RESUMO
Interleukin 10 (IL-10) is an anti-inflammatory cytokine with a protective role in the formation and the development of the atherosclerotic plaque. The aim of the present study was to establish if IL-10 gene polymorphisms are associated with the development of premature coronary artery disease (pCAD) and cardiovascular risk factors in Mexican individuals. Three IL-10 gene polymorphisms [-592C/A (rs1800872), -819C/T (rs1800871), and -1082 A/G (rs1800896)] and IL-10 plasma levels were analyzed in 2266 individuals (1160 pCAD patients and 1106 healthy controls). Under recessive and co-dominant2 models, the -1082 A/G (rs1800896) G allele was associated with decreased risk of developing pCAD (ORâ¯=â¯0.572, Precâ¯=â¯0.022 and ORâ¯=â¯0.567, Pcod2â¯=â¯0.023). In pCAD patients, the polymorphisms were associated with hyperinsulinemia, small and dense LDLs, hypertension, and diabetes mellitus. In the control group, the polymorphisms were associated with hypertension, hyperuricemia, and small and dense LDLs. pCAD patients have significantly higher IL-10 plasma levels than healthy controls [0.91 (0.55-1.67) pg/mL vs 0.45 (0.24-0.98) pg/mL, respectively, Pâ¯<â¯0.0001]. Nevertheless, these levels were not associated with the genotypes analyzed in the present study. The results suggest that the IL-10-1082 A/G (rs1800896) G allele is associated with a decreased risk of developing pCAD. In patients and controls, the polymorphisms analyzed were associated with some cardiovascular risk factors. Although, in pCAD patients the IL-10 plasma levels were higher, they were not associated with the genotypes of the polymorphisms examined.
Assuntos
Alelos , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/metabolismo , Estudos de Associação Genética , Predisposição Genética para Doença , Interleucina-10/genética , Polimorfismo de Nucleotídeo Único/genética , Estudos de Casos e Controles , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/epidemiologia , Feminino , Humanos , Interleucina-10/sangue , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de RiscoRESUMO
A Nahua Aztec isolated group from Morelos State (Mexico) was studied for their HLA profile. The relationship with other Amerindians and worldwide populations was studied by using 13,818 chromosomes and calculating Nei's chord genetic distances (DA), neighbor-joining dendrograms and correspondence multidimensional values. Three new HLA extended haplotypes were found in our group: A*30-B*49-DRB1*1001-DQB1*0501 (the most frequent one in this population), A*02-B*52-DRB1*1402-DQB1*0301 and A*68-B*61-DRB1*1602-DQB1*0303. Both genetic distances and correspondence analyses clearly show that our Nahua isolated group is genetically close to some of the most ancient groups living in Mexico (Mayans, Zapotecans, Mixtecans). This suggests that Nahua language (Nahuatl) may have been imposed to scattered groups throughout Mexico; otherwise Aztecs may have been living in Mexico long before their postulated immigration in the XII century AD.
