorphisms. We also created and compared a 'high producer' and 'low producer' genotype with different genes achieving the same result of no significant difference. Our results may be due either to the fact that the association between these genes and the regulation of Hb F levels are influenced by environmental history and population genetics, or to the small number of samples being analyzed.


Assuntos
Anemia Falciforme/genética , Hemoglobina Fetal/genética , Genes myb/genética , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição SOXD/genética , Talassemia beta/genética , Frequência do Gene , Hemoglobinopatias/genética , Humanos , Sicília/epidemiologia
3.
Immun Ageing ; 9(1): 8, 2012 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-22524430

RESUMO

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 over-expression 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.

4.
Eur J Dermatol ; 21(1): 47-52, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21227888

RESUMO

The mechanisms of chronic spontaneous urticaria (CSU) continue to be unknown. Our working hypothesis is that polymorphisms of cyclo-oxygenases and 5-lipo-oxygenase-activating protein may be involved in the pathways leading to CSU. We examined five candidate polymorphisms of cyclo-oxygenases 1 and 2 and of 5-lipo-oxygenase-activating protein in 109 controls and in 94 CSU patients from Northern Italy. We also examined the levels of urinary leukotriene E4 (LTE4) before and after challenge with ASA. A multiple regression model was found to show that COX-2 5'UTR T/G, COX-2 Exon 10 T/C, and FLAP -336 G/A polymorphisms were significantly associated with CSU, with the minor allele more represented in CSU group. Similar results were obtained as regards the specific association with ASA-tolerated CSU and ASA-exacerbated CSU. Evaluating a polygenic model, reflecting the sum of the concomitant alleles associated with CSU (i.e. COX-2 5'UTR G allele, COX-2 Exon 10 C allele, and FLAP -336 G/A allele), the proportion of CSU patients increased progressively with the increasing number of unfavourable alleles. Finally, in a linear regression model after adjustment for disease status COX-1 22 T carriership remained a significant predictor of post-challenge high urinary LTE4 levels. Our results support the hypothesis that polymorphisms of cyclo-oxygenases and 5-lipo-oxygenase-activating protein may be associated with CSU.


Assuntos
Proteínas Ativadoras de 5-Lipoxigenase/genética , Leucotrieno E4/urina , Polimorfismo Genético , Prostaglandina-Endoperóxido Sintases/genética , Urticária/genética , Adolescente , Adulto , Idoso , Doença Crônica , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
5.
Cancer Immunol Immunother ; 58(12): 1919-33, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19221747

RESUMO

In this paper, we consider the role of the genetics of inflammation in the pathophysiology of prostate cancer (PCa). This paper is not an extensive review of the literature, rather it is an expert opinion based on data from authors' laboratories on age-related diseases and inflammation. The aim is the detection of a risk profile that potentially allows both the early identification of individuals at risk for disease and the possible discovery of potential targets for medication. In fact, a major goal of clinical research is to improve early detection of age-related diseases, cancer included, by developing tools to move diagnosis backward in disease temporal course, i.e., before the clinical manifestation of the malady, where treatment might play a decisive role in preventing or significantly retarding the manifestation of the disease. The better understanding of the function and the regulation of inflammatory pathway in PCa may help to know the mechanisms of its formation and progression, as well as to identify new targets for the refinement of new treatment such as the pharmacogenomics approach.


Assuntos
Neoplasias da Próstata/genética , Neoplasias da Próstata/imunologia , Envelhecimento/genética , Envelhecimento/imunologia , Predisposição Genética para Doença , Humanos , Inflamação/genética , Inflamação/imunologia , Mediadores da Inflamação/imunologia , Masculino , Farmacogenética , Polimorfismo Genético
6.
Brain Res Rev ; 58(1): 96-105, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18190968

