RESUMO
BACKGROUND: Human papillomavirus is the major cause of cervical cancer, but only few cases develop into cancer. Nevertheless, HuR (ELAVL1) gene has been implicated in the oncogenesis of certain cancers. The correlation between ELAVL1 gene and the risk of cervical cancer remains unclear. Therefore, this study investigated the effect of ELAVL1 gene polymorphisms (SNPs) in cervical cancer development in Tunisian women. METHOD: ELAVL1 gene SNPs: ELAVL1 rs12983784 T > C, ELAVL1 rs14394 T > C, ELAVL1 rs74369359 G > T, ELAVL1 rs35986520 G > A, ELAVL1 rs10402477 C > T, ELAVL1 rs12985234 A > G and ELAVL1 rs2042920 T > G, were genotyped by High resolution melting (HRM). SNPStats software was used to perform linkage disequilibrium (LD) and haplotype analysis. RESULTS: Comparing the cervical cancer patients with healthy control participants, the SNPs rs12983784 (P = 0.032), rs74369359 (p = < 10- 3) and rs10402477 (P = 0.001) were associated with an increased cervical cancer risk. Contrary to the SNPs rs14394, rs7469359, rs35986520, rs12985234 and rs2042920 (pË0.05). The haplotype analysis of the seven SNPs of ELAVL1 gene showed that there is no association between the different haplotypes and a possible risk of cervical cancer disease. Moreover, there was a significant Linkage disequilibrium between rs35986520 and rs2042920 (D'=0.9972) and between rs2042920 and rs10402477 (D'=0.9977). CONCLUSION: Our results indicated that genetic variants in the ELAVL1 gene might be associated with susceptibility to cervical cancer in the Tunisian population.
Assuntos
Predisposição Genética para Doença , Neoplasias do Colo do Útero , Humanos , Feminino , Polimorfismo de Nucleotídeo Único/genética , Neoplasias do Colo do Útero/genética , Estudos de Casos e Controles , Genótipo , Haplótipos/genética , Desequilíbrio de Ligação/genética , Frequência do Gene , Proteína Semelhante a ELAV 1/genéticaRESUMO
MicroRNAs (miRNAs) are currently investigated as crucial regulatory factors which may serve as a potential therapeutic target. Reports on the role of miRNA in patients with coronary artery aneurysmal disease (CAAD) are limited. The present analysis aims to confirm the differences in the expression of previously preselected miRNAs in larger study groups and evaluate their usefulness as potential markers of CAAD. The study cohort included 35 consecutive patients with CAAD (Group 1), and two groups of 35 patients matched Group 1 regarding sex and age from the overall cohort of 250 patients (Group 2 and Group 3). Group 2 included patients with angiographically documented coronary artery disease (CAD), while Group 3 enrolled patients with normal coronary arteries (NCA) assessed during coronary angiography. We applied the RT-qPCR method using the custom plates for the RT-qPCR array. We confirmed that the level of five preselected circulating miRNAs was different in patients with CAAD compared to Group 2 and Group 3. We found that miR-451a and miR-328 significantly improved the CAAD prediction. In conclusion, miR-451a is a significant marker of CAAD compared to patients with CAD. In turn, miR-328-3p is a significant marker of CAAD compared to patients with NCA.
Assuntos
MicroRNA Circulante , Doença da Artéria Coronariana , MicroRNAs , Humanos , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/genética , MicroRNA Circulante/genética , MicroRNAs/genética , Angiografia Coronária , BiomarcadoresRESUMO
For non-syndromic cleft lip with or without cleft palate (ns-CL/P), the proportion of heritability explained by the known risk loci is estimated to be about 30% and is captured mainly by common variants identified in genome-wide association studies. To contribute to the explanation of the "missing heritability" problem for orofacial clefts, a candidate gene approach was taken to investigate the potential role of rare and private variants in the ns-CL/P risk. Using the next-generation sequencing technology, the coding sequence of a set of 423 candidate genes was analysed in 135 patients from the Polish population. After stringent multistage filtering, 37 rare coding and splicing variants of 28 genes were identified. 35% of these genetic alternations that may play a role of genetic modifiers influencing an individual's risk were detected in genes not previously associated with the ns-CL/P susceptibility, including COL11A1, COL17A1, DLX1, EFTUD2, FGF4, FGF8, FLNB, JAG1, NOTCH2, SHH, WNT5A and WNT9A. Significant enrichment of rare alleles in ns-CL/P patients compared with controls was also demonstrated for ARHGAP29, CHD7, COL17A1, FGF12, GAD1 and SATB2. In addition, analysis of panoramic radiographs of patients with identified predisposing variants may support the hypothesis of a common genetic link between orofacial clefts and dental abnormalities. In conclusion, our study has confirmed that rare coding variants might contribute to the genetic architecture of ns-CL/P. Since only single predisposing variants were identified in novel cleft susceptibility genes, future research will be required to confirm and fully understand their role in the aetiology of ns-CL/P.
