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BACKGROUND: Tumor necrosis factor-alpha (TNF-α) is among the vital pro-inflammatory cytokines that potentially exerts a significant influence on the immune response, hence potentially regulating the advancement of cervical lesions. OBJECTIVE: Our study objective was to examine the relationship between two single nucleotide polymorphisms (SNPs) (rs1799724 and rs1800629) of TNF-α and the risk of cervical cancer in women from Bangladesh. METHODS: We recruited 133 patients with cervical cancer and 126 healthy individuals for this study. Genotyping was performed using real-time PCR SNP genotyping assay. Multivariate logistic regression analysis was used to determine the odds ratio (OR) along with 95% confidence intervals (CI) and p-values. RESULTS: For rs1799724 (Câ>âT) polymorphism, TT mutant homozygous genotype carried 3.26 times increased risk of developing cervical cancer (ORâ=â3.26, 95% CIâ=â1.15-9.28, pâ=â0.027). Polymorphism of rs1800629 (Gâ>âA) was also related to an elevated risk of cervical cancer. Individuals with the AG heterozygous genotype (ORâ=â2.85, 95% CIâ=â1.20-6.74, pâ=â0.017) and AA mutant homozygous genotype (ORâ=â4.55, 95% CIâ=â1.24-16.60, pâ=â0.022) also had a higher likelihood of having cervical cancer. Moreover, we found that injectable contraceptives increase the risk of cervical cancer. Individuals who smoked and/or had first-degree relatives with cancer were more likely to carry the risk allele, which increases the likelihood of developing cervical cancer. CONCLUSION: TNF-α polymorphisms in rs1799724 and rs1800629 increase the susceptibility of developing cervical cancer in women from Bangladesh.
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Predisposição Genética para Doença , Genótipo , Polimorfismo de Nucleotídeo Único , Fator de Necrose Tumoral alfa , Neoplasias do Colo do Útero , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Bangladesh/epidemiologia , Estudos de Casos e Controles , Estudos de Associação Genética , Fatores de Risco , Fator de Necrose Tumoral alfa/genética , Neoplasias do Colo do Útero/genéticaRESUMO
BACKGROUND: Alopecia areata (AA) is an autoimmune disease which results in non-scarring hair loss on the scalp or any surface with hair. Several genetic polymorphisms of the interleukin genes have been linked with this disease but the results are inconsistent. This systematic review and meta-analysis were done to find the association between rs3118470, rs2275913, rs3212227, and rs10889677 of the IL2RA, IL17A, IL12B, and IL23R genes, respectively, of the interleukin family with alopecia areata. METHODS: A comprehensive search for relevant research articles was conducted in Pubmed, Google Scholar, and Embase databases. Our search yielded 8 relevant articles with 1940 cases and 1788 controls. The odds ratio with 95% confidence intervals was calculated using fixed effect and random effect models. Heterogeneity was determined using the Q-test and I2 test. Publication bias was determined and funnel plots were used to adjust the odds ratio. RESULTS: We found a significant risk effect for rs3118470 of the IL2RA gene with alopecia areata in the dominant model (CCâ +â CT vs TT; ORâ =â 1.54, 95% confidence intervalâ =â 1.05-2.26, Pâ <â .05, I2â =â 69.03%) and homozygous model (CC vs TT; ORâ =â 2.00, 95% confidence intervalâ =â 1.07-3.71, Pâ <â .05, I2â =â 72.84%). For the other single nucleotide polymorphisms, we could not find any statistically significant association with the disease. CONCLUSION: Our analysis showed that mutation of rs3118470 of IL2RA gene possesses a significant risk effect for alopecia areata. Future studies with larger sample sizes and ethnic backgrounds are warranted to confirm our findings.
