Mutational landscape of risk variants in comorbid depression and obesity: a next-generation sequencing approach.

Major depression (MD) and obesity are complex genetic disorders that are frequently comorbid. However, the study of both diseases concurrently remains poorly addressed and therefore the underlying genetic mechanisms involved in this comorbidity remain largely unknown. Here we examine the contribution of common and rare variants to this comorbidity through a next-generation sequencing (NGS) approach. Specific genomic regions of interest in MD and obesity were sequenced in a group of 654 individuals from the PISMA-ep epidemiological study. We obtained variants across the entire frequency spectrum and assessed their association with comorbid MD and obesity, both at variant and gene levels. We identified 55 independent common variants and a burden of rare variants in 4 genes (PARK2, FGF21, HIST1H3D and RSRC1) associated with the comorbid phenotype. Follow-up analyses revealed significantly enriched gene-sets associated with biological processes and pathways involved in metabolic dysregulation, hormone signaling and cell cycle regulation. Our results suggest that, while risk variants specific to the comorbid phenotype have been identified, the genes functionally impacted by the risk variants share cell biological processes and signaling pathways with MD and obesity phenotypes separately. To the best of our knowledge, this is the first study involving a targeted sequencing approach toward the study of the comorbid MD and obesity. The framework presented here allowed a deep characterization of the genetics of the co-occurring MD and obesity, revealing insights into the mutational and functional profile that underlies this comorbidity and contributing to a better understanding of the relationship between these two disabling disorders.

Analyzing the role of ACE2, AR, MX1 and TMPRSS2 genetic markers for COVID-19 severity.

BACKGROUND: The use of molecular biomarkers for COVID-19 remains unconclusive. The application of a molecular biomarker in combination with clinical ones that could help classifying aggressive patients in first steps of the disease could help clinician and sanitary system a better management of the disease. Here we characterize the role of ACE2, AR, MX1, ERG, ETV5 and TMPRSS2 for trying a better classification of COVID-19 through knowledge of the disease mechanisms. METHODS: A total of 329 blood samples were genotyped in ACE2, MX1 and TMPRSS2. RNA analyses were also performed from 258 available samples using quantitative polymerase chain reaction for genes: ERG, ETV5, AR, MX1, ACE2, and TMPRSS2. Moreover, in silico analysis variant effect predictor, ClinVar, IPA, DAVID, GTEx, STRING and miRDB database was also performed. Clinical and demographic data were recruited from all participants following WHO classification criteria. RESULTS: We confirm the use of ferritin (p < 0.001), D-dimer (p < 0.010), CRP (p < 0.001) and LDH (p < 0.001) as markers for distinguishing mild and severe cohorts. Expression studies showed that MX1 and AR are significantly higher expressed in mild vs severe patients (p < 0.05). ACE2 and TMPRSS2 are involved in the same molecular process of membrane fusion (p = 4.4 × 10-3), acting as proteases (p = 0.047). CONCLUSIONS: In addition to the key role of TMPSRSS2, we reported for the first time that higher expression levels of AR are related with a decreased risk of severe COVID-19 disease in females. Moreover, functional analysis demonstrates that ACE2, MX1 and TMPRSS2 are relevant markers in this disease.

Follow-Up Biomarkers in the Evolution of Prostate Cancer, Levels of S100A4 as a Detector in Plasma.

The management and screening of prostate cancer (PC) is still the main problem in clinical practice. In this study, we investigated the role of aggressiveness genetic markers for PC stratification. We analyzed 201 plasma samples from PC patients and controls by digital PCR. For selection and validation, 26 formalin-fixed paraffin-embedded tissues, 12 fresh tissues, and 24 plasma samples were characterized by RNA-Seq, immunochemistry, immunofluorescence, Western blot, and extracellular-vesicles analyses. We identified three novel non-invasive biomarkers; all with an increased expression pattern in patients (PCA3: p = 0.002, S100A4: p ≤ 0.0001 and MRC2: p = 0.005). S100A4 presents the most informative AUC (area under the curve) (0.735). Combination of S100A4, MRC2, and PCA3 increases the discriminatory power between patients and controls and between different more and less aggressive stages (AUC = 0.761, p ≤ 0.0001). However, although a sensitivity of 97.47% in PCA3 and a specificity of 90.32% in S100A4 was reached, the detection signal level could be variable in some analyses owing to tumor heterogeneity. This is the first time that the role of S100A4 and MRC2 has been described in PC aggressiveness. Moreover, the combination of S100A4, MRC2, and PCA3 has never been described as a non-invasive biomarker for PC screening and aggressiveness.