Assuntos
Antígenos HLA-A/genética , Antígenos HLA-B/genética , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Indígenas Norte-Americanos/genética , Frequência do Gene , Cadeias beta de HLA-DQ , Cadeias HLA-DRB1 , Haplótipos , Humanos , Desequilíbrio de Ligação , México , Filogenia , Polimorfismo Genético , Análise de Sequência de DNARESUMO
The secretory phospholipase A2 II A (sPLA2-IIA) encoded by PLA2G2A gene hydrolyzes phospholipids liberating free fatty acids (FFAs) and lysophospholipids. If lipolysis exceeds lipogenesis, the free fatty acids undergo a continuous release into circulation. A sustained excessive increase in this release contributes to metabolic disease. The aim of the present study was to evaluate the role of PLA2G2A gene polymorphisms as susceptibility markers for metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM) in Mexican population. Three PLA2G2A gene polymorphisms (rs876018, rs3753827 and rs11573156) were genotyped by 5' exonuclease TaqMan assays in a group of 338 patients with T2DM, 460 individuals with MetS and 366 healthy controls. Under codominant 1(codom1), dominant (dom) and additive (add) models adjusted by age, gender, body mass index (BMI), smoking habit, and hypertension, the rs876018T allele was associated with increased risk of MetS [Odds Ratio (OR)=1.66, Pcodom1=0.005; OR=1.67, Pdom=0.003; OR=1.49, Padd=0.005] as compared to controls. On the other hand, under several models adjusted by the same variables, the rs3753827A (OR=1.52, Pcodom1=0.039 and OR=1.49, Pdom=0.039) and rs11573156C alleles (OR=6.46, Pcodom1=0.013; OR=6.70, Pcodom2=0.009; OR=6.65, Pdom=0.009) were associated with increased risk of T2DM when compared with controls. In addition, the rs876018T allele was associated with hypercholesterolemia (Pdom=0.017, Padd=0.009) and risk of subclinical atherosclerosis (SA) (Pdom=0.041) in MetS when compared with controls. Also, this allele was associated with SA in T2DM patients (Pdom=0.007). The TAG haplotype was significantly associated with increased risk of MetS (OR=1.54, P=0.006). Results suggest that PLA2G2A polymorphisms are involved in the risk of developing MetS and T2D and are associated with SA in this group of patients.
Assuntos
Aterosclerose/genética , Diabetes Mellitus Tipo 2/genética , Fosfolipases A2 do Grupo II/genética , Hipercolesterolemia/genética , Síndrome Metabólica/genética , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Desequilíbrio de Ligação , Lipogênese , Lipólise , México , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Several studies suggest an important role of Interleukin-27 in the development of atherosclerosis. The aim of this study was to establish whether the IL-27p28 gene polymorphisms are associated with premature coronary artery disease and/or other cardiovascular risk factors. Four IL-27p28 gene polymorphisms were selected and genotyped in 1162 premature coronary artery disease cases and 1107 controls. rs26528 T and rs40837 A alleles were significantly associated with a lower risk of premature coronary artery disease under different inheritance models (Pdominant = 0.046; Pover-dominant = 0.002; Pco-dominant1 = 0.007 for rs26528T; Pover-dominant = 0.008 and Pco-dominant1 = 0.031 for rs40837). The rs40837 A allele was also associated with a lower risk of insulin resistance, in cases (Pover-dominant = 0.037) and controls (Padditive = 0.008; Pdominant = 0.047; Precessive = 0.014; Pco-dominant2 = 0.006), while the rs26528 T allele was associated with a lower risk of insulin resistance only in the control group (Precessive = 0.016; Pco-dominant2 = 0.021). Interleukin-27 plasma levels were measured in 450 controls and 450 cases, and were significantly higher in cases compared to controls (P = 0.004). However, Interleukin-27 plasma levels were not associated with IL-27p28 polymorphisms. Luciferase assays showed that co-transfection of the rs40837 A allele and miR-379-5p significantly decreased luciferase gene expression. Our study shows for the first time, that IL-27p28 gene polymorphisms are associated with premature coronary artery disease and with some metabolic parameters. The rs40837 A allele in presence of miR-379-5p significantly decreased luciferase gene expression.
RESUMO
BACKGROUND: Rheumatic heart disease (RHD) is an autoimmune sequel of group A streptococcal infection that has been associated with the presence of some major histocompatibility complex (MHC) genes. Thus, the aim of the present study was to investigate the role of class II alleles in the genetic susceptibility to RHD in Mexican patients and establish the relationship of these alleles with the pattern of valve damage. METHODS: HLA-DR, -DQA1 and -DQB1 allele frequencies were determined by PCR-SSO reverse dot blot and PCR-SSP in 98 Mexican Mestizo patients with RHD and 99 healthy controls. Patients were divided into mitral valve damage (n=46), multivalvular lesion (n=49) and aortic damage (n=3). RESULTS: RHD patients presented an HLA-DR16 increased frequency (pC=0.009, OR=3.9) and a decreased HLA-DR11 frequency (pC=0.018) when compared to healthy controls. HLA-DR16 subtyping showed that DRB1*1602 was the DR16 allele increased in patients (pC=0.007, OR=5.3). Haplotype analysis showed increased frequency of DR16-DQA1*0501-DQB1*0301 in RHD patients when compared to healthy controls (pC=0.011). HLA-DR16 frequency remained significantly increased on patients with multivalvular lesion (pC=0.004, OR=4.8). CONCLUSIONS: Our data suggest an important participation of Amerindian autochthonous HLA-DR16 (DRB1*1602) allele and DR16-DQA1*0501-DQB1*0301 haplotype as markers for RHD genetic susceptibility in the Mexican Mestizo population. HLA-DR16 allele could also play an important role in determining the pattern of valve damage on these patients.