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Alopecia em Áreas , Humanos , Alopecia em Áreas/genética , Predisposição Genética para Doença , Interleucinas/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
OBJECTIVE: Multiple sclerosis is a serious neurodegenerative disorder that causes disability in young adults. Genetic predisposition of multiple sclerosis is well documented and several single nucleotide polymorphisms (SNPs) of the CD58 were found to be associated with this disease. This systematic review and meta-analysis were done with the aim of finding the association between CD58 gene SNPs (rs12044852 and rs2300747) and the risk of multiple sclerosis (MS). METHOD: A comprehensive search was done in PubMed, Google Scholar, Embase, and MSGene.org to find the relevant data. Our search yielded 13 relevant publications which were included for meta-analysis consisting of 5194 cases and 5766 controls. All the statistical analysis was conducted using meta and metafor packages in R studio. The odds ratio (OR) along with 95 % confidence intervals and p values were determined using the fixed effects and random effects model. The I2 test was done to measure heterogeneity. Subgroup analysis was performed along with analysis for publication bias. RESULTS: We found significant association for both rs12044852 (allelic, dominant, over-dominant, heterozygous, and homozygous models) and rs2300747 (allelic, dominant, over-dominant, heterozygous models) with multiple sclerosis. Both the SNPs provided a protective effect for multiple sclerosis. Subgroup analysis indicated that rs12044852 polymorphism provided a protective effect in both Asians and Caucasians. However, for rs2300747, the Asian population showed no statistically significant association with the risk of MS. CONCLUSION: Polymorphism of rs12044852 and rs2300747 of the CD58 gene provided a protective effect for multiple sclerosis. The protective effect is more prominent in Caucasian populations compared to Asians.
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Antígenos CD58 , Esclerose Múltipla , Humanos , Alelos , Povo Asiático/genética , Antígenos CD58/genética , Predisposição Genética para Doença , Esclerose Múltipla/genética , Polimorfismo de Nucleotídeo Único , População BrancaRESUMO
Background and Aims: Cervical cancer is characterized by abnormal cell growth in the lining of cervix and it is the second major cause of cancer-related deaths among females in Bangladesh. Interleukin-6 (IL-6) is a multifunctional cytokine that has been heavily linked with cervical cancer. Our aim was to investigate the association of two promoter single-nucleotide polymorphisms (SNPs) of IL-6 (rs1800795 and rs1800797) with the susceptibility of cervical cancer in Bangladeshi women. Methods: DNA was extracted from venous blood samples from cervical cancer patients (n = 126) and healthy controls (n = 120). Polymerase chain reaction-restriction fragment length polymorphism was used for genotyping of the selected SNPs. Logistic regression was performed to calculate the odds ratio (OR) with 95% confidence interval (CI) and p values. Results: We found a significant association between rs1800795 and rs1800797 polymorphisms and cervical cancer. For, rs1800795 (G > C) the GC heterozygous genotype (OR = 2.80, 95% CI = 1.55-5.07, p = 0.0007) and CC mutant homozygous genotype (OR = 3.5, 95% CI = 1.29-9.51, p = 0.014) conferred an increased risk of cervical cancer. In case of rs1800797 (G > A) polymorphism, the AG heterozygous genotype (OR = 6.94, 95% CI = 3.76-12.81, p < 0.0001) and AA mutant homozygous genotype (OR = 3.88, 95% CI = 1.12-13.51, p = 0.0332) also exhibited an elevated risk of cervical cancer. Use of contraceptives was found as risk factor and patients who smoke were carriers of both the risk alleles and thus had an increased risk of cervical cancer. Conclusion: Our findings suggest that polymorphism of rs1800795 and rs1800797 of the IL-6 gene play a significant role in cervical cancer susceptibility in Bangladeshi women.
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Pharmacogenetics (PGx)-guided prescribing is an evidence-based precision medicine strategy. Although the past two decades have reported significant advancements in both the quality and quantity of PGx research studies, they are seldom done in developing countries like Bangladesh. This review identified and summarized PGx studies conducted in the Bangladeshi population by searching PubMed and Google Scholar. Additionally, a quality evaluation of the identified studies was also carried out. Eleven PGx studies were identified that looked at the effects of genetic variants on blood thinners (CYP2C9, VKORC1, and ITGB3), cancer drugs (TPMT, MTHFR, DPYD, ERCC1, GSTP1, XPC, XRCC1, TP53, XPD, and ABCC4), statins (COQ2, CYP2D6, and CYP3A5), and prednisolone (ABCB1, CYP3A5, and NR3C1) in the Bangladeshi population. Most studies were of low to moderate quality. Although the identified studies demonstrated the potential for PGx testing, the limited PGx literature in the Bangladeshi population poses a significant challenge in the widespread implementation of PGx testing in Bangladesh.
