1,721,031 research outputs found
Molecular basis of gene-environment interactions in the pathogenesis of asthma and COPD
No full textThe origins of respiratory disease, such as asthma in childhood and COPD in later life are unclear. Maternal smoking during pregnancy and low birth weight is associated with increased risk of asthma, poor lung function in adults and COPD in old age. Exposure to oxidative stress and poor nutrition in utero is thought to cause damage to the lung and alter the normal course of lung development.Glutathione S-transferases (GST) are potent antioxidants. In this work, genetic polymorphisms that alter GST enzyme activity were genotyped in a family-based childhood asthma cohort (341 families, n = 1508) and analysed to investigate whether they alter the risk of developing asthma when individuals are exposed to environmental tobacco smoke. Real-time PCR based copy number variation methodology was developed to genotype the common gene deletion polymorphism of GSTT1 and GSTM1 genes, for other GST genes (GSTP1 and GSTO2) SNP haplotypes were constructed. A rare GSTO2 haplotype was negatively associated with asthma susceptibility, atopy severity, and FEV1 values. Asthmatic children with a GSTT1 gene deletion, or a common GSTP1 haplotype, developed more severe asthma compared to individuals with a GSTT1 gene or non-carriers of the GSTP1 haplotype. Total IgE levels were increased in GSTT1*0 individuals when exposed to tobacco smoke in early life, suggesting a gene-environment interaction. GSTO2 may be a shared susceptibility locus for asthma in childhood and COPD in later life.Animal models of maternal protein-restriction during pregnancy can induce hypertension, diabetes and endothelial dysfunction in offspring and in some of these models alterations to lung gene expression and lung architecture have been reported. This work established that a rat model of maternal dietary protein-restriction during pregnancy known to induce hypertension in the offspring, results in persistent alterations to the expression of genes in the lungs of adult offspring (120 days), including genes involved in glucocorticoid action (Hsd11b2), growth (Igf1 & 2 and Pcdh1) and alveolar development (Tp53). Lung microRNA expression profiles were also altered in response to exposure to protein restriction in utero. These findings suggest a role for nutritional programming in respiratory disease susceptibility in later life and a role for microRNAs in the study of the developmental origins of health and disease in general. Further work will include the investigation of epigenetic mechanisms that control nutritional programming in lungs of animals exposed to protein-restriction in utero.This work has demonstrated that GST polymorphism is a risk factor for childhood asthma and certain genotypes can offer some protection against the development of severe asthma. There was little evidence to suggest that GST polymorphism modulates the effects of smoke exposure in early life. In addition, we have demonstrated that maternal diets that are poor in nutrition could predispose her offspring to respiratory disease in later life by altering the course of normal lung development in early life or response to environmental stimuli in later life
Cytokine gene polymorphisms, cancer susceptibility, and prognosis
No full textIL-10 is a multifunctional cytokine with both immunosuppressive and antiangiogenic functions and may have both tumor-promoting and -inhibiting properties. A large number of polymorphisms (primarily single-nucleotide polymorphisms) have been identified in the IL10 gene promoter. Convincing evidence that certain of these polymorphisms are associated with differential expression of IL-10 in vitro and in some cases in vivo was obtained, and a number of studies investigated associations between IL10 polymorphisms and cancer susceptibility and prognosis. The results from 22 studies in 13 different malignancies are reviewed. In 17 of these studies, positive associations between IL10 genotype or haplotype and disease susceptibility, progression, or both were reported. In some of these cancers genotypes associated with low IL-10 expression were a risk factor for disease or disease progression, whereas in others genotypes associated with high IL-10 expression were a risk factor. Published findings in breast cancer are as yet conflicting. Most but not all of the studies reviewed are based on small sample sizes and a limited number of IL10 polymorphisms. However, the preliminary data indicate that larger studies are required in a number of cancers to confirm initial results, extend studies to include more detailed genotype and haplotype analysis, and combine genotype and gene expression studies in the same subjects. Such studies will contribute significantly to our understanding of the biological role of IL-10 in cancer development