Metabolic pathways, alterations in miRNAs expression and effects of genetic polymorphisms of bisphenol a analogues: A systematic review.

Bisphenol A (BPA) is one of the most common endocrine disruptors found in the environment and its harmful health effects in humans and wildlife have been extensively reported One of the main aims of this review was to examine the metabolic pathways of BPA and BPA substitutes and the endocrine disrupting properties of their metabolites. According to the available literature, phase I and phase II metabolic reactions play an important role in the detoxification process of bisphenols (BPs), but their metabolism can also lead to the formation of highly reactive metabolites. The second part of this work addresses the associations between exposure to BPA and its analogues with the alterations in miRNAs expression and the effects of single nucleotide polymorphisms (SNPs). Available scientific evidence shows that BPs can dysregulate the expression of several miRNAs, and in turn, these miRNAs could be considered as epigenetic biomarkers to prevent the development of a variety of BP-mediated diseases. Interestingly, genetic polymorphisms are able to modify the relationship of BPA exposure with the risk of adverse health effects, suggesting that interindividual genetic differences modulate the susceptibility to the effects of environmental contaminants.

Influence of Oxidative Stress-Related Genes on Susceptibility to Fibromyalgia.

BACKGROUND: Fibromyalgia (FM) is a complex syndrome to diagnose and treat because of its unknown etiology. However, previous studies reported that patients with FM experience oxidative stress. OBJECTIVES: In this study, we investigated single-nucleotide polymorphisms (SNPs) in genes encoding enzymes involved in oxidative stress (superoxide dismutase 1 [SOD1], catalase, and NADPH oxidase [CYBA]) in patients with FM and in healthy subjects, as well as the possible relation with demographic and clinical manifestations of FM. METHODS: A total of 141 patients with FM and 73 healthy subjects participated in this case-control study. For DNA extraction, buccal swabs were collected from patients with FM, and a peripheral blood sample was extracted from controls. We analyzed SNPs in genes related to oxidative stress (rs10432782 in SOD1, rs1001179 in catalase, and rs4673 in CYBA) using TaqMan probes. In patients with FM, severity of FM, fatigue, and pain were assessed by Fibromyalgia Impact Questionnaire, Multidimensional Fatigue Inventory, and Visual Analogue Scale (VAS), respectively. Physical (PCS-12) and mental (MCS-12) health statuses were evaluated by the 12-Item Short-Form Health Survey. RESULTS: The selected SNPs did not show significant differences between patients with FM and controls. The rs10432782 (SOD1) was associated with Fibromyalgia Impact Questionnaire scores in patients with FM, whereas the rs4673 (CYBA) was associated with the Multidimensional Fatigue Inventory score, MCS-12 score, and duration of the disease. DISCUSSION: We have identified significant correlations between SOD1 and CYBA variants with clinical manifestations of FM. These results provide new insights into the pathogenesis of FM that could be useful for guiding future studies along the way to find the cause(s) of this syndrome.

Combined Genome, Transcriptome and Metabolome Analysis in the Diagnosis of Childhood Cerebellar Ataxia.

Ataxia in children is a common clinical sign of numerous neurological disorders consisting of impaired coordination of voluntary muscle movement. Its most common form, cerebellar ataxia, describes a heterogeneous array of neurologic conditions with uncountable causes broadly divided as acquired or genetic. Numerous genetic disorders are associated with chronic progressive ataxia, which complicates clinical management, particularly on the diagnostic stage. Advances in omics technologies enable improvements in clinical practice and research, so we proposed a multi-omics approach to aid in the genetic diagnosis and molecular elucidation of an undiagnosed infantile condition of chronic progressive cerebellar ataxia. Using whole-exome sequencing, RNA-seq, and untargeted metabolomics, we identified three clinically relevant mutations (rs141471029, rs191582628 and rs398124292) and an altered metabolic profile in our patient. Two POLR1C diagnostic variants already classified as pathogenic were found, and a diagnosis of hypomyelinating leukodystrophy was achieved. A mutation on the MMACHC gene, known to be associated with methylmalonic aciduria and homocystinuria cblC type, was also found. Additionally, preliminary metabolome analysis revealed alterations in our patient's amino acid, fatty acid and carbohydrate metabolism. Our findings provided a definitive genetic diagnosis reinforcing the association between POLR1C mutations and hypomyelinating leukodystrophy and highlighted the relevance of multi-omics approaches to the disease.

