RESUMO
BACKGROUND: Gelatinase A (matrix metalloproteinase-2 [MMP-2]) has been shown to play an important role in the pathogenesis of several disorders, including periodontal diseases. In this study, we test the hypothesis that variations in this gene influence the development and severity of chronic periodontitis. METHODS: Four promoter polymorphisms (-1575G/A, -1306C/T, -790T/G, and -735C/T) were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods in 149 patients with mild to severe chronic periodontitis and 127 age-matched controls in the Czech population. RESULTS: No significant differences in distribution of the -1575G/A, -1306C/T, and -735C/T variants between periodontitis and control groups were detected in our study. However, a trend to decreased frequency of the -790 GG homozygotes was observed in patients with chronic periodontitis compared to healthy controls (P = 0.036, P (corr) >0.05). Haplotype analysis of four single nucleotide polymorphisms (SNP) in the MMP-2 gene showed no significant association of any haplotype with chronic periodontitis. CONCLUSION: Our findings suggest that polymorphisms in the MMP-2 gene promoter do not contribute significantly to the interindividual periodontitis susceptibility and/or severity in European Caucasians, and they are not regulatory variants in this disease.
Assuntos
Metaloproteinase 2 da Matriz/genética , Periodontite/genética , Adulto , Estudos de Casos e Controles , Doença Crônica , Feminino , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Periodontite/enzimologia , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Polimorfismo de Nucleotídeo Único , Regiões Promotoras GenéticasRESUMO
Vascular lesion development is associated with an accumulation of extracellular matrix proteins within the vessel wall. The proteins are degraded by matrix metalloproteinases (MMPs). There is also evidence indicating a participation of the MMPs in the weakening of atherosclerotic plaque that predisposes to lesion disruption. The aim of the study was to test an association among haplotypes of four single nucleotide MMP-2 promoter polymorphisms and the angiographically confirmed coronary triple-vessel disease (TVD). Incidence of haplotypes of four MMP-2 promoter polymorphisms (-1575G/A, -1306C/T, -790T/G and -735C/T) determined by PCR reactions with restriction analyses in 187 patients with coronary TVD (153 men, 34 women, age median 65 years) was compared to 196 control subjects without clinical signs of coronary heart disease (131 men and 65 women, age median 60 years). The incidence of two similar haplotypes was found to be different between patients and healthy subjects. The haplotype GCTC was more frequent in the TVD patients (P=0.01) though the haplotype GCGC was identified only in healthy subjects (P=0.001). Interestingly, the GCTC is the most frequent polymorphic haplotype composed of four promoter SNPs localized in the MMP-2 gene (53% in healthy subjects vs. 66% in patients with TVD) and the haplotype GCGC is the least frequent polymorphic one (4.4% in healthy subjects vs. 0% in patients with TVD). Two different MMP-2 promoter haplotypes differing only in -790T/G allele are significantly more or less frequent in coronary TVD compared to non-ischemic persons. Thus, the -790T/G MMP-2 genotype might be used as a genetic marker representing MMP-2 promoter variability for the TVD with odds ratio for TT and TG genotypes 2.59, 95% confidential interval 1.21-5.55, P=0.009. The analysis of promoter MMP-2 gene variability could help us to understand individual susceptibility to MMP inhibitor treatment of the coronary artery disease.