Assuntos
Genes MHC da Classe II , Predisposição Genética para Doença , Indígenas Norte-Americanos/genética , Cardiopatia Reumática/genética , População Branca/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Frequência do Gene , Haplótipos , Humanos , Masculino , México , Pessoa de Meia-IdadeRESUMO
Life expectancy has always been associated to several determinants, such as environmental and genetic factors. Studies have related human lifespan as being 25-32 % due to genetic polymorphisms between individuals associated to longevity and aging. Nonetheless, no single gene will convey a phenotype like longevity. Aging is a process that occurs from changes in various levels of the cell, from genes to functions. Longevity is the ability to cope and repair the damage that results from these changes. It has been described as the result of an optimal performance of immune system and as an overexpression of anti-inflammatory sequence variants of immune/inflammatory genes.Longevity gene candidates can be separated into the following categories: inflammatory and immune-related, stress response elements, mediators of glucose and lipid metabolism, DNA repair components and cellular proliferation, and DNA haplogroups.Studies have related lifespan with Common Single-Nucleotide Polymorphisms (SNPs); polygenic effects can explain an important part of how genetics influence it. In this chapter we describe how to sequence Class I HLA allele polymorphism, as well as SNP sequencing, two methodologies most frequently used in polymorphism detection.
Assuntos
Envelhecimento/genética , Genes MHC Classe I/genética , Antígenos de Histocompatibilidade Classe I/genética , Teste de Histocompatibilidade/métodos , Longevidade/genética , Sequência de Bases , Genótipo , Humanos , Expectativa de Vida , Polimorfismo de Nucleotídeo Único/genética , Análise de Sequência de DNARESUMO
Immunisation with neural-derived peptides is a promising strategy in models of spinal cord (SC) injury. Recent studies have also demonstrated that the addition of glutathione monoethyl ester (GHSE) to this strategy further improves motor recovery, tissue protection and neuronal survival after SC injury. As it is realistic to envision that this combination therapy could be tested in clinical trials, the therapeutic window should be experimentally explored before implementing its use in SC-injured human beings. For this purpose, 50 rats (10 per group) were subjected to a moderate SC contusion. The combined therapy was initiated at 10 min., 24, 72 or 120 hr after injury. Motor recovery and the survival of rubrospinal (RS) and ventral horn (VH) neurones were evaluated 60 days after injury. Results showed a significant motor improvement even if the combined therapy was initiated up to 72 hr after injury. BBB scores were as follows: 10 min.: 10.5 ± 0.7, 24 hr: 10.7 ± 0.5, 72 hr: 11.0 ± 1.3 and PBS: 6.7 ± 1 (mean ± S.D.). Initiation of combined therapy 120 hr after injury had no beneficial effect on motor recovery. Survival of RS and VH neurones was significantly higher in animals treated during the first 72 hr than those treated only with PBS. In this case again, animals treated with combined therapy 120 hr after injury did not present significant survival of neurones. Treatment with this combined strategy has a clinically feasible therapeutic window. This therapy provides enough time to transport and diagnose the patient and allows the concomitant use of other neuroprotective therapies.