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Citocromo P-450 CYP3A , Testes Farmacogenômicos , Humanos , Citocromo P-450 CYP3A/genética , Farmacogenética , Citocromo P-450 CYP2D6/genética , Anticoagulantes , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética , Vitamina K Epóxido Redutases/genéticaRESUMO
Alzheimer's disease (AD) is a neurodegenerative disease with rapid progression. Black cumin (Nigella sativa) is a nutraceutical that has been investigated as a prophylactic and therapeutic agent for this disease due to its ability to prevent or retard the progression of neurodegeneration. Thymoquinone (TQ) is the main bioactive compound isolated from the seeds of black cumin. Several reports have shown that it has promising potential in the prevention and treatment of AD due to its significant antioxidative, anti-inflammatory, and antiapoptotic properties along with several other mechanisms that target the altered signaling pathways due to the disease pathogenesis. In addition, it shows anticholinesterase activity and prevents α-synuclein induced synaptic damage. The aim of this review is to summarize the potential aspects and mechanisms by which TQ imparts its action in AD.
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Differential expression of p53 has been reported in cervical cancer, primarily in tumor tissue biopsies. In this study, we examined the association of TP53 codon 47 and codon 72 polymorphisms and serum level expression of p53 in cervical cancer patients (n = 129) and healthy controls (n = 122). We found elevated levels of serum p53 protein levels in cervical cancer patients (p = 0.0442) compared to healthy controls. Moreover, we found higher levels of serum p53 in patients with grade-III tumor (p = 0.001) compared to healthy controls. Examination of SNPs showed TP53 Arg/Pro heterozygosity (adjusted OR = 2.126, 95% CI = 1.181-3.827, p = 0.012), Pro/Pro mutant homozygosity (adjusted OR = 3.564, 95% CI = 1.647-7.713, p = 0.001), along with the combined genotype (Arg/Pro+Pro/Pro) (adjusted OR 2.542, 95% CI = 1.517-4.260, p<0.001) significantly increases the risk of cervical cancer. Expression quantitative trait analysis revealed no significant association with protein expression. Our results represent for the first time the upregulation of serum p53 in cervical cancer in Bangladeshi women and supports the association of TP53 codon 72 polymorphisms with cervical cancer.
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Genes p53 , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Proteína Supressora de Tumor p53/sangue , Neoplasias do Colo do Útero/genética , Adulto , Bangladesh/epidemiologia , Biópsia , Estudos de Casos e Controles , Códon , Feminino , Genótipo , Heterozigoto , Humanos , Modelos Lineares , Pessoa de Meia-Idade , Razão de Chances , Locos de Características Quantitativas , Risco , Medição de Risco , Neoplasias do Colo do Útero/sangueRESUMO
OBJECTIVES: Genetic susceptibility to cervical cancer in relation to transforming growth factor beta 1 (TGFB1) gene polymorphisms has not been investigated extensively among the women in Bangladesh. So, the aim of this study was to find out the correlation of the polymorphisms of TGFB1 C509T (rs1800469) and T869C (rs1800470) with the risk of cervical cancer among the Bangladeshi women. STUDY DESIGN: 134 cervical cancer patients and 102 age-sex matched healthy controls were included from two institutions in Bangladesh. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used for genotyping two TGFB1 single nucleotide polymorphisms C509T (rs1800469) and T869C (rs1800470) in patients and controls. RESULTS: No significant correlation was found between polymorphisms C509T (rs1800469) and T869C (rs1800470) of TGFB1 gene with cervical cancer in Bangladeshi women. In case of the cervical cancer patients who had first degree relatives with cancer were prone to carry the polymorphic version of the TGFB1 gene polymorphism at C509T (ORâ=â5.597, 95% CIâ=â1.224-25.597, pâ<â0.05) but may not result in the increase of developing cervical cancer. CONCLUSION: In summary, two polymorphisms C509T and T869C of TGFB1 gene may not be associated with cervical cancer risk in Bangladeshi women.