Assuntos
Doença das Coronárias/genética , Haplótipos , Metaloproteinase 2 da Matriz/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas/genética , Adenina , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Casos e Controles , Citosina , Feminino , Frequência do Gene , Variação Genética , Genótipo , Guanina , Humanos , Masculino , Pessoa de Meia-Idade , TiminaRESUMO
BACKGROUND: Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional endocytic receptor with an important role in regulating the activity of proteinases in extracellular matrix. Several studies have also described its role in intracellular signaling. Previous studies showed that the expression of LRP1 is related to invasiveness of cancer cells. However, recent data on LRP1 suggest that this receptor can also be involved in tumor establishment and progression. METHODS: We investigated an association between the C766T polymorphism of the third exon of the LRP1 gene and breast cancer in a sample of women of Caucasian origin. Allele and genotype frequencies of this polymorphism were assessed in 164 women with breast cancer and in 183 age-compatible women without a history of any cancer disease. RESULTS: An increase in LRP1 T allele frequency in subjects with breast cancer was observed compared with controls (0.21 versus 0.15, P = 0.01963). A significant excess of genotypes with the T allele (homozygotes plus heterozygotes) was also observed (odds ratio 1.743, 95% confidence interval 1.112-2.732). CONCLUSION: The T allele of the C766T polymorphism in the LRP1 gene is associated with an increased risk of breast cancer development in women of Caucasian origin.
Assuntos
Neoplasias da Mama/genética , Citosina , Predisposição Genética para Doença/genética , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Polimorfismo Genético/genética , Timina , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Biomarcadores Tumorais/genética , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , População Branca/genéticaRESUMO
Basic fibroblast growth factor (bFGF) is a member of the fibroblast growth factor family that possess broad mitogenic and cell survival activities and is involved in a variety of biological processes. We investigated possible genetic polymorphism in the promoter and 5' flanking region of the bFGF gene. Polymorphism was analysed by means of heteroduplex analysis, fragments with altered mobility were sequenced. Three novel substitutions (-553T/A, -834T/A and -921C/G) were identified in the promoter region. Allele frequencies in a sample of healthy Caucasian subjects (n=126) were determined by polymerase chain reactions followed by restriction analyses with specific endonucleases. The frequencies of the mutated alleles (-553A, -834A and -921G) were 0.04, 0.05 and 0.14, respectively. Newly identified variants in the bFGF gene promoter appear to be common polymorphisms in the Czech population.
Assuntos
Fator 2 de Crescimento de Fibroblastos/genética , Variação Genética , Regiões Promotoras Genéticas , Região 5'-Flanqueadora , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação PuntualRESUMO
Associations of the genetic polymorphisms in the promoter region and the signal peptide sequence of the transforming growth factor-beta (TGF-beta1) gene with proliferative diabetic retinopathy (PDR) in patients with non-insulin-dependent diabetes mellitus (NIDDM) were studied. A total of 245 Caucasian subjects comprised the two groups: NIDDM patients with PDR (n = 73) and NIDDM patients without PDR (n = 172). Allele frequencies of common TGF-beta1 polymorphisms (at positions -988C/A, -800G/A, -509C/T, +869T/C (L10P), and +915G/C (R25P)) were determined by PCR-based methodology. All polymorphisms were in strong linkage disequilibrium (P < 10(-2)). Significantly higher frequencies of both the L allele and the R allele of the signal sequence polymorphisms in PDR subjects were found (after a correction for multiple comparisons, P(corr) < 10(-2) and P(corr) < 10(-4), respectively). Calculated odds ratios (ORs) for the LL and RR genotypes were 2.89 (95% confidence interval (CI), 1.6-5.1) and 19.73 (95% CI, 2.6-146.8), respectively. No significant differences between groups were found for the -800G/A and -509C/T polymorphisms. The -988A allele was not represented in our sample. Multiple logistic regression identified age, diabetes duration, and R25P polymorphism as significant predictors (P = 0.002, P = 0.000003, and P = 0.007, respectively). The frequencies of genotype combinations of the -800G/A, -509C/T, L10P, and R25P TGF-beta(1) polymorphisms were significantly different between the PDR and non-PDR groups (chi(2) = 37.83, df = 20, P < 10(-2)). The frequency of haplotype consisting of majority alleles was found significantly associated with PDR (P < 0.03). The presented data indicate that the R25P polymorphisms in the TGF-beta1 gene could be regarded as a strong genetic risk factor for PDR.