Cost-effectiveness analysis of pharmacogenomics-guided clopidogrel treatment in Spanish patients undergoing percutaneous coronary intervention.

Clopidogrel is an antiplatelet drug given to patients before and after having a percutaneous coronary intervention (PCI). Genomic variants in the CYP2C19 gene are associated with variable enzyme activities affecting drug metabolism and hence, patients with reduced or increased enzymatic function have increased risk of bleeding. We conducted a cost-effectiveness analysis to compare a pharmacogenomics versus a non-pharmacogenomics-guided clopidogrel treatment for coronary artery syndrome patients undergoing PCI in the Spanish healthcare setting. A total of 549 patients diagnosed with coronary artery disease followed by PCI were recruited. Dual antiplatelet therapy was administrated to all patients from 1 to 12 months after PCI. Patients were classified into two groups: the Retrospective group was treated with clopidogrel based on the clinical routine practice and the Prospective group were initially genotyped for the presence of CYP2C19 variant alleles before treatment with those carrying more than one CYP2C19 variant alleles given prasugrel treatment. We collected data on established clinical and health outcome measures, including, per treatment arm: the percentage of patients that suffered from (a) myocardial infraction, (b) major bleeding and minor bleeding, (c) stroke, (d) the number of hospitalization days, and (e) the number of days patients spent in Intensive Care Unit. Our primary outcome measure for the cost-effectiveness analysis was Quality Adjusted Life Years (QALYs). To estimate the treatment cost for each patient, individual data on its resource used were combined with unit price data, obtained from Spanish national sources. The analysis predicts a survival of 0.9446 QALYs in the pharmacogenomics arm and 0.9379 QALYs in the non-pharmacogenomics arm within a 1-year horizon. The cumulative costs per patient were €2971 and €3205 for the Prospective and Retrospective groups, respectively. The main cost driver of total cost in both arms was hospitalization costs. The incremental cost-effectiveness ratio (ICER) was negative indicating that the PGx was a dominant option. Our data show that pharmacogenomics-guided clopidogrel treatment strategy may represent a cost-effective choice compared with non-pharmacogenomics-guided strategy for patients undergoing PCI.

The influence of nutritional factors on prostate cancer incidence and aggressiveness.

There is an increasing evidence for a link between nutrition, lifestyle and prostate cancer (PCa) development and/or progression of disease. The objective of this study was to examine the association between dietary factors and PCa incidence and aggressiveness in a case-control study. After the analysis of the anatomic pathology, subjects were classified in patients with PCa (n = 157) and controls (n = 158). Clinical data including Gleason score, PSA values and biopsy results, were compiled. Frequencies of food consumption and sociodemographic data were also obtained. The results showed that physical activity was significantly higher in control (p < .022). It was also found that some nutritional habits offer a protective effect among studied subjects, like high nuts (p = .041) and fish (p = .041) intakes. Moreover, there was a significant reduction in risk (p = .029) in cases with a higher fruits and vegetables intakes. A decreased risk of aggressive PCa was associated with fruits, vegetables, legumes and fish intakes. However, these relationships were not statistically significant when data were adjusted for covariates. In conclusion, this study found an inverse association between PCa risk and the intake of fruits and vegetables, fish and nuts. The results suggested that a diet with higher intakes of these foods as Mediterranean diet may lower the risk of PCa in the studied population. As dietary factors are modifiable, identifying food groups or dietary patterns that modulate the risk of PCa and its aggressiveness can offer effective and practical strategies for its primary prevention.

Next generation sequencing: an application in forensic sciences?