RESUMO

Alzheimer's disease (AD) is a heterogeneous and progressive neurodegenerative disease which in Western society mainly accounts for clinical dementia. AD has been linked to inflammation and metal biological pathway. Neuro-pathological hallmarks are senile plaques, resulting from the accumulation of several proteins and an inflammatory reaction around deposits of amyloid, a fibrillar protein, Abeta, product of cleavage of a much larger protein, the beta-amyloid precursor protein (APP) and neurofibrillary tangles. Amyloid deposition, due to the accumulation of Abeta peptide, is the main pathogenetic mechanism. Inflammation clearly occurs in pathologically vulnerable regions of AD and several inflammatory factors influencing AD development, i.e. environmental factors (pro-inflammatory phenotype) and/or genetic factors (pro-inflammatory genotype) have been described. At the biochemical level metals such as zinc are known to accelerate the aggregation of the amyloid peptide and play a role in the control of inflammatory responses. In particular, zinc availability may regulate mRNA cytokine expression, so influencing inflammatory network phenotypic expression.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/fisiopatologia , Inflamação/fisiopatologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/biossíntese , Peptídeos beta-Amiloides/metabolismo , Animais , Apolipoproteínas E/metabolismo , Colesterol/metabolismo , Citocinas/biossíntese , Citocinas/genética , Citocinas/metabolismo , Humanos , Inflamação/metabolismo , Modelos Biológicos , Zinco/metabolismo
7.
Rejuvenation Res ; 11(2): 425-32, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18442326

RESUMO

Aging is a complex process that negatively impacts the development of the immune system and its ability to function. Progressive changes in the T and B cell systems over the life span have a major impact on the capacity to respond to immune challenge. These cumulative age-associated changes in immune competence are termed immunosenescence. This process is mostly characterized by: (1) shrinkage of the T cell repertoire and accumulation of oligoclonal expansions of memory/effector cells directed toward ubiquitary infectious agents; (2) involution of the thymus and the exhaustion of naive T cells; and (3) chronic inflammatory status. Here we discuss possible strategies to counteract these main aspects of immunosenescence, in particular the role of the normalization of intestinal microflora by probiotics. A better understanding of immunosenescence and the development of new strategies to counteract it are essential for improving the quality of life of the elderly population.


Assuntos
Envelhecimento/efeitos dos fármacos , Envelhecimento/imunologia , Imunoterapia , Probióticos/farmacologia , Animais , Humanos
8.
Mech Ageing Dev ; 128(1): 83-91, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17118425

RESUMO

Inflammation is considered a response set by the tissues in response to injury elicited by trauma or infection. It is a complex network of molecular and cellular interactions that facilitates a return to physiological homeostasis and tissue repair. The individual response against infection and trauma is also determined by gene variability. Ageing is accompanied by chronic low-grade inflammation state clearly showed by 2-4-fold increase in serum levels of inflammatory mediators. A wide range of factors has been claimed to contribute to this state; however, the most important role seems to be played by the chronic antigenic stress, which affects immune system thorough out life with a progressive activation of macrophages and related cells. This pro-inflammatory status, interacting with the genetic background, potentially triggers the onset of age-related inflammatory diseases as atherosclerosis. Thus, the analysis of polymorphisms of the genes that are key nodes of the natural immunity response might clarify the patho-physiology of age-related inflammatory diseases as atherosclerosis. On the other hand, centenarians are characterized by marked delay or escape from age-associated diseases that, on average, cause mortality at earlier ages. In addition, centenarian offspring have increased likelihood of surviving to 100 years and show a reduced prevalence of age-associated diseases, as cardiovascular disease (CVD) and less prevalence of cardiovascular risk factors. So, genes involved in CVD may play an opposite role in human longevity. Thus, the model of centenarians can be used to understand the role of these genes in successful and unsuccessful ageing. Accordingly, we report the results of several studies in which the frequencies of pro-inflammatory alleles were significantly higher in patients affected by infarction and lower in centenarians whereas age-related controls displayed intermediate values. These findings point to a strong relationship between the genetics of inflammation, successful ageing and the control of cardiovascular disease at least in men, in which these studies were performed. These data are also briefly discussed in the light of antagonistic pleiotropy theory and in order to pursuit a pharmacogenomics approach.


Assuntos
Envelhecimento/patologia , Envelhecimento/fisiologia , Inflamação/metabolismo , Longevidade/fisiologia , Animais , Humanos , Inflamação/patologia
9.
Mech Ageing Dev ; 128(1): 67-75, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17116319

RESUMO

Clinically and pathologically Alzheimer's disease (AD) represents a sequential progressive neurodegenerative disorder. AD is etiologically heterogeneous and accounts for a majority of dementia in western societies. Inflammation clearly occurs in pathologically vulnerable regions of the AD brain and the search for genetic factors influencing the pathogenesis of AD has lead to the identification of numerous gene polymorphisms that might act as susceptibility modifiers. Accordingly, several reports have indicated that the risk of AD is substantially influenced by several genetic polymorphisms in the promoter region, or other untranslated regions, of genes encoding inflammatory mediators, although not all the studies were replied. Here, we review several data suggesting that inflammatory genetic variation may contribute to AD susceptibility. All together this information may represent the basis both for future recognition of individuals at risk and for the pharmacogenomic driving of drug responsiveness.