Assuntos
Fenda Labial , Fissura Palatina , Alelos , Fenda Labial/genética , Fissura Palatina/genética , Fatores de Crescimento de Fibroblastos , Proteínas Ativadoras de GTPase , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Fatores de Alongamento de Peptídeos , Polimorfismo de Nucleotídeo Único , Ribonucleoproteína Nuclear Pequena U5RESUMO
BACKGROUND: To explore associations between PON1 rs854560, rs662, 705,379, HCV clearance, and interactions between tested PON1 single nucleotide variants (SNVs) and interferon-λ4 gene (IFNL4) rs368234815 variant in hemodialyzed individuals. METHODS: The study included 83 HD individuals who spontaneously resolved HCV infection (all had known IFNL4 rs368234815 variant) and 104 individuals with persistently positive blood tests for HCV RNA (102 were IFNL4 rs368234815 variant successfully genotyped). We genotyped PON1 by high-resolution melt analysis (rs662) or predesigned TaqMan SNV Genotyping Assay (rs854560, rs705379). We used a logistic regression model to assess the association between genetic data and HCV outcome while adjusting for clinical confounding variables. Epistatic interactions between tested PON1 SNVs and IFNL4 rs368234815 were analyzed by the multifactor dimensionality reduction method. RESULTS: In the recessive inheritance model, PON1 rs662 GG (OR 9.94, 95% CI 1.20-82.7, P = 0.022) and rs854560 TT (OR 4.31, 95% CI 1.62-11.5, P = 0.003) genotypes were associated with a higher probability for HCV clearance. The haplotype composed of rs662A_rs854560A_rs705379 was not associated with spontaneous HCV clearance. The IFNL4 rs368234815 TT/TT variant was equally distributed among individuals bearing different PON1 SNVs. The epistatic gene-gene analysis did not reveal the interaction between tested PON1 SNVs and IFNL4 rs368234815 (P = 0.094). Regression model, including the PON1 rs662 GG genotype, the PON1 rs854560 genotype, the IFNL4 rs368234815 TT/TT genotype, age at RRT onset, RRT duration, and chronic glomerulonephritis as possible explanatory variables for spontaneous HCV clearance, showed that significant predictors of spontaneous HCV clearance were the IFNL4 rs368234815 TT/TT genotype (OR 2.607, 95% CI 1.298-5.235, P = 0.007), PON1 rs854560 TT (OR 6.208, 1.962-19.644, P = 0.002), PON1 rs662 GG (OR 10.762, 1.222-94.796, P = 0.032), and RRT duration (OR 0.930, 95% CI 0.879-0.984, P = 0.011). CONCLUSION: In HD individuals, PON1 rs662 GG and rs854560 TT are associated with a higher frequency of spontaneous HCV clearance.
Assuntos
Hepatite C Crônica , Hepatite C , Arildialquilfosfatase/genética , Estudos de Casos e Controles , Genótipo , Hepacivirus/genética , Hepatite C Crônica/genética , Humanos , Interleucinas/genética , Polimorfismo de Nucleotídeo Único , Diálise RenalRESUMO
BACKGROUND: In non-uremic subjects, IFNL4 rs368234815 predicts HCV clearance. We investigated whether rs368234815 is associated with spontaneous HCV clearance in haemodialysis patients and whether it is a stronger predictor of HCV resolution than the IFNL polymorphisms already associated with HCV clearance in dialysis subjects. We also evaluated an association of rs368234815 with patients` survival and alterations in transcription factor binding sites (TFBS) caused by IFNL polymorphisms. METHODS: Among 161 haemodialysis patients with positive anti-HCV antibodies, 68 (42.2%) spontaneously resolved HCV infection, whereas 93 remained HCV RNA positive. Patients were tested for near IFNL3 rs12980275, IFNL3 rs4803217, IFNL4 rs12979860, IFNL4 rs368234815, and near IFNL4 rs8099917. IFNL4 rs368234815 polymorphism (TT/TT, ΔG/TT, ΔG/ΔG) was genotyped by restriction fragment length polymorphism analysis; other IFNL polymorphisms - by high resolution melting curve analysis. We used the Kaplan-Meier method with the log-rank test for survival analysis. In silico analysis included the use of ENCODE TFBS ChIP-seq data, HOCOMOCO, JASPAR CORE, and CIS-BP databases, and FIMO software. RESULTS: The probability (OR, 95%CI, P) of spontaneous HCV clearance for rs368234815 TT/TT patients was higher than for the ΔG allele carriers (2.63, 1.38-5.04, 0.003). This probability for other major homozygotes varied between 2.80, 1.45-5.43, 0.002 for rs12980275 and 2.44, 1.27-4.69, 0.007 for rs12979860. In the additive model, rs368234815 TT/TT was the strongest predictor of HCV clearance (6.38, 1.69-24.2, 0.003). Survival analysis suggested an association of the ΔG allele with mortality due to neoplasms (log-rank P = 0.005). The rs368234815 ∆G allele caused TFBS removal for PLAGL1. CONCLUSIONS: In haemodialysis patients, the association of rs368234815 with the spontaneous HCV clearance is better than that documented for other IFNL3/IFNL4 polymorphisms only in the additive mode of inheritance. However, identifying the homozygosity in the variant ∆G allele of rs368234815 means a more potent prediction of persistent HCV infection in haemodialysis subjects that we observe in the case of the variant homozygosity of other tested IFNL3/IFNL4 polymorphisms. Removal of PLAGL1 TFBS in subjects harbouring the rs368234815 ∆G allele may contribute to cancer susceptibility. The association of rs368234815 with cancer-related mortality needs further studies in HCV-exposed subjects.