CONTEXT: Over the last few decades, advances in sequencing have improved greatly. One of the most important achievements of Next Generation Sequencing (NGS) is to produce millions of sequence reads in a short period of time, and to produce large sequences of DNA in fragments of any size. Libraries can be generated from whole genomes or any DNA or RNA region of interest without the need to know its sequence beforehand. This allows for looking for variations and facilitating genetic identification. OBJECTIVES: A deep analysis of current NGS technologies and their application, especially in forensics, including a discussion about the pros and cons of these technologies in genetic identification. METHODS: A systematic literature search in PubMed, Science Direct and Scopus electronic databases was performed for the period of December 2012 to June 2015. RESULTS: In the forensic field, one of the main problems is the limited amount of sample available, as well as its degraded state. If the amount of DNA input required for preparing NGS libraries continues to decrease, nearly any sample could be sequenced; therefore, the maximum information from any biological remains could be obtained. Additionally, microbiome typification could be an interesting application to study for crime scene characterisation. CONCLUSIONS: NGS technologies are going to be crucial for DNA human typing in cases like mass disasters or other events where forensic specimens and samples are compromised and degraded. With the use of NGS it will be possible to achieve the simultaneous analysis of the standard autosomal DNA (STRs and SNPs), mitochondrial DNA, and X and Y chromosomal markers.

Lifestyle and dietary factors in relation to prostate cancer risk.

The aim of the present study was to determine the association between the socio-demographic, lifestyle factors, and dietary habits with the risk of prostate cancer (PC) in a case-control study of Spanish men. None of the socio-demographic, lifestyle or dietetic variables was found predictors of PC risk. Body mass index was associated with an increased risk for aggressive PC and fruit consumption with lower Gleason scores, thus less aggressive cancers. Nonetheless, after applying Bonferroni correction, these variables were not still associated with PC aggressiveness. More adequately, powered epidemiological studies that measure the effect of lifestyle and dietary intake in PC risk and aggressiveness are warranted to further elucidate the role of these modifiable factors on PC etiology.

Targeted next-generation sequencing panel to investigate antiplatelet adverse reactions in acute coronary syndrome patients undergoing percutaneous coronary intervention with stenting.

Antiplatelet therapy, the gold standard of care for patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI), is one of the therapeutic approaches most associated with the development of adverse drug reactions (ADRs). Although numerous studies have shown that pharmacological intervention based on a limited number of high-evidence variants (primarily CYP2C19*2 and *3) can reduce the incidence of major adverse cardiovascular events (MACEs), ADRs still occur at variable rates (10.1 % in our case) despite personalized therapy. This study aimed to identify novel genetic variants associated with the endpoint of MACEs 12 months after PCI by designing and analyzing a targeted gene panel. We sequenced 244 ACS-PCI-stent patients (109 with event and 135 without event) and 99 controls without structural cardiovascular disease and performed an association analysis to search for unexpected genetic variants. No single nucleotide polymorphisms reached genomic significance after correction, but three novel variants, including ABCA1 (rs2472434), KLB (rs17618244), and ZNF335 (rs3827066), may play a role in MACEs in ACS patients. These genetic variants are involved in regulating high-density lipoprotein levels and cholesterol deposition, and as they are regulatory variants, they may affect the expression of nearby lipid metabolism-related genes. Our findings suggest new targets (both at the gene and pathway levels) that may increase susceptibility to MACEs, but further research is needed to clarify the role and impact of the identified variants before these findings can be incorporated into the therapeutic decision-making process.

Exposure to environmental pollutants and genetic variants related to oxidative stress and xenobiotic metabolism-Association with prostate cancer.

This study assessed whether genetic variants coding for certain enzymes involved in xenobiotic detoxification, antioxidant defences and DNA repair, along with exposure to environmental chemicals, were associated with an increased prostate cancer (PCa) risk. The study population consisted of 300 men (150 PCa cases and 150 controls) which underwent prostate biopsy as their serum prostate specific antigen (PSA) levels were greater than 4 ng/ml. Genetic variants in GSTM1, GSTP1, SOD2, CAT, GPX1, XRCC1 were determined and data for chemical exposures was obtained through a structured questionnaire and by biomonitoring in a subsample of cases and controls. High serum PSA levels were associated with a greater risk of PCa, while physical exercise appears to exert a protective effect against its development. In addition, elevated urinary levels of certain organic pollutants, such as benzo(a)pyrene (BaP), bisphenol A (BPA), and ethyl-paraben (EPB), were associated with an increased risk of PCa.

Association of genetic polymorphisms in detoxifying systems and urinary metal(loid) levels with excess body weight among Spanish children: A proof-of-concept study.