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Polimorfismo de Nucleotídeo Único , Fator de Crescimento Transformador beta1/genética , Neoplasias do Colo do Útero/genética , Adulto , Bangladesh/epidemiologia , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Humanos , Pessoa de Meia-Idade , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/patologiaRESUMO
Pharmacogenetic study of TP53 gene polymorphisms has not been conducted extensively in cervical cancer. The aim of this study was to assesses the TP53 codon 72 and codon 47 polymorphisms and their relation to cervical cancer risk in Bangladeshi women. 134 cervical cancer patients and 102 age matched healthy controls were included from two institutions in Bangladesh. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used for genotyping two TP53 single nucleotide polymorphisms (codon 72 and codon 47) in patients and controls. The results indicate that the TP53 Arg/Pro heterozygosity (adjusted OR 2.32, 95% CI 1.28-4.34, p = 0.01), Pro/Pro mutant homozygosity (adjusted OR 4.15, 95% CI 1.75-9.86, p = 0.001), along with the combined genotype (Arg/Pro + Pro/Pro) (adjusted OR 2.83, 95% CI 1.61-4.97, p < 0.001) significantly increases the risk of cervical cancer. Moreover, the cervical cancer patients with a first-degree relative cancer patient possesses 4.45 folds more risk (p = 0.019) of carrying a proline allele in codon 72 of the TP53 gene compared to those patients who do not have any first-degree relative with cancer. Finally, polymorphism in the codon 47 of the TP53 gene did not significantly increase the risk of cervical cancer in Bangladeshi women. To conclude, this is the first study to identify that polymorphism in the TP53 codon 72 significantly increases the risk of cervical cancer in a female population in Bangladesh.
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Proteína Supressora de Tumor p53/genética , Neoplasias do Colo do Útero/genética , Adulto , Alelos , Bangladesh/epidemiologia , Estudos de Casos e Controles , Códon/genética , Suscetibilidade a Doenças/metabolismo , Etnicidade , Feminino , Frequência do Gene/genética , Genes p53/genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Proteína Supressora de Tumor p53/metabolismo , Neoplasias do Colo do Útero/epidemiologiaRESUMO
Over 3000 candidate gene association studies have been performed to elucidate the genetic underpinnings of schizophrenia. However, a comprehensive evaluation of these studies' findings has not been undertaken since the decommissioning of the schizophrenia gene (SzGene) database in 2011. As such, we systematically identified and carried out random-effects meta-analyses for all polymorphisms with four or more independent studies in schizophrenia along with a series of expanded meta-analyses incorporating published and unpublished genome-wide association (GWA) study data. Based on 550 meta-analyses, 11 SNPs in eight linkage disequilibrium (LD) independent loci showed Bonferroni-significant associations with schizophrenia. Expanded meta-analyses identified an additional 10 SNPs, for a total of 21 Bonferroni-significant SNPs in 14 LD-independent loci. Three of these loci (MTHFR, DAOA, ARVCF) had never been implicated by a schizophrenia GWA study. In sum, the present study has provided a comprehensive summary of the current schizophrenia genetics knowledgebase and has made available all the collected data as a resource for the research community.