Assuntos
Retinopatia Diabética/genética , Fator de Crescimento Transformador beta/genética , Idoso , Alelos , Substituição de Aminoácidos , DNA/química , DNA/genética , Análise Mutacional de DNA , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Retinopatia Diabética/etiologia , Feminino , Frequência do Gene , Genótipo , Haplótipos , Humanos , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo Genético , Polimorfismo Conformacional de Fita Simples , Fatores de RiscoRESUMO
The endothelins are peptides with vasoconstricting and growth-promoting properties. Endothelin-1 (ET-1) is known with its direct positive inotropic and chronotropic effects on isolated heart and with growth effects. The aim of this pilot study was to investigate the frequency distribution of the common polymorphism of the ET-1 gene and its possible relation with hemodynamic consequences of malignant ventricular arrhythmias in patients with structural heart disease. We studied 26 consecutive patients with malignant ventricular arrhythmias and implantable cardioverterdefibrillators with a mean age of 62.7 +/- 12.2 years and a mean left ventricular ejection fraction of 0.37 +/- 11.0. Taq polymorphism of ET-1 was detected using our original polymerase chain reaction method. The polymerase chain reaction product with a length of 358 basepairs (bp) (primers 5'-CAA ACC GAT GTC CTC TGT A-3' and 5'-ACC AAA CAC ATT TCC CTA TT-3') in its non-mutated form contains a target sequence for TaqI restrictive enzyme, while a mutated product loses this cleavage site. Of 26 patients, nine (34%) had recurrent palpitations and eight (30.8%) had syncopes during their malignant arrhythmias. Nineteen patients were given amiodarone after implantable cardioverter-defibrillator insertion and seven were not treated with amiodarone. Fifteen patients had (++), 11 (+-) and 0 (- -) ET-1 genotype. The risk for syncopes was associated with the (++) genotype of the ET-1 gene (P = 0.01). Patients receiving amiodarone had significantly higher frequency of the (++) genotype (P = 0.011). All our results indicate that the presence of the ET-1 genotype (++) in patients with structural heart disease, severe left ventricular dysfunction and malignant ventricular arrhythmias increases the risk for these patients of hemodynamic collapse during these arrhythmias.
Assuntos
Amiodarona/uso terapêutico , Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/genética , Desfibriladores Implantáveis , Endotelina-1/genética , Hemodinâmica/genética , Polimorfismo Genético , Idoso , Sequência de Aminoácidos , Arritmias Cardíacas/fisiopatologia , Arritmias Cardíacas/terapia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Hemodinâmica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Fenótipo , Projetos Piloto , Recidiva , Fatores de Risco , Volume Sistólico/genética , Síncope/genética , Síncope/fisiopatologia , Síncope/terapia , Fatores de Tempo , Resultado do Tratamento , Função Ventricular Esquerda/genéticaRESUMO
The aim of the study was to focus on the relationship between the angiotensinogen (AGT) gene polymorphisms, M235T and promoter G(-6)A, and chronic heart failure in the Czech population. A total of 158 patients with chronic heart failure (functional class NYHA II-IV, ejection fraction <40%, cardiothoracic index >50%) were compared with a control group of 200 subjects of similar age and sex distribution, without any personal history of cardiovascular diseases. The AGT gene polymorphisms were detected by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods. No significant differences in distributions of AGT genotypes between patients with chronic heart failure (CHF) and controls were found. The differences in distributions of alleles in AGT M235T (P(a)=0.02) and genotypes in AGT G(-6)A (P(g)=0.017) were found within women groups. Within CHF patients the distribution of AGT G(-6)A genotypes was not consistent with Hardy-Weinberg equilibrium (P=0.0001). We found significant relative risk of CHF in the GGMT genotype, OR=2.63 with 95% CI 1.39-4.95, P(corr)=0.01 (in the male group OR=1.83, 95% CI 0.92-3.66, P(corr)=0.3; in the female group OR=15.5, 95% CI 1.86-129.42, P(corr)=0.008). We provide evidence of increased risk in subjects with the GGMT variant of associated genotype of AGT gene for CHF, especially of fifteen-fold risk of this variant in women.
