RESUMO
BACKGROUND: Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is one of the essential brakes expressed on T cells that prevent T-cell hyperactivation-associated autoimmune disorders. Several CTLA4 polymorphisms were implicated in the regulation of gene expression. We aimed to explore the association of CTLA4 expression and rs231775 (c.49A>G) variant with vitiligo risk and severity of the disease in a sample of the Middle Eastern population. METHODS: The CTLA4 gene expression and genotyping for rs231775 (A/G) variant were assessed in 161 vitiligo patients and 165 controls using a real-time polymerase chain reaction. Vitiligo Area Severity Index (VASI) and Vitiligo Disease Activity score (VIDA) were evaluated. RESULTS: A higher frequency of rs231775 G allele was observed in vitiligo cases than controls (45% vs. 33%, p = 0.002). After adjustment of age, sex, family history of vitiligo, and CTLA expression level, using multivariate analysis, G/G carriers were associated with a higher risk of vitiligo under recessive (OR = 2.94, 95% CI = 1.61-5.35, p < 0.001), dominant (OR = 1.87, 95% CI = 1.14-3.06, p = 0.013), and homozygote comparison (OR = 3.34, 95% CI = 1.73-6.42, p = 0.001) models. Although the CTLA4 relative expression levels were comparable to that of controls, G/G carriers exhibited a significantly lower expression profile (median = 0.63, IQR = 0.34-1.75) than A/A (median = 1.43, IQR = 0.39-4.25, p = 0.018) and A/G carriers (median = 1.68, IQR = 0.49-3.92, p = 0.007). No significant associations of CTLA4 variant/expression with disease severity and/or activity were observed. CONCLUSION: The CTLA4 rs231775 variant was associated with vitiligo susceptibility and gene expression; the risky genotype (GG) was associated with lower CTLA4 relative expression levels than the other genotypes. Further large-scale studies in different populations are warranted.
Assuntos
Antígeno CTLA-4/genética , Vitiligo/genética , Adulto , Estudos de Casos e Controles , Feminino , Expressão Gênica , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Vitiligo/etiologia , População Branca/genética , Adulto JovemRESUMO
Alopecia areata (AA) is a type of immune-mediated alopecia. Recent studies have suggested microRNAs' (miRNAs) implication in several cellular processes, including epidermal and hair follicle biology. Single nucleotide polymorphisms (SNPs) can modify gene expression levels, which may induce an autoimmune response. This case−control study included 480 participants (240 for each case/control group). MicroRNA-34a gene (MIR-34A) rs2666433A/G variant was genotyped using real-time allelic discrimination polymerase chain reaction (PCR). Additionally, circulatory miR-34a levels were quantified by quantitative reverse transcription PCR (qRT-PCR). On comparing between alopecia and non-alopecia cohorts, a higher frequency of A variant was noted among patients when compared to controlsA allele: 28 versus 18% (p < 0.001); A/A genotype: 9 versus 2%; A/G genotype: 39 versus 32% (p < 0.001). A/A and A/G carriers were more likely to develop alopecia under heterozygote comparison (OR = 1.83, 95% CI = 1.14−2.93), homozygote comparison (OR = 4.19, 95% CI = 1.33−13.1), dominant (OR = 2.0, 95% CI = 1.27−3.15), recessive (OR = 3.36, 95% CI = 1.08−10.48), over-dominant (OR = 1.65, 95% CI = 1.04−32.63), and log additive (OR = 1.91, 95% CI = 1.3−2.82) models. Serum miR-34a expression levels were upregulated in alopecia patients with a median and quartile fold change of 27.3 (1.42−2430). Significantly higher levels were more pronounced in A/A genotype patients (p < 0.01). Patients carrying the heterozygote genotype (rs2666433 * A/G) were two times more likely to develop more severe disease grades. Stratified analysis by sex revealed the same results. A high expression level was associated with concomitant autoimmune comorbidities (p = 0.001), in particular SLE (p = 0.007) and vitiligo (p = 0.049). In conclusion, the MIR34A rs2666433 (A/G) variant is associated with AA risk and severity in the studied population. Furthermore, high miR-34a circulatory levels could play a role in disease pathogenesis.