Assuntos
Hepacivirus/isolamento & purificação , Hepatite C/genética , Hepatite C/virologia , Interleucinas/genética , Diálise Renal/estatística & dados numéricos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Casos e Controles , Criança , Feminino , Genótipo , Hepatite C/epidemiologia , Humanos , Interferons/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
This article describes several recent examples of miRNA governing the regulation of the gene expression involved in bone matrix construction. We present the impact of miRNA on the subsequent steps in the formation of collagen type I. Collagen type I is a main factor of mechanical bone stiffness because it constitutes 90-95% of the organic components of the bone. Therefore, the precise epigenetic regulation of collagen formation may have a significant influence on bone structure. We also describe miRNA involvement in the expression of genes, the protein products of which participate in collagen maturation in various tissues and cancer cells. We show how non-collagenous proteins in the extracellular matrix are epigenetically regulated by miRNA in bone and other tissues. We also delineate collagen mineralisation in bones by factors that depend on miRNA molecules. This review reveals the tissue variability of miRNA regulation at different levels of collagen maturation and mineralisation. The functionality of collagen mRNA regulation by miRNA, as proven in other tissues, has not yet been shown in osteoblasts. Several collagen-regulating miRNAs are co-expressed with collagen in bone. We suggest that collagen mRNA regulation by miRNA could also be potentially important in bone metabolism.
Assuntos
Remodelação Óssea/genética , Osso e Ossos/fisiologia , Colágeno/genética , MicroRNAs/genética , Animais , Calcificação Fisiológica/genética , Matriz Extracelular/genética , Humanos , Osteogênese/genéticaRESUMO
Responsiveness to the hepatitis B virus (HBV) vaccination in hemodialysis (HD) patients who had been exposed to the hepatitis E virus (HEV) and persistently generate antibodies against HEV remains unknown. Interferon (IFN)-λ3 positively correlates with the surface HBV antibodies (anti-HBs) in both healthy and HD subjects. We aimed to show whether HD patients differ in circulating IFN-λ3 and vaccine-induced anti-HBs titers concerning natural HEV immunization. HBV/HCV negative HD patients (31 HEV IgG positive, 45 HEV negative), HBV vaccinated and receiving booster doses as needed, had been tested for anti-HBs titers (CMIA) and IFN-λ3 concentrations (ELISA) in the blood collected before a dialysis session. There were no differences in circulating IFN-λ3 and anti-HBs titers between both groups. In responders to the HBV vaccine, there was a positive correlation between plasma IFN-λ3 levels and anti-HBs titers (râ¯=â¯0.505, adjusted Pâ¯=â¯0.01 in HEV exposed subjects; râ¯=â¯0.523, adjusted Pâ¯=â¯0.001 in controls). HEV past infection does not attenuate post-vaccination anti-HBs generation and does not influence a correlation between circulating IFN-λ3 levels and anti-HBs titers.
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Anticorpos Anti-Hepatite B/imunologia , Antígenos de Superfície da Hepatite B/imunologia , Vacinas contra Hepatite B/administração & dosagem , Vírus da Hepatite B/imunologia , Vírus da Hepatite E/imunologia , Hepatite E/imunologia , Interferons/imunologia , Diálise Renal , Vacinação , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Vacinas contra Hepatite B/imunologia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: The etiology of non-syndromic cleft lip with or without cleft palate (nsCL/P) is multifactorial, heterogeneous, and still not completely understood. The aim of the present study was to examine the associations between common and rare PAX7 nucleotide variants and the risk of this common congenital anomaly in a Polish population. SUBJECTS AND METHODS: Eight top nsCL/P-associated PAX7 variants identified in our cleft genome-wide association study (GWAS) were selected for replication analysis in an independent group of patients and controls (n = 247 and n = 445, respectively). In addition, mutation screening of the PAX7 protein-coding region was conducted. RESULTS: Analysis of the pooled data from the GWAS and replication study confirmed that common PAX7 nucleotide variants are significantly associated with the increased risk of nsCL/P. The strongest individual variant was rs1339062 (c.586 + 15617T > C) with a p-value = 2.47E-05 (OR = 1.4, 95%CI: 1.20-1.64). Sequencing analysis identified a novel synonymous PAX7 substitution (c.87G > A, p.Val29Val) in a single patient with nsCLP. This transition located in the early exonic position was predicted to disrupt potential splice enhancer elements. CONCLUSION: Our study confirmed that PAX7 is a strong candidate gene for nsCL/P. Nucleotide variants of this gene contribute to the etiology of nsCL/P in the homogenous Polish population.
Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Predisposição Genética para Doença/genética , Fator de Transcrição PAX7/genética , Fenda Labial/etnologia , Fissura Palatina/etnologia , Predisposição Genética para Doença/etnologia , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Nucleotídeos , Polônia/epidemiologia , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
The genus Acanthamoeba, which may cause different infections in humans, occurs widely in the environment. Lung inflammation caused by these parasites induces pulmonary pathological changes such as pulmonary necrosis, peribronchial plasma cell infiltration, moderate desquamation of alveolar cells and partial destruction of bronchial epithelial cells, and presence of numerous trophozoites and cysts among inflammatory cells. The aim of this study was to assess the influence of plant extracts from Artemisia annua L. on expression of the toll-like receptors TLR2 and TLR4 in lungs of mice with acanthamoebiasis. A. annua, which belongs to the family Asteraceae, is an annual plant that grows wild in Asia. In this study, statistically significant changes of expression of TLR2 and TLR4 were demonstrated. In the lungs of infected mice after application of extract from A. annua the expression of TLRs was observed mainly in bronchial epithelial cells, pneumocytes (to a lesser extent during the outbreak of infection), and in the course of high general TLR expression. TLR4 in particular was also visible in stromal cells of lung parenchyma. In conclusion, we confirmed that a plant extract of A. annua has a modulatory effect on components of the immune system such as TLR2 and TLR4.
Assuntos
Acanthamoeba/fisiologia , Amebíase/tratamento farmacológico , Artemisia annua/química , Pneumopatias Parasitárias/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Receptores Toll-Like/metabolismo , Amebíase/metabolismo , Animais , DNA Complementar/metabolismo , Imuno-Histoquímica , Pulmão/parasitologia , Pulmão/patologia , Pneumopatias Parasitárias/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Extratos Vegetais/farmacologia , RNA Mensageiro/metabolismo , RNA de Protozoário/genética , RNA de Protozoário/isolamento & purificação , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcrição Reversa , Receptor 2 Toll-Like/efeitos dos fármacos , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/efeitos dos fármacos , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Receptores Toll-Like/efeitos dos fármacos , Receptores Toll-Like/genéticaRESUMO
BACKGROUND: There is scarce data on CASR associations with dyslipidemia. We investigated in hemodialysis (HD) patients whether CASR single nucleotide polymorphisms (SNPs) rs7652589 and rs1801725 have associations with dyslipidemia and show epistatic interactions with SNPs of the energy homeostasis-associated gene (ENHO), retinoid X receptor α gene (RXRA), and liver X receptor α gene (LXRA). METHODS: The study included 1208 HD subjects. For diagnosis of dyslipidemia, both K/DOQI criteria and atherogenic index ≥3.8 were used. CASR rs1801725 was genotyped by TaqMan SNP Genotyping Assay, other SNPs - by high-resolution melting curve analysis or polymerase chain reaction-restriction fragment length polymorphism, as appropriate. Relative transcript levels of CASR, ENHO, RXRA, and LXRA were measured in peripheral blood mononuclear cells. The occurrence of dyslipidemic phenotypes concerning tested polymorphisms was compared using models of inheritance. Haplotypes were estimated using the Haploview 4.2 software. Epistatic interactions between tested SNPs were analyzed using the logistic regression and epistasis option in the PLINK software. RESULTS: Rs7652589 indicated a greater probability of atherogenic dyslipidemia in the dominant inheritance model (OR 1.4, 95%CI 1.0-2.0, P = 0.026), principally because of increased triglyceride (TG) levels. The rs1801725 variant allele was associated with a decreased probability of dyslipidemia characterized by non-HDL-cholesterol ≥130 mg/dL and TG ≥200 mg/dL (OR 0.6, 0.4-0.9, P = 0.012). There were no epistatic interactions between CASR and RXRA, LXRA, and ENHO regarding dyslipidemia. Both rs7652589 and rs1801725 SNPs were not in linkage disequilibrium (D' = 0.091, r2 = 0.003 for the entire HD group) and their haplotypes did not correlate with dyslipidemia. Relative CASR transcript was lower at a borderline significance level in patients harboring the rs1801725 variant allele compared with homozygotes of the major allele (0.20, 0.06-7.80 vs. 0.43, 0.04-5.06, P = 0.058). CASR transcript correlated positively with RXRA transcript (adjusted P = 0.001), LXRA transcript (adjusted P = 0.0009), ENHO transcript (borderline significance, adjusted P = 0.055), dry body weight (adjusted P = 0.035), and renal replacement therapy duration (adjusted P = 0.013). CONCLUSIONS: CASR polymorphisms (rs7652589, rs1801725) are associated with dyslipidemia in HD patients. CASR correlates with RXRA, LXRA, and ENHO at the transcript level. Further investigations may elucidate whether other CASR SNPs contribute to associations shown in this study.