V-ATPase inhibition decreases mutant androgen receptor activity in castrate-resistant prostate cancer
No full textProstate cancer is critically dependent on androgen receptor (AR) signaling. Despite initial responsiveness to androgen deprivation, most patients with advanced prostate cancer subsequently progress to a clinically aggressive castrate-resistant prostate cancer (CRPC) phenotype, typically associated with expression of splice-variant or mutant AR forms. Although current evidence suggests that the vacuolar-ATPase (V-ATPase), a multiprotein complex that catalyzes proton transport across intracellular and plasma membranes, influences wild-type AR function, the effect of V-ATPase inhibition on variant AR function is unknown. Inhibition of V-ATPase reduced AR function in wild-type and mutant AR luciferase reporter models. In hormone-sensitive prostate cancer cell lines (LNCaP, DuCaP) and mutant AR CRPC cell lines (22Rv1, LNCaP-F877L/T878A), V-ATPase inhibition using bafilomycin-A1 and concanamycin-A reduced AR expression, and expression of AR target genes, at mRNA and protein levels. Furthermore, combining chemical V-ATPase inhibition with the AR antagonist enzalutamide resulted in a greater reduction in AR downstream target expression than enzalutamide alone in LNCaP cells. To investigate the role of individual subunit isoforms, siRNA and CRISPR-Cas9 were used to target the V
1C1 subunit in 22Rv1 cells. Whereas transfection with ATP6V1C1-targeted siRNA significantly reduced AR protein levels and function, CRISPR-Cas9–mediated V
1C1 knockout showed no substantial change in AR expression, but a compensatory increase in protein levels of the alternate V
1C2 isoform. Overall, these results indicate that V-ATPase dysregulation is directly linked to both hormone-responsive prostate cancer and CRPC via impact on AR function. In particular, V-ATPase inhibition can reduce AR signaling regardless of mutant AR expression.
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A single-nucleotide polymorphism in intelectin 1 is associated with increased asthma risk
No full textRapid microfluidic isolation of virally infected primary bronchial epithelial cells for single-cell RNA sequencing
No full textSingle-cell RNA sequencing (scRNA-seq) of the bronchial epithelium enables examination of cellular subtypes and their responses to viral infections. Here, an optimized method for the isolation of virally infected primary bronchial epithelial cells using a commercially available microfluidic device is presented. Using this method single cells can be rapidly isolated with minimal equipment available in most laboratories. Isolation can be carried out inside biological safety cabinets, permitting the use of virally infected cells. Both cell-line and primary cells isolated using the device retained sufficient RNA integrity for the generation of short-read sequencing-compatible cDNA libraries to facilitate scRNA-seq
Association analysis of brain-derived neurotrophic factor gene polymorphisms in asthmatic families
No full textBackground: A role for neuronal modulation of inflammation and airway hyper-responsiveness has been well described in asthma, and neurotrophins provide the link between inflammation and neuronal dysfunction. Brain-derived neurotrophic factor (BDNF) is an important mediator in this interaction. The aim of this study was to analyze the possible relationship between polymorphisms of the gene encoding BDNF and susceptibility to asthma. Methods: 341 families with at least 2 siblings with asthma were genotyped for 4 BDNF polymorphisms (rs6265, rs2030324, rs988748 and rs7124442). Results: Analysis by family-based association tests revealed no significant association between any polymorphisms analyzed and asthma susceptibility. Furthermore, BDNF polymorphism was not associated with asthma-related phenotypes such as FEV1 % predicted, bronchial hyper-responsiveness, IgE level, asthma and atopy severity scores. Conclusions: Our results suggest that genetic variation in the BDNF gene does not contribute significantly to asthma susceptibility or severity.<br/