Assuntos
Alopecia em Áreas , MicroRNAs , Alopecia em Áreas/genética , Estudos de Casos e Controles , Estudos Transversais , Predisposição Genética para Doença , Folículo Piloso , Humanos , MicroRNAs/sangue , MicroRNAs/genéticaRESUMO
Toll-like receptor (TLR) family signature has been implicated in sepsis etiopathology. We aimed to evaluate the genetic profile of TLR pathway-related key genes; the myeloid differentiation protein 88 (MYD88), IL1 receptor-associated kinase 1 (IRAK1), the nuclear factor kappa-B1 (NFKB1), and interleukin 6 (IL6) in the blood of neonates with sepsis at the time of admission and post-treatment for the available paired-samples. This case-control study included 124 infants with sepsis admitted to the neonatal intensive care unit and 17 controls. The relative gene expressions were quantified by TaqMan Real-Time qPCR and correlated to the clinic-laboratory data. MYD88, NFKB1, and IL6 relative expressions were significantly higher in sepsis cases than controls. Higher levels of MYD88 and IL6 were found in male neonates and contributed to the sex-based separation of the cases by the principal component analysis. ROC analysis revealed MYD88 and NFKB1 transcripts to be good biomarkers for sepsis. Furthermore, patients with high circulatory MYD88 levels were associated with poor survival, as revealed by Kaplan-Meier curves analysis. MYD88, NFKB1, and IL6 transcripts showed association with different poor-outcome manifestations. Clustering analysis split the patient cohort into three distinct groups according to their transcriptomic signature and CRP levels. In conclusion, the study TLR pathway-related transcripts have a gender-specific signature, diagnostic, and prognostic clinical utility in neonatal sepsis.
Assuntos
Interleucina-6/sangue , Fator 88 de Diferenciação Mieloide/sangue , Subunidade p50 de NF-kappa B/sangue , Sepse Neonatal/sangue , Sepse Neonatal/mortalidade , Biomarcadores/sangue , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Recém-Nascido , Masculino , Sepse Neonatal/patologia , Prognóstico , Transdução de Sinais/genéticaRESUMO
OBJECTIVE: MicroRNAs are large family clusters of small noncoding RNAs that implicated in genetic and epigenetic regulation of several immunological processes and pathways. As an epigenetic modifier, the microRNA 17-92 cluster host gene (MIR17HG) has been shown to regulate the expression of genes involved in systemic lupus erythematosus (SLE) pathway. This study aimed to explore the association of MIR17HG (rs4284505; A>G) variant with SLE development and phenotype in a sample of the Eastern Mediterranean population. METHODS: A total of 326 participants (163 patients with SLE and 163 healthy controls) were enrolled in this study. The different genotypes of the MIR17HG (rs4284505) variant were characterized using the TaqMan real-time polymerase chain reaction technique. Association with the available clinical and laboratory data, including the systemic lupus erythematosus disease activity index (SLEDAI), was also executed. RESULTS: The MIR17HG (rs4284505) variant showed a protective effect against developing SLE under heterozygote (A/G vs A/A; odds ratio [OR] = 0.10, 95% confidence interval [CI] = 0.05-0.20, P < 0.001) and dominant (A/G+G/G vs A/A; OR = 0.39, 95% CI = 0.25-0.61, P < .001) models. This association was consistent even after SLE stratified by lupus nephritis. In contrast, rs4284505 (G/G) genotype conferred increased susceptibility to SLE (G/G vs A/A+A/G; OR = 2.15, 95% CI = 1.31-3.53, P = .002). Moreover, the rs4284505 variant showed a statistically significant association with mucocutaneous lesions and SLEDAI scores (all P < .05). CONCLUSION: This study is the first one to explore that the MIR17HG rs4284505 is associated with SLE risk; (A/G) genotype conferred a protective effect, while the (G/G) genotype showed increased susceptibility to SLE and association with the disease severity in the study population.
