RESUMO
Immune-mediated and neurodegenerative mechanisms are involved in multiple sclerosis (MS). Growing evidences highlight the role of HSP70 genes in the susceptibility of some neurological diseases. In this explorative study we analyzed a polymorphism (i.e. HSP70-hom rs2227956) of the gene HSPA1L, which encodes for the protein hsp70-hom. We sequenced the polymorphism by polymerase chain reaction (PCR), in 191 MS patients and 365 healthy controls. The hsp70-hom protein expression was quantified by western blotting. We reported a strong association between rs2227956 polymorphism and MS risk, which is independent from the association with HSP70-2 rs1061581, and a significant link between hsp70-hom protein expression and MS severity.
Assuntos
Predisposição Genética para Doença/genética , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Esclerose Múltipla/genética , Esclerose Múltipla/metabolismo , Polimorfismo Genético/genética , Adulto , Avaliação da Deficiência , Feminino , Frequência do Gene , Genótipo , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Funções Verossimilhança , Masculino , Entrevista Psiquiátrica Padronizada , Pessoa de Meia-IdadeRESUMO
Inflammation plays an important role in the pathogenesis of atherosclerosis and coronary syndromes; moreover, various lines of evidence suggest that genetic factors contribute significantly to the risk of coronary artery disease (CAD). Through its effects on endothelial function, coagulation, insulin resistance and lipid metabolism, the proinflammatory cytokine TNF could be involved in cardiovascular pathophysiology. The aim of our study is to analyze whether TNF gene promoter (-308 G/A; -857 G/A) and TNF receptor polymorphisms (TNFR1 MspA1 I exon 1 and TNFR2 Nla III exon 6) show involvement in CAD predisposition in a group of Italian patients compared with healthy controls. Genotyping was performed by PCR-RFLP. Consecutive Italian patients with angiographically proven CAD (n= 248) were compared with controls (n=241), matched for age, sex and geographical origins. CAD patients showed a higher frequency of the TNF -308 A allele than healthy controls (p=0.046). After stratification according to risk factors for CAD, our analysis revealed that CAD patients with diabetes (p=0.042) and CAD patients without hypertension (p= 0.0495) displayed a higher frequency of the TNF -308 AA genotype compared with healthy controls. Our data stress the inflammatory nature of CAD and show a possible involvement of TNF -308G/A promoter polymorphisms in the predisposition to the development of this disease. The less frequent A allele seems to be a predisposing factor for development of CAD in particular pathological settings associated with the disease itself, such as diabetes.
Assuntos
Aterosclerose/genética , Aterosclerose/patologia , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/patologia , Inflamação/genética , Inflamação/patologia , Receptores do Fator de Necrose Tumoral/genética , Fator de Necrose Tumoral alfa/genética , Idoso , Angiografia Coronária , DNA/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético/genética , Polimorfismo de Fragmento de Restrição , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Upregulation of the receptor for advanced glycation end products (RAGE) may play a crucial role in neointimal formation upon vessel injury. The -374T/A variant of the RAGE gene promoter, which has been associated with an altered expression of the cell-surface receptor, could exert a protective effect toward the development of vascular disease. The aim of this study is to determine the impact of this common genetic variant in the occurrence of clinical in-stent restenosis after coronary stent implantation. The -374T/A polymorphism of the RAGE gene promoter was evaluated by PCR-RFLPs in 267 patients with coronary artery disease who underwent coronary stent implantation and a subsequent coronary angiography 6-9 months later for suspected restenosis. In-stent restenosis was assessed by means of quantitative angiography. Carriers of the -374AA genotype showed a significantly reduced risk of developing restenosis after percutaneous transluminal intervention than non-carriers. To determine whether the protective effect of the homozygous AA genotype toward clinical restenosis was independent of potential confounders, we performed multivariable logistic regression analysis. After allowance for clinical and biochemical risk factors and stent length, the AA genotype remained significantly associated with a reduced prevalence of in-stent restenosis. No relation was evident between the RAGE genotype and established cardiovascular risk factors. In conclusion, the -374AA genotype of the RAGE gene promoter could be associated with a reduced risk of in-stent restenosis after coronary stent implantation.