Assuntos
Dislipidemias/genética , Falência Renal Crônica , Efeitos Adversos de Longa Duração , Receptores de Detecção de Cálcio , Diálise Renal , Idoso , Estudos Transversais , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/metabolismo , Falência Renal Crônica/terapia , Receptores X do Fígado/genética , Efeitos Adversos de Longa Duração/etiologia , Efeitos Adversos de Longa Duração/genética , Efeitos Adversos de Longa Duração/metabolismo , Masculino , Pessoa de Meia-Idade , Polônia/epidemiologia , Polimorfismo de Nucleotídeo Único , Receptores de Detecção de Cálcio/genética , Receptores de Detecção de Cálcio/metabolismo , Diálise Renal/efeitos adversos , Diálise Renal/métodos , Receptor X Retinoide alfa/genéticaRESUMO
BACKGROUND: The energy homeostasis-associated gene (ENHO), retinoid X receptor alpha gene (RXRA), and liver X receptor alpha gene (LXRA) are involved in adipogenic/lipogenic regulation. We investigated whether single-nucleotide polymorphisms in these genes (ENHO rs2281997, rs72735260; RXRA rs749759, rs10776909, rs10881578; LXRA rs2279238, rs7120118, rs11039155) are associated with dyslipidaemia, related comorbidities and survival of haemodialysis (HD) patients also tested for T-helper (Th) cell interleukin genes (IL). METHODS: The study was carried out in 873 HD patients. Dyslipidaemia was diagnosed by the recommendations of the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines (2003); atherogenic dyslipidaemia was referred to if the TG/HDL cholesterol ratio was equal to or higher than 3.8. Genotyping of ENHO SNPs, LXRA SNPs, and IL12A rs568408 was carried out using HRM analysis. RXRA SNPs, IL12B rs3212227, and IL18 rs360719 were genotyped using PCR-RFLP analysis. The circulating adropin concentration was determined in 126 patients by enzyme-linked immunosorbent assay. Survival probability was analysed using the Kaplan-Meier method in 440 patients followed through 7.5 years. RESULTS: Dyslipidaemia by K/DOQI was diagnosed in 459 patients (91% revealed hyper-LDL- cholesterolaemia), atherogenic dyslipidaemia was diagnosed in 454 patients, and 231 patients were free of dyslipidaemia by both criteria. The variant allele (T) of ENHO rs2281997 was associated with the hyper-LDL cholesterolaemic pattern of dyslipidaemia by K/DOQI. The frequency of atherogenic dyslipidaemia was lower in T-allele bearers than in CC-genotype patients. The rs2281997 T allele was associated with lower cardiovascular mortality in HD patients showing atherogenic dyslipidaemia. ENHO, RXRA, and LXRA showed epistatic interactions in dyslipidaemia. Circulating adropin was lower in atherogenic dyslipidaemia than in non-atherogenic conditions. RXRA rs10776909 was associated with myocardial infarction. Bearers of LXRA rs2279238, rs7120118 or rs11039155 minor alleles showed higher mortality. ENHO SNP positions fell within the same DNase 1 hypersensitivity site expressed in the Th1 cell line. Epistatic interactions occurred between rs2281997 and Th1 IL SNPs (rs360719, rs568408). CONCLUSIONS: Atherogenic dyslipidaemia occurs in HD patients in whom ENHO encodes less adropin. ENHO, RXRA, and LXRA SNPs, separately or jointly, are associated with dyslipidaemia, myocardial infarction, and survival in HD patients. Differences in the availability of transcription binding sites may contribute to these associations.
Assuntos
Proteínas Sanguíneas/genética , Dislipidemias/genética , Receptores X do Fígado/genética , Infarto do Miocárdio/genética , Peptídeos/genética , Polimorfismo de Nucleotídeo Único , Diálise Renal , Insuficiência Renal Crônica/genética , Receptor X Retinoide alfa/genética , Adipogenia/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Proteínas Sanguíneas/imunologia , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Comorbidade , Estudos Transversais , Dislipidemias/imunologia , Dislipidemias/mortalidade , Dislipidemias/terapia , Epistasia Genética , Feminino , Genótipo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Subunidade p40 da Interleucina-12/genética , Subunidade p40 da Interleucina-12/imunologia , Interleucina-18/genética , Interleucina-18/imunologia , Estimativa de Kaplan-Meier , Receptores X do Fígado/imunologia , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/terapia , Peptídeos/imunologia , Insuficiência Renal Crônica/imunologia , Insuficiência Renal Crônica/mortalidade , Insuficiência Renal Crônica/terapia , Receptor X Retinoide alfa/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/patologia , Triglicerídeos/sangueRESUMO
Although the aetiology of non-syndromic cleft lip with or without cleft palate (nsCL/P) has been studied extensively, knowledge regarding the role of genetic factors in the pathogenesis of this common craniofacial anomaly is still limited. We conducted a follow-up association study to confirm that CDKAL1 nucleotide variants identified in our genome-wide association study (GWAS) for nsCL/P are associated with the risk of this anomaly. In addition, we performed a sequence analysis of the selected CDKAL1 exons. A mega-analysis of the pooled individual data from the GWAS and a replication study revealed that six out of thirteen CDKAL1 variants were positively replicated and reached the threshold of statistical significance (Ptrend < 3.85E-03). They represented a single association signal and were located within the fifth intron of CDKAL1. The strongest individual variant was rs9356746 with a Ptrend value = 5.71E-06 (odds ratio (OR) = 1.60, 95% confidence interval (CI): 1.30-1.97). Sequencing analysis did not reveal any pathogenic mutations of this gene. This study provides the first evidence that chromosomal region 6p22.3 is a novel susceptibility locus for nsCL/P. The location of the risk variants within the CDKAL1 intronic sequence containing enhancer elements predicted to regulate the SOX4 transcription may suggest that SOX4, rather than CDKAL1, is a potential candidate gene for this craniofacial anomaly.