Assuntos
Angiotensinogênio/genética , Insuficiência Cardíaca/genética , Polimorfismo Genético/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Doença Crônica , República Tcheca , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores SexuaisRESUMO
BACKGROUND: Chronic periodontitis is an inflammatory disease, which is a major cause of tooth loss. The proinflammatory cytokines interleukin-1 (IL-1) and interleukin-6 (IL-6) are key regulators of the host response to microbial infection and major modulators of extracellular matrix catabolism and bone resorption. The purpose of this study was to investigate the associations of chronic periodontitis with IL-6 gene polymorphisms (at positions -597 [G/A], -572 [G/C], and -174 [G/C]). METHODS: We analyzed allele, genotype, and haplotype distributions of the IL-6 promoter variants in a case-control study involving 148 patients with chronic periodontitis and 107 unrelated controls. RESULTS: Our results showed significant differences in the distributions of alleles and genotypes of the IL-6 (-572 G/C) polymorphism between patients and the control population (chi2 = 10.393, P= 0.001, P(corr) < 0.01). The difference was due to the underrepresentation of the -572 G/C heterozygotes in patients (6.1%) compared to controls (19.6%). Although no variant "CC" homozygotes were detected in our cases and controls, heterozygosity protected against chronic periodontitis, representing a 73% reduction of risk (odds ratio [OR] = 0.27, 95% confidence interval: 0.12-0.61) compared to wild-type homozygotes. However, there were no significant differences in genotype or allele frequencies between both groups for IL-6 -597 G/A and -174 G/C polymorphisms. CONCLUSION: This study is the first, to our knowledge, suggesting that the -572 G/C polymorphism of the IL-6 gene may be one of the protective factors associated with lower susceptibility to chronic periodontitis.
Assuntos
Interleucina-6/genética , Periodontite/genética , Adulto , Alelos , Estudos de Casos e Controles , Doença Crônica , Feminino , Frequência do Gene , Predisposição Genética para Doença/genética , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Método de Monte Carlo , Razão de Chances , Periodontite/imunologia , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Regiões Promotoras Genéticas/genética , FumarRESUMO
Susceptibility to the development of asthma and other atopic diseases is known to be associated with genetic components. Several investigators have linked the tumor necrosis factor (TNF) genes and nearby markers located on chromosome 6p to atopy and asthma. A recent study has demonstrated that the TNF-alpha*2 allele of a polymorphism in the TNF-alpha gene promoter region (G-308 A) is associated with a higher risk for the development of atopy in Spanish patients. This study evaluates the possible role of two described bi-allelic polymorphisms in the TNF locus [a G to A transition at position-308 in the 5'-promoter region of the TNF-alpha gene and an NcoI restriction fragment length polymorphism (RFLP) in the first intron (+252A/G) of the LT-alpha(TNF-beta) gene] in atopic diseases in a Czech population. We investigated the distribution of these polymorphisms in a case-control study. The genotypes were determined in 151 patients with atopic asthma and 155 randomly sampled control subjects. The genotype frequencies for both polymorphisms were similar in cases and controls. No significant differences in allele frequencies were found between either of the patients groups and the reference subjects. Similarly, there were no associations of any of the examined variants of the TNF genes with total IgE, specific IgE or pulmonary function tests in patients with allergic diseases. We conclude that these polymorphisms of the TNF genes are unlikely to contribute to atopic disease risk in our population. Significant associations that have been reported in other studies may reflect the genetic heterogeneity of these complex diseases.