Assuntos
Doença de Alzheimer/genética , Genoma , Mediadores da Inflamação/fisiologia , Farmacogenética , Polimorfismo Genético , Doença de Alzheimer/patologia , Animais , Humanos , Risco
10.
Ann N Y Acad Sci ; 1100: 111-22, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17460169

RESUMO

Life-long antigenic burden determines a condition of chronic inflammation, with increased lymphocyte activation and proinflammatory cytokine production. A large number of studies have documented changes in zinc metabolism in experimental animal models of acute and chronic inflammation and in human chronic inflammatory conditions. In particular, modification of zinc plasma concentration, as well as intracellular disturbance of antioxidant intracellular pathways, has been found in aging and in some age-related diseases. Zinc deficiency is diffused in aged individuals in order to avoid meat and other high zinc content foods due to fear of cholesterol. Rather, they increase the consumption of refined wheat products that lack zinc and other critical nutrients as a consequence of the refining process. On the other hand, plasma zinc concentration is influenced by proinflammatory cytokines (IL-6 and TNF-alpha) and by metallothioneins (MT) homeostasis, which is in turn affected by proinflammatory cytokines. MT increase in aging and chronic inflammation allowing a continuous sequestration of intracellular zinc with subsequent low zinc ion availability against stressor agents and inflammation. This phenomenon leads to an impaired inflammatory/immune response in the elderly. A major target of zinc is NF-kappaB, a transcription factor critical for the expression of proinflammatory cytokines whose production is regulated by extra- and intracellular activating and inhibiting factors interacting with the regulatory elements on cytokine genes. Effects of zinc on translocation of NF-kappaB have been attributed to the suppression of phosphorylation and degradation of the inhibitory proteins (A20) that normally sequester it in the cytoplasm. Moreover, this factor and A20 are regulated by specific genes involved in inflammation and by intracellular zinc ion availability. So, it is not so surprising that zinc deficiency is constantly observed in chronic inflammation, such as in old individuals. On the other hand, cytokine genes are highly polymorphic and some of these polymorphisms are associated with atherosclerosis and diabetes type 2. Therefore, zinc turnover, via MT homeostasis, in individuals genetically predisposed to a dysregulation of the inflammatory/immune response may play a crucial role in causing possible adverse events with the appearance of age-related diseases.


Assuntos
Envelhecimento , Sistema Imunitário , Inflamação , Zinco/farmacologia , Animais , Antioxidantes/farmacologia , Aterosclerose/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Interleucina-6/metabolismo , Metalotioneína/química , Modelos Biológicos , Modelos Genéticos , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Zinco/química , Zinco/metabolismo
11.
Ann N Y Acad Sci ; 1119: 203-7, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18056968

RESUMO

The total burden of infection at various sites may affect the progression of atherosclerosis and Alzheimer's disease (AD), the risk being modulated by host genotype. The role of lipopolysaccharide (LPS) receptor TLR4 is paradigmatic. It initiates the innate immune response against gram-negative bacteria, and TLR4 single nucleotide polymorphisms (SNPs), such as +896A/G, known to attenuate receptor signaling, have been described. This SNP shows a significantly lower frequency in patients affected by myocardial infarction or AD. Thus, people genetically predisposed to developing lower inflammatory activity seem to have less chance of developing cardiovascular disease (CVD) or AD. In the present report, to validate this hypothesis, the levels of the eicosanoids, leukotriene B4 (LTB4) and prostaglandin E2 (PGE2), known to be involved as mediators in age-related diseases, were determined by an enzyme-linked immunosorbent assay in supernatants from a whole blood assay, after stimulation with subliminal doses of LPS from Escherichia coli. The samples, genotyped for the +896A/G SNP, were challenged with LPS for 4, 24, and 48 h. Both LTB4 and PGE2 values were significantly lower in carriers bearing the TLR4 mutation. Therefore, the pathogen burden, by interacting with the host genotype, determines the type and intensity of the inflammatory responses accountable for proinflammatory status, CVD, AD, and unsuccessful aging (i.e., age-related inflammatory diseases).