Exposure to metal(loid)s during critical developmental windows could result in permanent damage to the target organ system, increasing susceptibility to disease later in life. In view of the fact that metals(loid)s have been shown to work as obesogens, the aim of the present case-control study was to evaluate the modification effect of exposure to metal(loid)s on the association between SNPs in genes involved in metal(loid) detoxification and excess body weight among children. A total of 134 Spanish children aged 6-12 years old were included (88 controls and 46 cases). Seven SNPs (GSTP1 rs1695 and rs1138272; GCLM rs3789453, ATP7B rs1061472, rs732774 and rs1801243; and ABCC2 rs1885301) were genotyped on GSA microchips, and ten metal(loid)s were analysed in urine samples through Inductively coupled plasma mass spectrometry (ICP-MS). Multivariable logistic regressions were conducted to assess the genetic and metal exposures' main association and interaction effects. GSTP1 rs1695 and ATP7B rs1061472 showed significant effects on excess weight increase in those children carrying two copies of the risk G allele and being highly exposed to chromium (ORa = 5.38, p = 0.042, p interaction = 0.028 for rs1695; and ORa = 4.20, p = 0.035, p interaction = 0.012 for rs1061472) and lead (ORa = 7.18, p = 0.027, p interaction = 0.031 for rs1695, and ORa = 3.42, p = 0.062, p interaction = 0.010 for rs1061472). Conversely, GCLM rs3789453 and ATP7B rs1801243 appeared to play a protective role against excess weight in those exposed to copper (ORa = 0.20, p = 0.025, p interaction = 0.074 for rs3789453) and lead (ORa = 0.22, p = 0.092, p interaction = 0.089 for rs1801243). Our findings provide the first proof that interaction effects could exist between genetic variants within GSH and metal transporting systems and exposure to metal(loid)s, on excess body weight among Spanish children.

Explainable artificial intelligence to predict and identify prostate cancer tissue by gene expression.

BACKGROUND AND OBJECTIVE: Prostate cancer is one of the most prevalent forms of cancer in men worldwide. Traditional screening strategies such as serum PSA levels, which are not necessarily cancer-specific, or digital rectal exams, which are often inconclusive, are still the screening methods used for the disease. Some studies have focused on identifying biomarkers of the disease but none have been reported for diagnosis in routine clinical practice and few studies have provided tools to assist the pathologist in the decision-making process when analyzing prostate tissue. Therefore, a classifier is proposed to predict the occurrence of PCa that provides physicians with accurate predictions and understandable explanations. METHODS: A selection of 47 genes was made based on differential expression between PCa and normal tissue, GO gene ontology as well as the literature to be used as input predictors for different machine learning methods based on eXplainable Artificial Intelligence. These methods were trained using different class-balancing strategies to build accurate classifiers using gene expression data from 550 samples from 'The Cancer Genome Atlas'. Our model was validated in four external cohorts with different ancestries, totaling 463 samples. In addition, a set of SHapley Additive exPlanations was provided to help clinicians understand the underlying reasons for each decision. RESULTS: An in-depth analysis showed that the Random Forest algorithm combined with majority class downsampling was the best performing approach with robust statistical significance. Our method achieved an average sensitivity and specificity of 0.90 and 0.8 with an AUC of 0.84 across all databases. The relevance of DLX1, MYL9 and FGFR genes for PCa screening was demonstrated in addition to the important role of novel genes such as CAV2 and MYLK. CONCLUSIONS: This model has shown good performance in 4 independent external cohorts of different ancestries and the explanations provided are consistent with each other and with the literature, opening a horizon for its application in clinical practice. In the near future, these genes, in combination with our model, could be applied to liquid biopsy to improve PCa screening.

Genetic polymorphisms in ADRB1, ADRB2 and CYP2D6 genes and response to beta-blockers in patients with acute coronary syndrome.