Assuntos
Asma/genética , Hipersensibilidade Imediata/genética , Polimorfismo Genético/genética , Fator de Necrose Tumoral alfa/genética , Adulto , Alelos , Estudos de Casos e Controles , República Tcheca , Feminino , Frequência do Gene , Genótipo , Humanos , Íntrons , Linfotoxina-alfa/genética , Masculino , Regiões Promotoras GenéticasRESUMO
PURPOSE: Tissue inhibitor of metalloproteinase-3 (TIMP-3) is a member of the TIMP family of proteins, playing a significant role in the control of extracellular matrix remodelling. TIMP-3 might play a role in the regulation of retinal neovascularization during progression of diabetic retinopathy. Recently, three novel polymorphisms (-899T/A, -915A/G and -1296T/C) in the promoter region of the TIMP-3 gene have been identified. The aim of the study was to investigate a possible association of these polymorphisms with proliferative diabetic retinopathy (PDR) in type 2 diabetes mellitus (T2DM). METHODS: Genotypes were detected by polymerase chain reaction and subsequent restriction with specific endonucleases. Allele frequencies were determined in an association study comprising three groups of subjects (n = 371). RESULTS: Linkage disequilibrium was found among the three polymorphisms (P < or = 0.01). Allele frequencies did not differ between neither T2DM + PDR and T2DM non-PDR subjects (P > 0.05) nor between all T2DM versus non-diabetic subjects (P > 0.05). CONCLUSIONS: Polymorphisms in the promoter region of the TIMP-3 gene were not associated with the PDR in the Caucasian T2DM patients.
Assuntos
Diabetes Mellitus Tipo 2/genética , Retinopatia Diabética/genética , Polimorfismo Genético , Regiões Promotoras Genéticas/genética , Inibidor Tecidual de Metaloproteinase-3/genética , Retinopatia Diabética/enzimologia , Feminino , Frequência do Gene , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da PolimeraseRESUMO
Angiotensin-I converting enzyme (ACE) is involved not only in intracellular volume regulation but also in proliferation control. Since both ACE gene polymorphism (I/D ACE) and ABO blood group determine ACE level in peripheral blood and probably also in bone marrow, the hypothesis to the interindividual differences in survival of leukemic patients was suggested. The data of 25 patients of both sexes with acute myelogenous (AML), acute lymphatic (ALL), chronic myelogenous (CML) and chronic lymphatic (CLL) leukemia treated by conventional were used for the study. The overall survival (SUR) was estimated as the time from the date of diagnosis to the date of death. The difference between patient's individual SUR (iSUR) and median SUR according to the type of leukemia (mSUR) was calculated. This difference (iSUR-mSUR) varied with I/D ACE genotype (p<0.02) but neither with diagnosis nor with ABO blood group. The regression model for iSUR calculation, from mSUR and I/D ACE genotype, has been suggested.
Assuntos
Leucemia/genética , Leucemia/mortalidade , Peptidil Dipeptidase A/genética , Polimorfismo Genético , Adulto , Idoso , Alelos , Divisão Celular , Eletrólitos/metabolismo , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeos/química , Projetos Piloto , Fatores de TempoRESUMO
OBJECTIVE: To evaluate the association of three endothelin-1 (ET-1) gene polymorphisms with essential hypertension, as well as with two cardiovascular risk factors: body mass index (BMI) and smoking. DESIGN: Three gene polymorphisms and the genotype and allelic distributions were compared between normotensive healthy volunteers and patients with essential hypertension. The genetic association of the three genotypes with BMI and smoking status was calculated. PATIENTS AND METHODS: CA/CT dinucleotide repeat polymorphism, G(8002)A polymorphism and -3A/-4A polymorphism (-138 insertion/deletion) were examined in the gene coding for ET-1 (6p21.3) in 398 subjects: 192 normotensives (healthy volunteers) and 206 patients with essential hypertension. Normotension was verified by 24 h ambulatory blood pressure monitoring. RESULTS: Significant inner associations were observed between all three polymorphisms, which suggests possible complex interactions inside the gene. The only significant difference in a single gene case control study was in the lengths of allelic variants of CA/CT dinucleotide repeat polymorphism. In hypertensive patients, the alleles of G(8002)A and -3A/-4A ET-1 polymorphisms were found to be significantly associated (G with -3A and A with -4A). None of the ET-1 gene polymorphisms was associated with BMI. A highly significant increase of the -3A allele of the -3A/-4A ET-1 polymorphism was found in hypertensive men who were current smokers or had smoked at least seven cigarettes a week for at least one year at any time in their life compared with hypertensive men who had never smoked (odds ratio 1.54, 95% CI 1.03 to 2.32, P=0.009). CONCLUSIONS: Smoking seems to be an independent cardiovascular risk factor genetically codetermined by the ET-1 gene variant.