Assuntos
Envelhecimento/genética , Envelhecimento/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Polimorfismo de Nucleotídeo Único , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Adulto , Células Sanguíneas/metabolismo , Células Cultivadas , Dinoprostona/biossíntese , Escherichia coli , Infecções por Escherichia coli/genética , Infecções por Escherichia coli/metabolismo , Feminino , Genótipo , Humanos , Imunidade Inata/genética , Inflamação/genética , Inflamação/metabolismo , Leucotrieno B4/biossíntese , Lipopolissacarídeos/farmacologia , Masculino , Pessoa de Meia-Idade , Fatores de Tempo
12.
Ann N Y Acad Sci ; 1100: 132-9, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17460171

RESUMO

Inflammation has recently proven to be associated with the pathogenesis of atherosclerosis and inflammatory genes are good candidates for the risk of developing atherosclerosis. The early phase of atherosclerosis involves the recruitment of inflammatory cells from the circulation and their transendothelial migration. This process is mainly mediated by cellular adhesion molecules, which are expressed by the vascular endothelium and by circulating leukocytes in response to several inflammatory stimuli. Adhesion of circulating cells to the arterial surface is among the first detectable events in atherogenesis. Cellular adhesion molecules, expressed by the vascular endothelium and by circulating leukocytes, mediate cell recruitment and their transendothelial migration. Platelet endothelial cellular adhesion molecule-1 (PECAM-1/CD31), involved in this migration, has been associated with the developmental course of atherosclerosis. Studies have investigated an association between coronary heart disease (CHD) and single nucleotide polymorphisms (SNP) located in functionally important domains of the PECAM-1/CD31 gene, with contrasting results. In particular, we previously analyzed for the following PECAM-1/CD31 SNP: Val125Leu, Asn563Ser, and Gly670Arg. The frequency of the Gly670Arg polymorphism was significantly higher in patients with myocardial infarction (MI), whereas the frequencies of the other two SNP (Leu125Val and Ser563Asn) were not significantly different between patients and controls. To check the validity of our results, we have analyzed the distribution of these SNP in centenarian men (age >99) from our homogeneous Sicilian population, since our previous studies have demonstrated that alleles associated with MI susceptibility are not included in the genetic background favoring longevity. We showed, as regard to polymorphisms of PECAM-1/CD31, that there were no significant differences between male patients affected by MI, male controls, and male centenarians. According to our hypothesis present results seemingly do not support a role for these SNP in conferring the susceptibility to MI at least in this Italian population.


Assuntos
Longevidade , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Molécula-1 de Adesão Celular Endotelial a Plaquetas/fisiologia , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Adesão Celular , Doença das Coronárias/metabolismo , Predisposição Genética para Doença , Genótipo , Humanos , Inflamação , Itália , Masculino , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Fatores Sexuais
13.
Ann N Y Acad Sci ; 1100: 162-72, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17460174

RESUMO

The CC chemokine receptor 5 (CCR5) is a member of CC-chemokine receptor family. CCR5 has the characteristic structure of a seven transmembrane G protein-coupled receptor (GPCR), which regulates trafficking and effector functions of memory/effector Th1 cells, macrophages, NK cells, and immature dendritic cells. CCR5 and its ligands are important molecules in viral pathogenesis. CCR5 represents the co-receptor for macrophage (M) and dual (T cell and M)-tropic immunodeficiency viruses. Recent evidence has also demonstrated the role of CCR5 in a variety of human diseases, ranging from infectious and inflammatory diseases to cancer. In this article, we describe the involvement of CCR5 in two age-related diseases, atherosclerosis and Alzheimer's disease, suggesting a possible role of chemokine system on these diseases' pathophysiology. Finally, we review the data on the probable association between CCR5Delta32 deletion and cardiovascular diseases and Alzheimer's disease.