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Fenda Labial/diagnóstico , Fenda Labial/genética , Fissura Palatina/diagnóstico , Fissura Palatina/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , tRNA Metiltransferases/genética , Alelos , Estudos de Casos e Controles , Análise Mutacional de DNA , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Haplótipos , Humanos , Masculino , Razão de Chances , Fenótipo , Risco , Fatores SexuaisRESUMO
BACKGROUND/AIMS: The calcium-sensing receptor gene (CASR) rs1801725 variant is responsible for a non-conservative amino-acid change (A986S) in the calcium-sensing receptor cytoplasmic tail. We hypothesized that rs1801725 polymorphism might be helpful in understanding Ca-related abnormalities in HD patients. METHODS: In 1215 subjects (245 on cinacalcet), we determined the associations of rs1801725 with secondary hyperparathyroidism (sHPT)-related laboratory parameters, PTH-decreasing effect of cinacalcet hydrochloride, coronary artery disease (CAD), myocardial infarction (MI), nephrolithiasis-related ESRD, and mortality. CASR rs7652589(A
Assuntos
Hiperparatireoidismo Secundário/genética , Falência Renal Crônica/complicações , Polimorfismo de Nucleotídeo Único , Receptores de Detecção de Cálcio/genética , Cálcio/sangue , Cinacalcete/uso terapêutico , Doença da Artéria Coronariana/complicações , Feminino , Humanos , Infecções/mortalidade , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Fenótipo , Diálise Renal , Vitamina D/metabolismoRESUMO
The treatment of acanthamoebiasis is a still a problem. Our previous studies showed that the application of extracts from Artemisia annua L. significantly prolonged the survival of mice infected by Acanthamoeba. This plant has medicinal properties in the treatment of human parasitic diseases. The aim of this study was to evaluate the effects of A. annua on expression of Toll-like receptors (TLRs) 2 and 4 in brain of mice with Acanthamoeba infection. Mice were infected with Acanthamoeba sp. strain Ac309 (KY203908) by intranasal inoculation without and after application of A. annua extract. The administration of extract from A. annua significantly reduced the level of expression of TLR2 and modified the level of expression of TLR4. A. annua extract is a natural substance that is well tolerated in animals and may be considered as a combination therapy in treatment of acanthamoebiasis. Our study suggested that A. annua extract may be used as an alternative therapeutic tool.
Assuntos
Acanthamoeba/efeitos dos fármacos , Amebíase/tratamento farmacológico , Artemisia annua/química , Encéfalo/metabolismo , Fitoterapia , Receptores Toll-Like/efeitos dos fármacos , Amebíase/metabolismo , Animais , Encéfalo/patologia , Expressão Gênica , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos BALB C , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Receptor 2 Toll-Like/efeitos dos fármacos , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/efeitos dos fármacos , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismoRESUMO
Little is known about the differences in ten-eleven translocation 1, 2, and 3 (TET1-3) expression in the endometrial phases in eutopic endometrium from infertile women with endometriosis (IWE) and fertile women without endometriosis (FW). Using RT-qPCR and western blot analysis, we assessed the TET expression in the mid-follicular and mid-luteal phases in eutopic endometrium from IWE (n = 38) and FW (n = 18). Both IWE and FW underwent laparoscopic and histological examinations for endometriosis. In the mid-luteal eutopic endometrium in IWE, compared to that of FW, we found significantly reduced levels of TET1 transcripts and proteins (p = .001 and p = .003, respectively) at the severity stage of I/II (p = .029 and p = .003, respectively) and transcripts only at the severity stage of III/IV (p = .003). In the mid-follicular eutopic endometrium of IWE, compared to that of FW, there was a statistically significant reduction in TET2 transcript levels at the severity stage of III/IV (p = .037). Compared to the mid-follicular endometrium, we found a statistically significant increase in TET3 transcript levels during the mid-luteal phase in the eutopic endometrium of all IWE (p = .034) and in the severity stage of III/IV (p = .025). We observed a change in the expression levels of TET1-3 in the eutopic endometrium of IWE.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Dioxigenases/metabolismo , Endometriose/metabolismo , Infertilidade Feminina/metabolismo , Oxigenases de Função Mista/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Estudos de Casos e Controles , Endometriose/complicações , Feminino , Humanos , Infertilidade Feminina/etiologia , Ciclo Menstrual/metabolismoRESUMO