Betablockers (BBs) are prescribed for ischaemia in patients with acute coronary syndrome (ACS). In Spain, bisoprolol and carvedilol are the most prescribed BBs, but patients often had to discontinue them due to adverse effects. Single nucleotide polymorphisms (SNPs) in ADRB1, ADRB2 and CYP2D6 genes have strong evidence of pharmacogenetic association with BBs in heart failure or hypertension, but the evidence in ACS is limited. Therefore, our study focuses on investigating how these genes influence the response to BBs in ACS patients. We analysed the association between SNPs in ADRB1 Gly389Arg (rs1801253) and Ser49Gly (rs1801252), ADRB2 Gly16Arg (rs1042713) and Glu27Gln (rs1042714), and CYP2D* 6 (*2- rs1080985, *4- rs3892097, *10 - rs1065852) and the occurrence of bradycardia/hypotension events during one year of follow-up. We performed an observational study and included 285 ACS-PCI-stent patients. A first analysis including patients treated with bisoprolol and a second analysis including patients treated with other BBs were performed. We found that the presence of the G allele (Glu) of the ADRB2 gene (rs1042714; Glu27Gln) conferred a protective effect against hypotension-induced by BBs; OR (CI 95%) = 0,14 (0,03-0,60), p < 0.01. The ADRB2 (rs1042713; Gly16Arg) GG genotype could also prevent hypotensive events; OR (CI 95%) = 0.49 (0.28-0.88), p = 0015. SNPs in ADRB1 and CYP2D6 * 2, CYP2D6 * 4 weren´t associated with primary events. The effect of CYP2D6 * 10 does not seem to be relevant for the response to BBs. According to our findings, SNPs in ADRB2 (rs1042713, rs1042714) could potentially affect the response and tolerance to BBs in ACS-patients. Further studies are necessary to clarify the impact of ADRB2 polymorphisms.

Genetic variants of antioxidant and xenobiotic metabolizing enzymes and their association with prostate cancer: A meta-analysis and functional in silico analysis.

The development and progression of prostate cancer (PCa) depends on complex interactions between genetic, environmental and dietary factors that modulate the carcinogenesis process. Interactions between chemical exposures and genetic polymorphisms in genes encoding xenobiotic metabolizing enzymes (XME), antioxidant enzymes and DNA repair enzymes have been reported as the main drivers of cancer. Thus, a better understanding of the causal risk factors for PCa will provide avenues to identify men at increased risk and will contribute to develop effective detection and prevention methods. We performed a meta-analysis on 17,518 cases and 42,507 controls obtained from 42 studies to determine whether seven SNPs and one CNV pertaining to oxidative stress, xenobiotic detoxification and DNA repair enzymes are associated with the risk of PCa (GPX1 (rs1050450), XRCC1 (rs25487), PON1 (rs662), SOD2 (rs4880), CAT (rs1001179), GSTP1 (rs1695) and CNV GSTM1). A significant increased risk of PCa was found for SOD2 (rs4880) ORGG+GA vs. AA 1.08; 95%CI 1.01-1.15, CAT (rs1001179) ORTT vs. TC+CC 1.39; 95%CI 1.17-1.66, PON1 (rs662) ORCT vs. CC+TT 1.17; 95%CI 1.01-1.35, GSTP1 (rs1695) ORGG vs. GA+AA 1.20; 95%CI 1.05-1.38 and GSTM1 (dual null vs. functional genotype) ORN vs. NN1+NN2 1.34; 95%CI 1.10-1.64. The meta-analysis showed that the CNV GSTM1, and the SNPs GSTP1 (rs1695) and CAT (rs1001179) are strongly associated with a greater risk of PCa and, to a lesser extent, the genetic variants SOD2 (rs4880) and PON1 (rs662). Although several antioxidant enzymes and XME play an important role in the PCa development, other risk factors such as chemical exposures should also be considered to gain insight on PCa risk. The functional in silico analysis showed that the genetic variants studied had no clinical implication regarding malignancy, except for GPX1 (rs1050450) SNP.

Genetic Polymorphisms in VEGFR Coding Genes (FLT1/KDR) on Ranibizumab Response in High Myopia and Choroidal Neovascularization Patients.

A severe form of myopia defined as pathologic/high myopia is the main cause of visual impairment and one of the most frequent causes of blindness worldwide. It is characterized by at least 6 diopters or axial length (AL) of eyeball > 26 mm and choroidal neovascularization (CNV) in 5 to 10% of cases. Ranibizumab is a humanized recombinant monoclonal antibody fragment targeted against human vascular endothelial growth factor A (VEGF-A) used in the treatment of CNV. It acts by preventing VEGF-A from interacting with its receptors (VEGFR-1 and -2) encoded by the FLT1 and KDR genes. Several studies found that the KDR and FLT1 genotypes may represent predictive determinants of efficacy in ranibizumab-treated neovascular age-related macular degeneration (nAMD) patients. We performed a retrospective study to evaluate the association of single nucleotide polymorphisms (SNPs) in VEGFR coding genes with the response rate to ranibizumab in patients with high myopia and CNV. In the association study of genotypes in FLT1 with the response to ranibizumab, we found a significant association between two FLT1 variants (rs9582036, rs7993418) with ranibizumab efficacy at the 12-month follow-up. About the KDR gene, we found that two KDR variants (rs2305948, rs2071559) are associated with best-corrected visual acuity (BCVA) improvement and KDR (rs2239702) is associated with lower rates of BCVA worsening considering a 12-month follow-up period.