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Predisposição Genética para Doença , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Esquizofrenia/genética , Alelos , Frequência do Gene , Estudos de Associação Genética , Loci Gênicos , Humanos , Bases de ConhecimentoRESUMO
A number of recent studies have suggested the ubiquitin proteasome system (UPS) in schizophrenia is dysfunctional. The purpose of this study was to investigate UBE2K, a ubiquitin-conjugating (E2) enzyme within the UPS that has been associated with psychosis symptom severity, in the blood and brain of individuals with schizophrenia. Whole blood and erythrocytes from 128 (71 treatment-resistant schizophrenia, 57 healthy controls) individuals as well as frozen dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC) post-mortem samples from 74 (37 schizophrenia, 37 controls) individuals were obtained. UBE2K gene expression was assayed in whole blood and DLPFC samples, whereas protein levels were assayed in erythrocytes and OFC samples. Elevated levels of UBE2K mRNA were observed in whole blood of individuals with schizophrenia (pâ¯=â¯0.03) but not in the DLPFC, while protein levels were raised in erythrocytes and the OFC (pâ¯<â¯0.001 and pâ¯=â¯0.002 respectively). Findings were not better explained by age, smoking, clozapine plasma levels or duration of illness. Although blood and brain samples were derived from independent samples, our findings suggest peripheral protein levels of UBE2K may serve as a surrogate of brain levels and further supports the notion of UPS dysfunction in schizophrenia. Future studies to determine the pathophysiological effects of elevated UBE2K protein levels in the brain of those with schizophrenia are warranted.
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Encéfalo/metabolismo , Esquizofrenia/genética , Esquizofrenia/metabolismo , Enzimas de Conjugação de Ubiquitina/genética , Enzimas de Conjugação de Ubiquitina/metabolismo , Adulto , Austrália , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esquizofrenia/sangue , Enzimas de Conjugação de Ubiquitina/sangueRESUMO
Dysregulation of the ubiquitin proteasome system (UPS) has been linked to schizophrenia but it is not clear if this dysregulation is detectable in both brain and blood. We examined free mono-ubiquitin, ubiquitinated proteins, catalytic ubiquitination, and proteasome activities in frozen postmortem OFC tissue from 76 (38 schizophrenia, 38 control) matched individuals, as well as erythrocytes from 181 living participants, who comprised 30 individuals with recent onset schizophrenia (mean illness duration = 1 year), 63 individuals with 'treatment-resistant' schizophrenia (mean illness duration = 17 years), and 88 age-matched participants without major psychiatric illness. Ubiquitinated protein levels were elevated in postmortem OFC in schizophrenia compared to controls (p = <0.001, AUC = 74.2%). Similarly, individuals with 'treatment-resistant' schizophrenia had higher levels of ubiquitinated proteins in erythrocytes compared to those with recent onset schizophrenia (p < 0.001, AUC = 65.5%) and controls (p < 0.001, AUC = 69.4%). The results could not be better explained by changes in proteasome activity, demographic, medication, or tissue factors. Our results suggest that ubiquitinated protein formation may be abnormal in both the brain and erythrocytes of those with schizophrenia, particularly in the later stages or specific sub-groups of the illness. A derangement in protein ubiquitination may be linked to pathogenesis or neurotoxicity in schizophrenia, and its manifestation in the blood may have prognostic utility.
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Encéfalo/metabolismo , Esquizofrenia/sangue , Esquizofrenia/metabolismo , Proteínas Ubiquitinadas/sangue , Proteínas Ubiquitinadas/metabolismo , Adulto , Feminino , Humanos , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Ubiquitina/metabolismo , Adulto JovemRESUMO
We investigated IL1B genetic variation previously associated with risk for transition to psychosis for its association with gene expression in human post-mortem dorsolateral prefrontal cortex (DLPFC) from 74 (37 schizophrenia, 37 control) individuals and brain structure in 92 (44 schizophrenia, 48 control) living individuals. The IL1B A-G-T 'risk for psychosis transition' haplotype (rs16944|rs4848306|rs12621220) was associated with upregulation of IL1B mRNA expression in the DLPFC as well as reduced total grey matter and left middle frontal volumes and enlarged left lateral ventricular volume. Our results suggest IL1B genetic variation may confer psychosis risk via elevated mRNA expression and/or brain structure abnormalities.