Assuntos
Envelhecimento , Doenças Cardiovasculares/genética , Receptores CCR5/genética , Receptores CCR5/fisiologia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Aterosclerose/genética , Doenças Cardiovasculares/metabolismo , Células Dendríticas/citologia , Deleção de Genes , Genoma , Humanos , Inflamação , Células Matadoras Naturais/metabolismo , Ligantes , Macrófagos/metabolismo , Microglia/patologia , Modelos Biológicos
14.
Ann N Y Acad Sci ; 1067: 276-81, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16803998

RESUMO

Inflammation plays a role in all the phases of atherosclerosis, and increased production of the acute-phase reactant, C-reactive protein (CRP), predicts future cardiovascular events. Furthermore, CRP has been claimed to play a role in the pathogenesis of atherosclerosis; therefore, CRP polymorphisms might be associated with acute myocardial infarction (AMI). We have analyzed male patients affected by AMI and healthy age-related male controls from Sicily for +1059G/C CRP single-nucleotide polymorphism (SNP). There was a significantly higher frequency of +1059C SNP (P = 0.0008; OR 3.86) in patients compared to controls. CRP serum levels were significantly higher in C+ healthy subjects rather than in C- subjects (P = 0.0075). The results of the present pilot case-control study performed in a homogeneous caucasoid population suggest that +1059C CRP gene SNP is associated with AMI. In any case, the results of the present study should add to the growing body of evidence on the role of pro-inflammatory genotypes in unsuccessful aging, determining susceptibility to immune-inflammatory diseases such as coronary heart disease.


Assuntos
Proteína C-Reativa/genética , Infarto do Miocárdio/genética , Polimorfismo Genético , Doença Aguda/epidemiologia , Adulto , Estudos de Casos e Controles , Estudos de Coortes , Frequência do Gene , Humanos , Imunogenética , Inflamação/sangue , Inflamação/epidemiologia , Inflamação/genética , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Infarto do Miocárdio/epidemiologia , Razão de Chances , Projetos Piloto , Polimorfismo de Nucleotídeo Único , Sicília/epidemiologia
15.
Ann N Y Acad Sci ; 1089: 454-61, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17261788

RESUMO

Alzheimer's disease (AD) is the most common cause of dementia in Western society. The prevalence of AD is greater in women than in men, largely due to longevity and survival differences favoring women. However, some studies suggest that incidence rates may really be increased in women. One possible factor influencing AD incidence in women is the loss of ovarian estrogens production after menopause, which might be involved in AD pathogenesis. Estrogens seem to influence some neuronal functions. Many of these actions appear beneficial (i.e., neuroprotective action against a variety of insults, as oxidative stress, and reduction of beta-amyloid plaques formation). Furthermore, several studies have shown that proinflammatory genotypes seem to significantly contribute to AD risk. In the present study, we evaluated whether the anti-inflammatory allele of chemokine receptor CCR5 is a component of the genetic protective background versus AD neuronal degeneration. We genotyped for Delta32 (a 32-bp deletion of the CCR5 gene that causes a frameshift at amino acid 185) in 191 AD patients (133 women and 58 men; age range: 53-98 years; mean age: 74.88 +/- 8.44) and 182 controls (98 women and 84 men; age range: 65-93; mean age 73.21 +/- 8.24) from northern Italy. No different distribution of the CCRDelta32 deletion in the two cohorts was clearly evident. Statistical analysis by gender stratification, demonstrated no differences in genotype distribution and allelic frequency both in women and in men. Further, studies should focus on identification of proinflammatory genetic variants involved in AD pathogenesis in women.


Assuntos
Doença de Alzheimer/genética , Polimorfismo Genético , Receptores CCR5/genética , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Frequência do Gene , Humanos , Inflamação/genética , Itália , Masculino , Pessoa de Meia-Idade , Deleção de Sequência , Razão de Masculinidade
16.
Ann N Y Acad Sci ; 1089: 472-86, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17261790