RESUMO
BACKGROUND: Adult periodontitis is a complex multifactorial disease whose etiology is not well defined. To investigate whether the genes encoded within the HLA class III region may confer susceptibility to periodontitis, polymorphisms in the ET-1 and TNF-ß genes were analyzed together with the I/D polymorphism of the ACE gene. METHODS: We determined allele and genotype frequencies of the NcoI bi-allelic polymorphism of the TNF-ß gene, the I/D (insertion/deletion) polymorphism of the ACE gene, and the TaqI polymorphism of the ET-1 gene in 63 Caucasian patients with adult periodontitis and 95 orally healthy controls. RESULTS: We found a significant difference in a 3 locus combination of genotypes between patients and controls (P <0.05). In the next analyses, no significant differences were found in allele frequencies of single genes, but we did find a significant difference in the genotype distribution between cases and controls for TNF-ß (P <0.03). Differences were also observed for 2 locus combinations of ACE and TNF-ß genotypes (P <0.03), and the ET-1 and TNF-ß (P <0.05) genes. Evidence of deviation from Hardy-Weinberg equilibrium was observed in the periodontitis group for TNF-ß, with an absence of the B1 B1 homozygotes in patients. CONCLUSIONS: This study is of an exploratory nature. Considering the number of significant results, however, at least a part of the observed associations may obviously be real and our findings suggest that interactions of the TNF-ß, ET-1, and ACE genes may be involved in susceptibility to adult periodontitis. J Periodontol 2001;72:85-89.
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Increased plasma concentration of lipoprotein(a) [Lp(a)] is an established independent risk factor for coronary artery disease (CAD), which is strongly genetically determined. This study was designed to investigate the relationship between the K-IV and (TTTTA)n apolipoprotein(a) [apo(a), protein; APOA, gene] polymorphisms, as well as the C766T low-density lipoprotein receptor-related protein (LRP) and the (CGG)n very low density lipoprotein receptor (VLDLR) polymorphisms on the one hand, and plasma Lp(a) levels in Czech subjects who underwent coronary angiography on the other hand. The lengths of the alleles of the APOA K-IV and (TTTTA)n polymorphisms were strongly inversely correlated with plasma Lp(a) levels in univariate analysis (r = -0.41, p < 10(-4) and r = -0.20, p < 0.01, respectively). Multivariate analysis revealed significant associations between the APOA polymorphisms studied and plasma Lp(a) levels in subjects expressing only one APOA K-IV allele (p < 10(-6) for K-IV and p < 0.001 for TTTTA). In subjects expressing both APOA K-IV alleles, the multivariate analysis revealed that only the APOA K-IV alleles were inversely correlated with plasma Lp(a) levels (p < 0.001). Associations between both the LRP and VLDLR gene polymorphisms and plasma Lp(a) levels were only of borderline significance (p < 0.06 and p < 0.07, respectively) and were not confirmed in multivariate analysis. In conclusion, both APOA length polymorphisms significantly influenced plasma Lp(a) concentration in the Czech population studied, and this circumstance could explain the association in this population observed earlier between APOA (TTTTA)n polymorphism and CAD (Benes et al. 2000). Only a minor role in the regulation of plasma Lp(a) levels is suggested for the C766T LRP and the (CGG)n VLDLR polymorphisms.