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Substância Cinzenta/patologia , Interleucina-1beta/genética , Ventrículos Laterais/patologia , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Esquizofrenia , Adulto , Feminino , Expressão Gênica/genética , Haplótipos , Humanos , Interleucina-1beta/metabolismo , Masculino , Pessoa de Meia-Idade , Esquizofrenia/genética , Esquizofrenia/metabolismo , Esquizofrenia/patologia , Regulação para CimaRESUMO
The aim of the study was to assess the pharmacokinetic and bioavailability of 2 formulations of 5-mg prednisolone tablets, reference product (Teva UK Limited) and Pred (Eskayef Bangladesh Ltd) as test product. The open-label, randomized, 2-way crossover studies were conducted on 14 healthy subjects. Participants were assigned to receive both products as a single dose (20 mg formulations, 4 × 5 mg tablets) followed by a 2 weeks' washout period. Following oral administration, samples were obtained at various time intervals and analyzed for prednisolone concentrations using a validated high-performance liquid chromatography assay method with ultraviolet detection. The obtained values for test and reference products were 683.00 ± 94.54 ng/mL and 635.16 ± 125.57 ng/mL for Cmax; 2716.54 ± 196.28 ng·h/mL and 2780.5 ± 119.73 ng·h/mL for AUC0-12; 3284.36 ± 138.12 ng·h/mL and 3317.96 ± 133.95 ng·h/mL for AUC0-∞, respectively. From the paired Student t test, no significant differences between 2 formulations were observed (P > .05). The 90% confidence intervals of Cmax, AUC0-12, and AUC0-∞ were found to be 99.0% to 100.9%, 99.4% to 100.5%, and 99.9% to 101.3%, respectively. Finally, it can be concluded that Pred (Test) of Eskayef Bangladesh Ltd and prednisolone (Reference) of Teva UK Limited are bioequivalent and interchangeable.
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Upregulation of selenium binding protein 1 (SELENBP1) mRNA expression has been reported in schizophrenia, primarily in the dorsolateral prefrontal cortex. However, peripheral blood studies are limited and results are inconsistent. In this study, we examined SELENBP1 mRNA expression in whole blood and protein expression in plasma from patients with recent-onset schizophrenia (nâ¯=â¯30), treatment-resistant schizophrenia (nâ¯=â¯71) and healthy controls (nâ¯=â¯57). We also examined the effects of SELENBP1 genetic variation on gene and protein expression. We found lower SELENBP1 plasma protein levels in patients with recent-onset schizophrenia (pâ¯=â¯0.042) but not in treatment-resistant schizophrenia (pâ¯=â¯0.81). Measurement of peripheral mRNA levels showed no difference between treatment-resistant schizophrenia and healthy controls (pâ¯=â¯0.234) but clozapine plasma levels (pâ¯=â¯0.036) and duration of illness (pâ¯=â¯0.028) were positively correlated with mRNA levels. Genetic variation was not associated with mRNA or protein expression. Our data represent the first peripheral proteomic study of SELENBP1 in schizophrenia and suggest that plasma SELENBP1 protein is downregulated in patients with recent-onset schizophrenia.
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Esquizofrenia/sangue , Proteínas de Ligação a Selênio/sangue , Doença Aguda , Adulto , Antipsicóticos/sangue , Antipsicóticos/uso terapêutico , Biomarcadores/sangue , Doença Crônica , Clozapina/sangue , Clozapina/uso terapêutico , Regulação para Baixo , Resistência a Medicamentos , Feminino , Haplótipos , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Proteoma/efeitos dos fármacos , Proteômica , RNA Mensageiro/sangue , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Proteínas de Ligação a Selênio/genética , Fatores de Tempo , Adulto JovemRESUMO
Differential expression of neuregulin-1 (NRG1) mRNA isoforms and proteins has been reported in schizophrenia, primarily in post-mortem brain tissue. In this study, we examined 12 NRG1 SNPs, eight NRG1 mRNA isoforms (type I, type I(Ig2), type II, type III, type IV, EGFα, EGFß, pan-NRG1) in whole blood, and NRG1-ß1 protein in serum of clozapine-treated schizophrenia patients (N = 71) and healthy controls (N = 57). In addition, using cultured peripheral blood mononuclear cells (PBMC) from 15 healthy individuals, we examined the effect of clozapine on NRG1 mRNA isoform and protein expression. We found elevated levels of NRG1 mRNA, specifically the EGFα (P = 0.0175), EGFß (P = 0.002) and type I(Ig2) (P = 0.023) containing transcripts, but lower NRG1-ß1 serum protein levels (P = 0.019) in schizophrenia patients compared to healthy controls. However, adjusting for smoking status attenuated the difference in NRG1-ß1 serum levels (P = 0.050). Examination of clinical factors showed NRG1 EGFα (P = 0.02) and EGFß (P = 0.02) isoform expression was negatively correlated with age of onset. However, we found limited evidence that NRG1 mRNA isoform or protein expression was associated with current chlorpromazine equivalent dose or clozapine plasma levels, the latter corroborated by our PBMC clozapine exposure experiment. Our SNP analysis found no robust expression quantitative trait loci. Our results represent the first comprehensive investigation of NRG1 isoforms and protein expression in the blood of clozapine-treated schizophrenia patients and suggest levels of some NRG1 transcripts are upregulated in those with schizophrenia.