RESUMO

Alzheimer's disease (AD) is a heterogeneous and progressive neurodegenerative disease which in Western societies mainly accounts for clinical dementia. A high proportion of women are affected by this disease, especially at a very advanced age, which might to a large extent be associated with the fact that women live longer. However, some studies suggest that incidence rates may be really increased in women. For this reason the influence of estrogens on the brain and the decrease of it during menopause are of special interest. After menopause, circulating levels of estrogens markedly decline, influencing several brain processes predicted to influence AD risk. The control of estrogens on oxidative stress, inflammation, and the cerebral vasculature might also be expected to increase AD risk. During the Women's Health Initiative Memory Study--a randomized, placebo-controlled trial of women 65-79 years of age--oral estrogen plus progestin was seen to double the rate of developing dementia, with risk appearing soon after the treatment was initiated. On the basis of current evidence, hormone therapy (HT) is thus not indicated for the prevention of AD. Inflammation clearly occurs in pathologically vulnerable regions of the AD brain and the search for genetic factors influencing the pathogenesis of AD has led to the identification of numerous gene polymorphisms that act as susceptibility modifiers. Accordingly, several reports have indicated that the risk of AD is substantially influenced by several genetic polymorphisms in the promoter region, or other untranslated regions, of genes encoding inflammatory mediators. Here we review several data suggesting that inflammatory genetic variation may contribute to higher AD susceptibility in women too. All together this information may represent the basis both for future recognition of individuals at risk as well as for a pharmacogenomic approach in achieving drug responsiveness.


Assuntos
Doença de Alzheimer/etiologia , Doença de Alzheimer/genética , Estrogênios/fisiologia , Inflamação/genética , Razão de Masculinidade , Fatores Etários , Idoso , Feminino , Humanos , Masculino , Polimorfismo Genético
17.
Ann N Y Acad Sci ; 1089: 487-95, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17261791

RESUMO

The literature on immunosenescence has focused mainly on T cell impairment. With the aim of gaining insight into B cell immunosenescence, we investigated the serum immunoglobulin levels in a cohort of 166 subjects (20-106 years). Serum IgG (and IgG subclasses) were quantified by the nephelometric technique, IgE by CAP system fluorescence enzyme immunoassay, and IgD by radial immunodiffusion (RID). There was an age-related increase of IgG and IgA; the IgG age-related increase was significant only in men, but IgG1 levels showed an age-related increase both in men and women, whereas IgG3 showed an age-related increase only in men. IgE levels remain unchanged, whereas IgD and IgM serum levels decreased with age; the IgM age-related decrease was significant only in women, likely due to the relatively small sample of aged men. Thus, in the elderly the B cell repertoire available to respond to new antigenic challenge is decreased. A lot of memory IgD- B cells are filling immunological space and the amount of naïve IgD+ B cells is dramatically decreased. This shift away from a population of predominantly naïve B cells obviously reflects the influences of cumulative exposure to foreign pathogens over time. These age-dependent B cell changes indicate that advanced age is a condition characterized by lack of clonotypic immune response to new extracellular pathogens. In any event, the increase of memory B cells and the loss of naïve B cells, as measured by serum IgD levels, could represent hallmarks of immunosenescence and could provide useful biomarkers possibly related to the life span of humans.


Assuntos
Linfócitos B/imunologia , Imunoglobulinas/sangue , Longevidade/imunologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Feminino , Humanos , Memória Imunológica , Masculino
18.
Ann N Y Acad Sci ; 1089: 496-501, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17261792

RESUMO

Centenarians are characterized by marked delay or escape from age-associated diseases that cause mortality at earlier ages. Jointly, atherosclerosis and its complications, such as myocardial infarction (AMI), significantly contribute to mortality in the elderly. Inflammation is a key component of atherosclerosis and inflammatory genes are good candidates for the risk of the development of atherosclerosis. Genetic traits contribute to the risk of AMI and allelic variations in inflammatory genes should boost the risk of disease. If proinflammatory genotypes significantly contribute to the risk of AMI, alleles associated with disease susceptibility should not be included in the genetic background favoring longevity. Hence, genotypes of natural immunity should play an opposite role in atherosclerosis and longevity. Metalloproteinase (MMPs) are involved in tissue remodeling and therefore play a remarkable role in inflammation-based disease. MMPs are a family of Zn(2+)-dependent enzymes with proteolytic activity against connective tissue proteins such as collagens, proteoglycans, and elastin, which appear to play important roles in the development and progression of the atherosclerotic lesion. There is evidence indicating a role played by the MMPs in the weakening of atherosclerotic plaque which predisposes to lesion disruption. In this study we performed a genetic study on -1562C/T MMP-9 single nucleotide polymorphism (SNP) in order to discern a possible role in AMI. We analyzed the distribution of this SNP in 115 AMI patients, 123 controls, and 34 centenarians from Sicily. We found no significant differences in the genetic distribution and allelic frequency of -1562C/T MMP-9 SNP between the studied groups. The present results are not in agreement with our previous findings, strengthening our hypothesis that genetic background protection against cardiovascular disease is a relevant component of the longevity trait, at least in the generation of Italian male centenarians under study. However, present results do not exclude that differential expression of MMP-9 playing an opposite role in AMI and longevity because other kinds of regulation might be more relevant than those linked to the SNP under study.