Assuntos
Glutationa/análogos & derivados , Atividade Motora/efeitos dos fármacos , Proteína Básica da Mielina/farmacologia , Fármacos Neuroprotetores/administração & dosagem , Traumatismos da Medula Espinal/terapia , Tempo para o Tratamento , Animais , Células do Corno Anterior/efeitos dos fármacos , Células do Corno Anterior/patologia , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Esquema de Medicação , Quimioterapia Combinada , Feminino , Glutationa/administração & dosagem , Glutationa/imunologia , Atividade Motora/fisiologia , Proteína Básica da Mielina/imunologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fármacos Neuroprotetores/imunologia , Ratos , Ratos Sprague-Dawley , Traumatismos da Medula Espinal/imunologia , Traumatismos da Medula Espinal/fisiopatologia , Fatores de TempoRESUMO
Apoptosis is one of the most destructive mechanisms that develop after spinal cord (SC) injury. Immunization with neural-derived peptides (INDPs) such as A91 has shown to reduce the deleterious proinflammatory response and the amount of harmful compounds produced after SC injury. With the notion that the aforementioned elements are apoptotic inducers, we hypothesized that INDPs would reduce apoptosis after SC injury. In order to test this assumption, adult rats were subjected to SC contusion and immunized either with A91 or phosphate buffered saline (PBS; control group). Seven days after injury, animals were euthanized to evaluate the number of apoptotic cells at the injury site. Apoptosis was evaluated using DAPI and TUNEL techniques; caspase-3 activity was also evaluated. To further elucidate the mechanisms through which A91 exerts this antiapoptotic effects we quantified tumor necrosis factor-alpha (TNF-α). To also demonstrate that the decrease in apoptotic cells correlated with a functional improvement, locomotor recovery was evaluated. Immunization with A91 significantly reduced the number of apoptotic cells and decreased caspase-3 activity and TNF-α concentration. Immunization with A91 also improved the functional recovery of injured rats. The present study shows the beneficial effect of INDPs on preventing apoptosis and provides more evidence on the neuroprotective mechanisms exerted by this strategy.
Assuntos
Apoptose/efeitos dos fármacos , Imunização , Proteínas do Tecido Nervoso/farmacologia , Peptídeos/farmacologia , Traumatismos da Medula Espinal/imunologia , Animais , Apoptose/imunologia , Feminino , Proteínas do Tecido Nervoso/imunologia , Peptídeos/imunologia , Ratos , Ratos Sprague-Dawley , Traumatismos da Medula Espinal/patologia , Fator de Necrose Tumoral alfa/imunologiaRESUMO
The major histocompatibility genes (MHC) have been associated with the genetic susceptibility to rheumatic heart disease (RHD). Results have been inconsistent and new genes located on the MHC region such as tumor necrosis factor (TNF-alpha) need to be analyzed. TNF-alpha polymorphisms (positions -238 and -308) were determined in 87 RHD Mexican Mestizo patients and 101 healthy controls. Patients were classified into mitral valve damage (MVD) and multivalvular lesion (MVL) categories. TNF-238 G allele and GG genotype were increased in patients when compared to healthy controls (pC=0.001, OR=14.1 and pC=0.003, OR=14.1, respectively). Also, decreased frequencies of TNF-238 A allele (pC=0.001) and AG genotype (pC=0.003) were found. TNF-308 polymorphism analysis showed increased frequencies of T2 (A) allele (pC<10(-3), OR=10.8) and T1T2 (AG) genotype (pC<10(-3), OR=9.85) and decreased frequencies of T1 (G) allele and T1T1 (GG) genotype (pC<10(-3)). When comparing valvular damage to healthy controls, patients with MVD showed increased frequencies of -238 GG (pC=0.03, OR=ND), -308 T1T2 (AG) (pC<10(-3), OR=14) and -308 T2 (A) (pC<10(-3), OR=11.7). Also, this group showed decreased frequencies of T1 (G) allele and T1T1 (GG) genotype (pC<10(-3)). Patients with MVL presented increased frequency of -308 T2 (A) allele (pC=0.0003, OR=8.65) and decreased frequencies of -308 T1 (G) allele and -308 T1T1 (GG) genotype (pC=0.0003 and pC=0.006, respectively). Distribution of -238 and -308 polymorphisms were similar between MVD and MVL. The data demonstrate that RHD is associated with TNF-alpha polymorphisms in the Mexican population; however, these polymorphisms do not have relation with the valve damage.