Assuntos
Apolipoproteínas A/genética , Doença das Coronárias/genética , Lipoproteína(a)/sangue , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Polimorfismo Genético , Receptores de LDL/genética , Alelos , Análise de Variância , Apolipoproteínas A/sangue , Doença das Coronárias/sangue , Doença das Coronárias/epidemiologia , República Tcheca/epidemiologia , Ensaio de Imunoadsorção Enzimática , Feminino , Frequência do Gene , Genótipo , Humanos , Modelos Lineares , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/sangue , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Receptores de LDL/sangue , Fatores de Risco , Estatísticas não ParamétricasRESUMO
We tested capabilities of drugs elevating extracellular adenosine and of granulocyte colony-stimulating factor (G-CSF) given alone or in combination to modulate regeneration from severe myelosuppression resulting from combined exposure of mice to ionizing radiation and carboplatin. Elevation of extracellular adenosine was induced by joint administration of dipyridamole (DP), a drug inhibiting the cellular uptake of adenosine, and adenosine monophosphate (AMP), serving as an adenosine prodrug. DP+AMP, G-CSF or all these drugs in combination were administered in a 4-d treatment regimen starting on day 3 after induction of myelosuppression. Comparable enhancements of haematopoietic regeneration due to elevation of extracellular adenosine or to action of G-CSF were demonstrated as shown by elevated numbers of haematopoietic progenitor cells for granulocytes/macrophages (GM-CFC) and erythrocytes (BFU-E) in the bone marrow and spleen in early time intervals after termination of the drug treatment, i.e. on days 7 and 10 after induction of myelosuppression. Coadministration of all the drugs further potentiated the restoration of progenitor cell pools in the haematopoietic organs. The effects of the drug treatments on progenitor cells were reflected in the peripheral blood in later time intervals of days 15 and 20 after induction of myelosuppression, especially as significantly elevated numbers of granulocytes and less pronounced elevation of lymphocytes and erythrocytes. The results substantiate the potential of drugs elevating extracellular adenosine for clinical utilization in myelosuppressive states, e.g. those accompanying oncological radio- and chemotherapy.
Assuntos
Monofosfato de Adenosina/uso terapêutico , Adenosina/metabolismo , Medula Óssea/efeitos dos fármacos , Dipiridamol/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Células-Tronco Hematopoéticas/patologia , Pancitopenia/tratamento farmacológico , Pró-Fármacos/uso terapêutico , Monofosfato de Adenosina/farmacologia , Animais , Contagem de Células Sanguíneas , Medula Óssea/patologia , Medula Óssea/efeitos da radiação , Carboplatina/toxicidade , Dipiridamol/farmacologia , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Células Precursoras Eritroides/patologia , Espaço Extracelular/metabolismo , Fator Estimulador de Colônias de Granulócitos/farmacologia , Linfócitos/patologia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Pancitopenia/etiologia , Pancitopenia/metabolismo , Pancitopenia/patologia , Pró-Fármacos/farmacologia , Irradiação Corporal Total/efeitos adversosRESUMO
BACKGROUND: The endothelins are peptides with vasoconstricting and growth-promoting properties. Endothelin-1 (ET-1) is known for its direct positive inotropic and chronotropic effects on isolated heart, and for growth effects. The aim of this pilot study was to investigate the frequency distribution of a common polymorphism of the endothelin (ET-1) gene and its possible relation to the hemodynamic consequences of malignant ventricular arrhythmia in patients with structural heart disease. MATERIAL/METHODS: We studied 26 consecutive patients with malignant ventricular arrhythmia and implantable cardioverter defibrillators (ICD), mean age 62.7 +/- 12.2 years, mean LVEF 0.37 +/- 11. The Taq polymorphism of ET-1 was detected using our original PCR method. The PCR product with a length of 358 bp in its non-mutated form contains a target sequence for the TaqI restrictive enzyme, while the mutated product loses this cleavage site. RESULTS: Out of the 26 patients, 9 (34%) had recurrent palpitations and 8 (30.8%) had syncopes during their malignant arrhythmic episodes. 19 of the patients were receiving amiodarone after ICD implantation, 7 were not. 15 patients had the (++) and 11 had the (+ -) ET-1 genotype; none had the (- -) genotype. The risk of syncopes was associated with the (++) genotype (p=0.01). Patients with amiodarone had a significantly higher frequency of the (++) genotype (p=0.011). CONCLUSIONS: All our results suggested that the presence of the (++)ET-1 genotype in patients with structural heart disease, severe left ventricular dysfunction, and malignant ventricular arrhythmia put these patients at a higher risk of hemodynamic collapse during arrhythmic episodes.