Fcγ receptors: genetic variation, function, and disease
No full textFcγ receptors (FcγRs) are key immune receptors responsible for the effective control of both humoral and innate immunity and are central to maintaining the balance between generating appropriate responses to infection and preventing autoimmunity. When this balance is lost, pathology results in increased susceptibility to cancer, autoimmunity, and infection. In contrast, optimal FcγR engagement facilitates effective disease resolution and response to monoclonal antibody immunotherapy. The underlying genetics of the FcγR gene family are a central component of this careful balance. Complex in humans and generated through ancestral duplication events, here we review the evolution of the gene family in mammals, the potential importance of copy number, and functionally relevant single nucleotide polymorphisms, as well as discussing current approaches and limitations when exploring genetic variation in this region
Molecular landscape of proliferative verrucous leukoplakia: a systematic review
No full textProliferative verrucous leukoplakia (PVL) is a rare oral potentially malignant disorder characterised by multifocal origin and unpredictable long-term evolution to oral squamous cell carcinoma (OSCC) or oral verrucous carcinoma (OVC). Currently no predictive biomarkers are in clinical use. We aimed to explore the genomic profile of PVL. A total of 685 cases in 26 studies were included in this review. Genomic data were presented in 15% of studies and biomarker analysis was reported in 85% of studies. At first clinical presentation, PVL is characterised by a high loss of heterozygosity (LOH), similar to OSCC, and low copy number alterations (CNA). As these progress, more CNAs and mutations in CDKN2A and alterations to ELAVL1 expression are noted, but no TP53 mutations are identified. There is significantly lower LOH at 17p in early PVL compared with OSCC (p = 0.037). Deletions in chromosomal loci 17q12, 5q31.1 and amplifications in 7q11.2, 7q22 are shared between early lesions and OVC. PVL shows CNAs at 11q31. WNT signalling pathway genes (SUZ12, CTTN and FOLR3) are enriched in CN-altered regions. PVL stroma shows significantly lower α-SMA and higher CD34 expression than OVC and OSCC. The exact genomic landscape is currently unclear, and further studies are necessary to unravel this mystery.</p
Single-nucleotide Fcγ receptor polymorphisms do not impact obinutuzumab/rituximab outcome in patients with lymphoma
No full textSingle-nucleotide polymorphisms (SNPs) have been shown to influence Fcγ receptor (FcγR) affinity and activity, but their effect on treatment response is unclear. We assessed their importance in the efficacy of obinutuzumab or rituximab combined with chemotherapy in untreated advanced follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) in the GALLIUM (www.clinicaltrials.gov #NCT01332968) and GOYA (#NCT01287741) trials, respectively. Genomic DNA was extracted from patients enrolled in GALLIUM (n = 1202) and GOYA (n = 1418). Key germline SNPs, FCGR2A R131H (rs1801274), FCGR3A F158V (rs396991), and FCGR2B I232T (rs1050501), were genotyped and assessed for their impact on investigator-assessed progression-free survival (PFS). In both cohorts there was no prognostic effect of FCGR2A or FCGR3A. In FL, FCGR2B was associated with favorable PFS in univariate and multivariate analyses comparing I232T with I232I, with a more modest association for rituximab-treated (univariate: Hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.54-1.14; P = .21) vs obinutuzumab-treated patients (HR, 0.56; 95% CI, 0.34-0.91; P = .02). Comparing T232T with I232I, an association was found for obinutuzumab (univariate: HR, 2.76; 95% CI, 1.02-7.5; P = .0459). Neither observation retained significance after multiple-test adjustment. FCGR2B was associated with poorer PFS in multivariate analyses comparing T232T with I232I in rituximab- but not obinutuzumab-treated patients with DLBCL (HR, 4.40; 95% CI, 1.71-11.32; P = .002; multiple-test-adjusted P = .03); however, this genotype was rare (n = 13). This study shows that FcγR genotype is not associated with response to rituximab/obinutuzumab plus chemotherapy in treatment-naive patients with advanced FL or DLBCL.</p
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