Assuntos
Lúpus Eritematoso Sistêmico , Adulto , Epigênese Genética , Feminino , Predisposição Genética para Doença , Humanos , Lúpus Eritematoso Sistêmico/genética , Nefrite Lúpica/genética , Masculino , MicroRNAs , Pessoa de Meia-Idade , RNA Longo não Codificante , Adulto JovemRESUMO
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide. The oncogenic function of the long non-coding RNA; metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in HCC remains unclear. We aimed to evaluate MALAT1 serum expression profile in HCC and explore its relation to the clinicopathological features. Quantitative Real Time-Polymerase Chain Reaction was applied in 70 cohorts (30 HCC, 20 HCV, 20 controls). Further meta-analysis of clinical studies and in vitro validated experiments was employed. Serum MALAT1 showed area under the curve of 0.79 and 0.70 to distinguish patients with cancer from normal and cirrhotic individuals at fold change of 1.0 and 1.26, respectively. Expression level was significantly higher in males (P <0.001) and patients with massive ascites (Pâ¯=â¯0.005). Correlation analysis showed positive correlation of MALAT1 with total bilirubin (râ¯=â¯0.456, P <0.001) and AST (râ¯=â¯0.280, Pâ¯=â¯0.019), and negative correlation with the hemoglobin level (râ¯=â¯0.312, Pâ¯=â¯0.009). Meta-analysis showed that the over-expressed MALAT1 was linked to tumor number [Cohen's dâ¯=â¯0.450, 95% CI (0.21 to 0.68)], clinical stage [Cohen's dâ¯=â¯0.048, 95% CI (-0.83 to 0.74)], and AFP level [Cohen's dâ¯=â¯0.354, 95% CI (0.1 to 0.57)]. In silico data analysis and systematic review confirmed MALAT1 oncogenic function in cancer development and progression. In conclusion, circulatory MALAT1 might represent a putative non-invasive prognostic biomarker indicating worse liver failure score in HCV-related HCC patients with traditional markers. Large-scale verification is warranted in future studies.
Assuntos
Carcinogênese/patologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/virologia , Hepacivirus/fisiologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virologia , RNA Longo não Codificante/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinogênese/genética , Carcinoma Hepatocelular/sangue , Estudos de Casos e Controles , Simulação por Computador , Demografia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/genética , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Viés de Publicação , RNA Longo não Codificante/sangue , RNA Longo não Codificante/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transcriptoma/genética , alfa-Fetoproteínas/metabolismoRESUMO
BACKGROUND AND AIMS: Ascites with unknown cause remains a diagnostic challenge, which needs novel noninvasive biomarkers for the precise diagnosis. We aimed to evaluate the ascitic fluid and serum C-reactive protein (CRP) and vascular endothelial growth factor (VEGF) as diagnostic markers in the differential diagnosis of malignant and benign ascites. METHODS: In this prospective work, 315 consecutive patients with ascites were studied. Ascitic fluid and serum levels of CRP and VEGF were evaluated by using an enzyme-linked immunosorbent assay. RESULTS: Patients were divided into a benign ascites group (group 1) (n = 256) and a malignant ascites group (group 2) (n = 59). Ascitic and serum CRP were significantly elevated in malignant ascites than benign ascites group [5.08 (3.62-6.58) vs. 1.82 (0.64-3.86) ng/ml; P < 0.001 and 12.7 (8.55-17.05) vs. 5.94 (2.57-10.64) ng/ml; P < 0.001], respectively. Ascitic and serum VEGF were significantly increased in malignant ascites than benign ascites patients [0.68 (0.39-0.96) vs. 0.41 (0.25-0.83) ng/ml; P < 0.001 and 0.74 (0.41-1.08) vs. 0.54 (0.23-0.86) ng/ml; P < 0.001], respectively. At a cutoff value of 7.3 and 0.63 ng/ml, serum CRP and VEGF had specificity (77.3 and 89.5 %) and sensitivity (83.1 and 94.9 %) for detecting malignant ascites [area under the curve (AUC) 0.821, 0.921], respectively. At a cutoff value of 2.5 and 0.57 ng/ml, ascitic CRP and VEGF had specificity (81.6 and 85.5 %) and sensitivity (84.7 and 91.5 %) for detecting malignant ascites (AUC 0.842, 0.894), respectively. CONCLUSION: Elevated ascitic fluid and serum CRP and VEGF values were related to the malignant ascites.