Assuntos
Arritmias Cardíacas/genética , Arritmias Cardíacas/patologia , Endotelina-1/genética , Polimorfismo Genético , Idoso , Feminino , Genótipo , Hemodinâmica , Heterozigoto , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Reação em Cadeia da PolimeraseRESUMO
Remodelling of extracellular matrix by activated matrix metalloproteinases is considered to contribute to progression of ventricle remodelling during chronic heart failure. The aim of this study was to associate two promoter polymorphisms, -790T/G and -735C/T, in the gene for matrix metalloproteinase (MMP)-2 (gelatinase A) with chronic heart failure (CHF). For this purpose, 164 patients (124 men, 40 women, median age 56 years, range 21-91 years) with CHF (functional class NYHA II-IV, ejection fraction median 25%, cardiothoracic index more than 50%) were compared with 196 control subjects without clinical signs of cardiovascular disease (131 men and 65 women, median age 56 years, range 27-84 years) in -790T/G and -735C/T MMP-2 genotype distributions and allelic frequencies. The genotypes were determined by polymerase chain reaction (PCR) with restriction analyses. A significant increase of the T allele of the -790T/G MMP-2 polymorphism (p = 0.04), as well as of the C allele of the -735C/T MMP-2 gene polymorphism, in patients with CHF was proven (p = 0.04). The heterozygote CT of the -735C/T MMP-2 polymorphism exhibits a 7 times higher odds ratio (OR) for the CHF patients with lower levels of total cholesterol (less than 5 mmol/l), especially for non-hypertensive CHF men (OR = 7.28, 95% confidence interval 1.51-35.03, p = 0.006). Determination of MMP polymorphisms in the regulatory area of the gene could help us to comprehend individual susceptibility of patients with CHF to MMP inhibitors based on known risks of MMP genotypes.
Assuntos
Baixo Débito Cardíaco/genética , Metaloproteinase 2 da Matriz/genética , Polimorfismo Genético , Regiões Promotoras Genéticas , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Over ten genome-wide screens and many candidate genes studies were performed worldwide to elucidate genetic factors involved in the pathogenesis of bronchial asthma and other atopic diseases. Results from these studies were often discordant, which might have reflected complexity and heterogeneity of these multifactorial diseases. Among a variety of other loci, specific variants of the gene for IKAP (IKK complex-associated protein) were shown to be associated with bronchial asthma in children in a Japanese study. To test the possible role of SNPs in the coding region of the IKAP gene in atopic asthma or other atopic phenotypes in a highly homogenous Czech population, a case-control study including 373 patients and 309 healthy control subjects was performed. There were no significant differences in the genotype and allele distributions for any of five SNPs in the IKAP gene (T819C, G2295A, A2490G, T3214A and C3473T) between patients with atopic asthma or other atopic diseases and healthy controls. These results suggest that the polymorphisms in the coding region of the IKAP gene are unlikely to contribute to atopic disease risk in the Czech population.