Assuntos
Doença da Artéria Coronariana/genética , Longevidade/genética , Metaloproteinase 9 da Matriz/genética , Infarto do Miocárdio/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso de 80 Anos ou mais , Alelos , Estudos de Coortes , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/enzimologia , Feminino , Frequência do Gene , Humanos , Inflamação/genética , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/etiologia , Sicília
19.
Ann N Y Acad Sci ; 1089: 516-37, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17261795

RESUMO

In this article we discuss relevant data on aging, longevity, and gender with particular focus on inflammation gene polymorphisms which could affect an individual's chance to reach the extreme limit of human life. The present review is not an extensive revision of the literature, but rather an expert opinion based on selected data from the authors' laboratories. In 2000-2005 in the more developed regions, the life expectancy at birth is 71.9 years for men (78.3 in Japan) and 79.3 years for women (86.3 in Japan). Indeed, gender accounts for important differences in the prevalence of a variety of age-related diseases. Considering people of far-advanced age, demographic data document a clear-cut prevalence of females compared to males, suggesting that sex-specific mortality rates follow different trajectories during aging. In Italy this female/male ratio is relatively lower (about 5/1; F/M ratios are usually 5-6:1 in other developed countries), but significant differences have been observed between Italian regions in the distribution of centenarians by gender--from two women per man in the South to more than eight in certain regions in the North. Thus, a complex interaction of environmental, historical, and genetic factors, differently characterizing the various parts of Italy, likely plays an important role in determining the gender-specific probability of achieving longevity. This can be due to gender-specific cultural and anthropological characteristics of Italian society in the last 100 years. Age-related immunoinflammatory factors increase during proinflammatory status, and the frequency of pro/anti-inflammatory gene variants also show gender differences. There is some suggestion that people genetically predisposed to weak inflammatory activity may be at reduced chance of developing coronary heart disease (CHD) and, therefore, may achieve longer lifespan if they avoid serious life-threatening infectious disease thoroughout life. Thus, the pathogen burden, by interacting with host genotype, could determine the type and intensity of the immune-inflammatory response responsible for both proinflammatory status and CHD. These findings point to a strong relationship between the genetics of inflammation, successful aging, and the control of cardiovascular disease, but seem to suggest that the evidence for men is much stronger. The importance of these studies lies in the fact that half of the population (males) lives approximately 10% shorter lives than the other half (females). Understanding the different strategies that men and women seem to follow to achieve longevity may help us to comprehend better the basic phenomenon of aging and allow us to search for safe ways to increase male lifespan.


Assuntos
Antígenos HLA/fisiologia , Longevidade/genética , Longevidade/imunologia , Razão de Masculinidade , Envelhecimento/genética , Envelhecimento/imunologia , Feminino , Antígenos HLA/genética , Humanos , Imunogenética , Inflamação/genética , Inflamação/imunologia , Masculino
20.
Ann N Y Acad Sci ; 1067: 270-5, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16803997

RESUMO

The major trait characterizing offspring in centenarians is a reduction in the prevalence of cardiovascular disease. Because a pro-inflammatory genotype seems to contribute significantly to the risk of coronary heart disease, alleles associated with disease susceptibility would not be included in the genetic background favoring longevity, as suggested by our previous studies on inflammatory cytokines. To confirm whether genotypes of inflammatory molecules play an opposite role in atherosclerosis and longevity, we are studying the role of other proinflammatory alleles, such as pyrin and CCR5, in acute myocardial infarction and longevity. The results support the hypothesis that the genetic background favoring cardiovascular diseases is detrimental to longevity. In addition, they suggest that the centenarian genetic background may be useful for investigating genetic key components of age-associated diseases that are characterized by a multifactorial etiology.


Assuntos
Alelos , Predisposição Genética para Doença/genética , Longevidade/genética , Infarto do Miocárdio/genética , Doença Aguda/epidemiologia , Idoso de 80 Anos ou mais , Proteínas do Citoesqueleto/genética , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/fisiopatologia , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/imunologia , Pirina , Receptores CCR5/genética , Sicília/epidemiologia
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