Effects of genetic polymorphisms in body mass index according to dietary exposure to bisphenols and parabens.

A growing body of evidence supports that more than 900 single nucleotide polymorphisms (SNPs) and exposure to endocrine disrupting chemicals, such as bisphenols and parabens, are important contributors to the development of obesity. The aim of this study was to evaluate the way in which fat mass and obesity-associated gene (FTO) rs9939609 and leptin receptor (LEPR) rs9436303 variants contribute to variability in body mass index (BMI) according to estimated dietary exposure of bisphenols and parabens. This cross-sectional study included 101 Spanish participants (16-24 years). SNP genotyping assays were performed through quantitative PCRs (qPCRs) using Taqman® probes. Dietary exposure to bisphenols and parabens was calculated from food frequency questionnaire and chemical determination in food samples by ultra-high performance liquid chromatography-tandem mass spectrometry system. Linear regression models were conducted to address the association of genetic variants and BMI according to levels of bisphenols/parabens exposure. Risk G allele of LEPR rs9436303 was significantly positively associated with BMI (exp (ß) = 1.20, 95% CI: 1.04-1.38, p = 0.011). In participants highly exposed to bisphenols, the LEPR rs9436303 G allele was related to a significant increased BMI (exp (ß) = 1.27, 95% CI: 1.03-1.57, p = 0.024). A more relevant trend was observed with high exposure to parabens (exp (ß) = 1.33, 95% CI: 1.08-1.63, p = 0.009). We provide the first evidence that interaction between LEPR polymorphism and dietary intake of bisphenols and parabens may be responsible for an increased BMI, suggesting a potential effect in obesity. Moreover, we proposed LEPR rs9436303 as a genetic marker of susceptibility to excess weight induced by exposure.

Identification of MicroRNAs as Viable Aggressiveness Biomarkers for Prostate Cancer.

MiRNAs play a relevant role in PC (prostate cancer) by the regulation in the expression of several pathways' AR (androgen receptor), cellular cycle, apoptosis, MET (mesenchymal epithelium transition), or metastasis. Here, we report the role of several miRNAs' expression patterns, such as miR-93-5p, miR-23c, miR-210-3p, miR-221-3p, miR-592, miR-141, miR-375, and miR-130b, with relevance in processes like cell proliferation and MET. Using Trizol® extraction protocol and TaqMan™ specific probes for amplification, we performed miRNAs' analysis of 159 PC fresh tissues and 60 plasmas from peripheral blood samples. We had clinical data from all samples including PSA, Gleason, TNM, and D'Amico risk. Moreover, a bioinformatic analysis in TCGA (The Cancer Genome Atlas) was included to analyze the effect of the most relevant miRNAs according to aggressiveness in an extensive cohort (n = 531). We found that miR-210-3p, miR-23c, miR-592, and miR-93-5p are the most suitable biomarkers for PC aggressiveness and diagnosis, respectively. In fact, according with our results, miR-93-5p seems the most promising non-invasive biomarker for PC. To sum up, miR-210-3p, miR-23c, miR-592, and miR-93-5p miRNAs are suggested to be potential biomarkers for PC risk stratification that could be included in non-invasive strategies such as liquid biopsy in precision medicine for PC management.

Phylogenetic Analysis of the 2020 West Nile Virus (WNV) Outbreak in Andalusia (Spain).

During recent decades West Nile Virus (WNV) outbreaks have continuously occurred in the Mediterranean area. In August 2020 a new WNV outbreak affected 71 people with meningoencephalitis in Andalusia and six more cases were detected in Extremadura (south-west of Spain), causing a total of eight deaths. The whole genomes of four viruses were obtained and phylogenetically analyzed in the context of recent outbreaks. The Andalusian viral samples belonged to lineage 1 and were relatively similar to those of previous outbreaks which occurred in the Mediterranean region. Here we present a detailed analysis of the outbreak, including an extensive phylogenetic study. As part on this effort, we implemented a local Nextstrain server, which has become a constituent piece of regional epidemiological surveillance, wherein forthcoming genomes of environmental samples or, eventually, future outbreaks, will be included.