PURPOSE: Previous studies have reported a significant contribution of NC_000008.10:g.128413305 G>T (rs6983267) single-nucleotide polymorphism (SNP) in the MYC enhancer region to the susceptibility of various cancers. However, the role of rs6983267 SNP in cervical cancer (CC) development and progression has not been demonstrated to date. Therefore, we evaluated the role of rs6983267 SNP in MYC expression in cervical cancers and non-cancerous cervical tissues. In addition, we assessed the role of this SNP in the development and progression of CC. METHODS: Using high-resolution melting analysis, we evaluated rs6983267 SNP frequency in women diagnosed with cervical squamous cell carcinoma (SCC) (n = 481) and controls (n = 502) in a Polish Caucasian population. Logistic regression analysis was employed to adjust for the effects of age, parity, oral contraceptive use, tobacco smoking, and menopausal status. RESULTS: Dividing patients based on clinical characteristics demonstrated an association of the rs6983267 genotype with tumor stage III and grade of differentiation G2 and G3. The p trend value calculated for the rs6983267 SNP in patients with stage III was 0.0006. We also observed a significant contribution of rs6983267 SNP to tumor grade of differentiation G2 and G3. Additional contributors were oral contraceptive use, smoking, and postmenopausal age. We found statistically significant increase of MYC transcript levels in cervical SCC tissues from carriers of the GG vs. T/T (p < 0.00001), G/T vs. T/T (p = 0.0002), and in the non-cancerous cervical tissues from carriers of the GG vs. T/T (p = 0.00046). CONCLUSION: The rs6983267 SNP may contribute to the increased MYC expression as well as the spread and rapid growth of cervical SCC as compared to lower grade carcinomas.
Assuntos
Carcinoma de Células Escamosas/genética , Genes myc/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , RNA Longo não Codificante/genética , Neoplasias do Colo do Útero/genética , Adulto , Idoso , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Estudos de Casos e Controles , Progressão da Doença , Feminino , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Polônia/epidemiologia , Prevalência , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia , População Branca/genéticaRESUMO
OBJECTIVES: Systemic lupus erythematosus (SLE) is a chronic relapsing autoimmune disease characterized by the presence of autoantibodies directed against nuclear antigens and by chronic inflammation. Although the etiology of SLE remains unclear, the influence of environment factors, which is largely reflected by the epigenetic mechanisms, with DNA methylation changes in particular, is generally considered as main players in the pathogenesis of SLE. We studied DNA methyltransferases' (DNMTs) type 1, 3A and 3B transcript levels in peripheral blood mononuclear cells from patients diagnosed with systemic lupus erythematosus and from the healthy control subjects. Furthermore, the association of DNMT1, DNMT3A, and DNMT3B mRNA levels with gender, age, and major clinical manifestations was analyzed. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from 32 SLE patients and 40 healthy controls. Reverse transcription and real-time quantitative polymerase chain reaction (RT-qPCR) analyses were used to determine DNMT1, DNMT3A, and DNMT3B mRNA expression levels. RESULTS: Significantly lower DNMT1 (p = 0.015543) and DNMT3A (p = 0.003652) transcript levels in SLE patients were observed compared with healthy controls. Nevertheless, the DNMT3B mRNA expression levels were markedly lower compared with DNMT1 and DNMT3A, both in PBMCs from affected patients and those from control subjects. Furthermore, the DNMT1 transcript levels were positively correlated with SLE disease activity index (SLEDAI) (r s = 0.4087, p = 0.020224), while the DNMT3A transcript levels were negatively correlated with patients age (r s = -0.3765, p = 0.03369). CONCLUSIONS: Our analyses confirmed the importance of epigenetic alterations in SLE etiology. Moreover, our results suggest that the presence of some clinical manifestations, such as phototosensitivity and arthritis, might be associated with the dysregulation of DNA methyltransferases' mRNA expression levels.