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Neuregulina-1/sangue , Esquizofrenia/sangue , Adulto , Antipsicóticos/administração & dosagem , Clozapina/administração & dosagem , Feminino , Genótipo , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Neuregulina-1/genética , Polimorfismo de Nucleotídeo Único , Isoformas de Proteínas/metabolismo , RNA Mensageiro/metabolismoRESUMO
Investigation of peripheral gene expression patterns of transcripts within the NRG-ErbB signaling pathway, other than neuregulin-1 (NRG1), among patients with schizophrenia and more specifically treatment-resistant schizophrenia (TRS) is limited. The present study built on our previous work demonstrating elevated levels of NRG1 EGFα, EGFß, and type I(Ig2) containing transcripts in TRS by investigating 11 NRG-ErbB signaling pathway mRNA transcripts (NRG2, ErbB1, ErbB2, ErbB3, ErbB4, PIK3CD, PIK3R3, AKT1, mTOR, P70S6K, eIF4EBP1) in whole blood of TRS patients (N = 71) and healthy controls (N = 57). We also examined the effect of clozapine exposure on transcript levels using cultured peripheral blood mononuclear cells (PBMCs) from 15 healthy individuals. Five transcripts (ErbB3, PIK3CD, AKT1, P70S6K, eIF4EBP1) were significantly elevated in TRS patients compared to healthy controls but only expression of P70S6K (Pcorrected = 0.018), a protein kinase linked to protein synthesis, cell growth, and cell proliferation, survived correction for multiple testing using the Benjamini-Hochberg method. Investigation of clinical factors revealed that ErbB2, PIK3CD, PIK3R3, AKT1, mTOR, and P70S6K expression were negatively correlated with duration of illness. However, no transcript was associated with chlorpromazine equivalent dose or clozapine plasma levels, the latter supported by our in vitro PBMC clozapine exposure experiment. Taken together with previously published NRG1 results, our findings suggest an overall upregulation of transcripts within the NRG-ErbB signaling pathway among individuals with schizophrenia some of which attenuate over duration of illness. Follow-up studies are needed to determine if the observed peripheral upregulation of transcripts within the NRG-ErbB signaling pathway are specific to TRS or are a general blood-based marker of schizophrenia.
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Clinical and pre-clinical evidence has implicated neuregulin 1 (NRG1) as a critical component in the pathophysiology of schizophrenia. However, the arrival of the genome-wide association study (GWAS) era has yielded results that challenge the relevance of NRG1 in schizophrenia due to the absence of a genome-wide significant NRG1 variant associated with schizophrenia. To assess NRG1's relevance to schizophrenia in the GWAS era, we provide a targeted review of recent preclinical evidence on NRG1's role in regulating several aspects of excitatory/inhibitory neurotransmission and in turn schizophrenia risk. We also present a systematic review of the last decade of clinical research examining NRG1 in the context of schizophrenia. We include concise summaries of genotypic variation, gene-expression, protein expression, structural and functional neuroimaging as well as cognitive studies conducted during this time period. We conclude with recommendations for future clinical and preclinical work that we hope will help prioritize a strategy forward to further advance our understanding of the relationship between NRG1 and schizophrenia.