Assuntos
DNA (Citosina-5-)-Metiltransferases/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , RNA Mensageiro/metabolismo , Adulto , DNA (Citosina-5-)-Metiltransferase 1 , DNA (Citosina-5-)-Metiltransferases/genética , Metilação de DNA , DNA Metiltransferase 3A , Feminino , Humanos , Leucócitos Mononucleares/metabolismo , Lúpus Eritematoso Sistêmico/genética , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , Adulto Jovem , DNA Metiltransferase 3BRESUMO
BACKGROUND: Circulating pro-inflammatory cytokines were associated with increased relative mortality risk, while immune parameters reflecting improved T-cell function were predictors of survival in hemodialysis (HD) patients. We evaluated in the prospective study whether variants in T helper cell cytokine-associated genes are determinants of mortality in HD patients. METHODS: The study was carried out in 532 prevalent HD subjects who were followed-up for 7 years. HRM analysis was used for IFNL3, IL12A, IL13, and IL4R genotyping. CCL2, IL12B, and IL18 were genotyped using PCR-RFLP analysis. Survival analyses were conducted using the Kaplan-Meier method and the Cox proportional hazard model. RESULTS: In univariate analyses, IFNL3 rs8099917 was associated with all-cause mortality in recessive model of inheritance (log-rank test P = 0.044), IL12A rs568408 - in dominant model (log-rank test P = 0.029). Minor homozygotes (the genotype GG) in IFNL3 rs8099917 showed shorter survival during the study (3.6, 1.0-7.0 years vs 4.7, 0.1-7.0 years, P = 0.009) than the major allele (T) bearers. The rs8099917 GG patients demonstrated higher risk of death than the remaining patients (GT + TT) (OR 1.94, 95%CI 1.11-3.40, P = 0.020). Major homozygosity (the genotype GG) in IL12A rs568408 was associated with higher mortality than that shown in bearers of the minor allele (AA + AG) (HR 1.31, 95%CI 1.02-1.69, P = 0.035). In multivariate analyses, however, the mentioned polymorphisms were not independent predictors of survival. CONCLUSIONS: Polymorphisms of IFNL3 rs8099917 and IL12A rs568408 contribute to survival of HD patients, but not as independent factors.
Assuntos
Subunidade p35 da Interleucina-12/genética , Interleucina-1/imunologia , Interleucinas/genética , Falência Renal Crônica/genética , Falência Renal Crônica/mortalidade , Polimorfismo de Nucleotídeo Único/genética , Diálise Renal/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Citocinas/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Humanos , Incidência , Interferons , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Polônia/epidemiologia , Diálise Renal/estatística & dados numéricos , Reprodutibilidade dos Testes , Fatores de Risco , Sensibilidade e Especificidade , Taxa de Sobrevida , Adulto JovemRESUMO
BACKGROUND/AIMS: Vitamin D status is announced among factors that may influence physical performance and mental health. Our aim was to evaluate self-reported physical activity, quality of life, psychiatric functioning, and affects with respect to plasma 25-hydroxyvitamin D [25(OH)D] concentrations in HD patients. METHODS: The study was carried out in HD patients not receiving vitamin D supplements (n = 112). IPAQ-L, QLI-D, GHQ-28, and PANAS were used in psychological evaluations. Plasma 25(OH)D concentration was determined by a chemiluminescent microparticle immunoassay. RESULTS: Plasma 25(OH)D level was suboptimal in all patients (14.6 ± 4.1 ng/ml). Adjusted correlates of 25(OH)D concentration included the GG genotype of GC rs7041 (ß±SE: 1.77± 0.70, P=0.014), female sex (ß±SE: -2.19±0.75, P=0.004), and treatment with high flux HD (ß±SE: 2.59±0.69, P=0.0003). In adjusted analyses, circulating 25(OH)D showed the independent association with total activity related to domestic and gardening domain (ß±SE: 53.2±23.8, P=0.028), and with moderate-intensity activities (ß±SE: 54.9±27.4, P=0.048), but not with any of quality of life, psychiatric functioning, or affects measures. CONCLUSIONS: Vitamin D status is independently positively associated with physical activity in HD patients. Quality of life and mental health do not seem to be associated with circulating 25(OH)D under condition of its suboptimal levels.
Assuntos
Exercício Físico , Diálise Renal , Vitamina D/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Saúde Mental , Pessoa de Meia-Idade , Qualidade de Vida , Autorrelato , Vitamina D/sangueRESUMO
Toll-like receptors (TLRs) play a key role in the innate immune responses to a variety of pathogens including parasites. TLRs are among the most highly conserved in the evolution of the receptor family, localized mainly on cells of the immune system and on other cells such as lung cells. The aim of this study was to determine for the first time the expression of TLR2 and TLR4 in the lung of Acanthamoeba spp. infected mice using quantitative real-time polymerase chain reaction (Q-PCR) and immunohistochemical (IHC) staining. The Acanthamoeba spp. were isolated from a patient with Acanthamoeba keratitis (AK) (strain Ac 55) and from environmental samples of water from Malta Lake (Poznan, Poland - strain Ac 43). We observed a significantly increased level of expression of TLR2 as well as TLR4 mRNA from 2 to 30 days post Acanthamoeba infection (dpi) in the lungs of mice infected with Ac55 (KP120880) and Ac43 (KP120879) strains. According to our observations, increased TLR2 and TLR4 expression in the pneumocytes, interstitial cells and epithelial cells of the bronchial tree may suggest an important role of these receptors in protective immunity against Acanthamoeba infection in the lung. Moreover, increased levels of TLR2 and TLR4 mRNA expression in infected Acanthamoeba mice may suggest the involvement of these TLRs in the recognition of this amoeba pathogen-associated molecular pattern (PAMP).