Exploring the role of genetic variability and exposure to bisphenols and parabens on excess body weight in Spanish children.

Gene-environment interaction studies are emerging as a promising tool to shed light on the reasons for the rapid increase in excess body weight (overweight and obesity). We aimed to investigate the influence of several polymorphisms on excess weight in Spanish children according to a short- and long-term exposure to bisphenols and parabens, combining individual approach with the joint effect of them. This case-control study included 144 controls and 98 cases children aged 3-12 years. Thirty SNPs in genes involved in obesity-related pathways, xenobiotic metabolism and hormone systems were genotyped using the GSA microchip technology and qPCRs with Taqman® probes. Levels of bisphenols and parabens in urine and hair were used to assess short- and long-term exposure, respectively, via UHPLC-MS/MS system. LEPR rs9436303 was identified as a relevant risk variant for excess weight (ORDom:AAvsAG+GG=2.65, p<0.001), and this effect persisted across exposure-stratified models. For long-term exposure, GPX1 rs1050450 was associated with increased excess weight at low single paraben exposure (ORGvsA=2.00, p=0.028, p-interaction=0.016), whereas LEPR rs1137101 exhibited a protective function at high co-exposure (ORDom:AAvsAG+GG=0.17, p=0.007, p-interaction=0.043). ESR2 rs3020450 (ORDom:GGvsAG+AA=5.17, p=0.020, p-interaction=0.028) and CYP2C19 rs4244285 (ORDom:GGvsAG+AA=3.54, p=0.039, p-interaction=0.285) were identified as predisposing variants at low and high co-exposure, respectively. In short-term exposure, higher odds were observed for INSIG2 rs7566605 at high bisphenol exposure (ORCvsG=2.97, p=0.035, p-interaction=0.017) and for GSTP1 rs1695 at low levels (ORDom:AAvsAG+GG=5.38, p=0.016, p-interaction=0.016). At low and medium co-exposure, SH2B1 rs7498665 (ORAvsG=0.17, p=0.015, p-interaction=0.085) and MC4R rs17782313 (ORAvsG=0.10, p=0.023, p-interaction=0.045) displayed a protective effect, whereas ESR2 rs3020450 maintained its contributing role (ORGvsA=3.12, p=0.030, p-interaction=0.010). Our findings demonstrate for the first time that understanding the genetic variation in excess weight and how the level of exposure to bisphenols and parabens might interact with it, is crucial for a more in-depth comprehension of the complex polygenic and multifactorial aetiology of overweight and obesity.

The T-cell repertoire of Spanish patients with COVID-19 as a strategy to link T-cell characteristics to the severity of the disease.

BACKGROUND: The architecture and dynamics of T cell populations are critical in orchestrating the immune response to SARS-CoV-2. In our study, we used T Cell Receptor sequencing (TCRseq) to investigate TCR repertoires in 173 post-infection COVID-19 patients. METHODS: The cohort included 98 mild and 75 severe cases with a median age of 53. We amplified and sequenced the TCR ß chain Complementary Determining Region 3 (CDR3b) and performed bioinformatic analyses to assess repertoire diversity, clonality, and V/J allelic usage between age, sex and severity groups. CDR3b amino acid sequence inference was performed by clustering structural motifs and filtering validated reactive CDR3b to COVID-19. RESULTS: Our results revealed a pronounced decrease in diversity and an increase in clonal expansion in the TCR repertoires of severe COVID-19 patients younger than 55 years old. These results reflect the observed trends in patients older than 55 years old (both mild and severe). In addition, we identified a significant reduction in the usage of key V alleles (TRBV14, TRBV19, TRBV15 and TRBV6-4) associated with disease severity. Notably, severe patients under 55 years old had allelic patterns that resemble those over 55 years old, accompanied by a skewed frequency of COVID-19-related motifs. CONCLUSIONS: Present results suggest that severe patients younger than 55 may have a compromised TCR repertoire contributing to a worse disease outcome.

Identification of SYNJ1 in a Complex Case of Juvenile Parkinsonism Using a Multiomics Approach.

This study aimed to elucidate the genetic causes underlying the juvenile parkinsonism (JP) diagnosed in a girl with several family members diagnosed with spinocerebellar ataxia type 2 (SCA2). To achieve this, whole-exome sequencing, analysis of CAG repeats, RNA sequencing analysis on fibroblasts, and metabolite identification were performed. As a result, a homozygous missense mutation SNP T>C (rs2254562) in synaptojamin 1 (SYNJ1), which has been implicated in the regulation of membrane trafficking in the synaptic vesicles, was identified. Additionally, we observed overexpression of L1 cell adhesion molecule (L1CAM), Cdc37, GPX1, and GPX4 and lower expression of ceruloplasmin in the patient compared to the control. We also found changes in sphingolipid, inositol, and inositol phosphate metabolism. These findings help to clarify the mechanisms of JP and suggest that the etiology of JP in the patient may be multifactorial. This is the first report of the rs2254562 mutation in the SYNJ gene identified in a JP patient with seizures and cognitive impairment.

Influence of Genetic Polymorphisms on Cognitive Function According to Dietary Exposure to Bisphenols in a Sample of Spanish Schoolchildren.

BACKGROUND: Neurodevelopmental disorders (NDDs) like intellectual disability (ID) are highly heritable, but the environment plays an important role. For example, endocrine disrupting chemicals (EDCs), including bisphenol A (BPA) and its analogues, have been termed neuroendocrine disruptors. This study aimed to evaluate the influence of different genetic polymorphisms (SNPs) on cognitive function in Spanish schoolchildren according to dietary bisphenol exposure. METHODS: A total of 102 children aged 6-12 years old were included. Ten SNPs in genes involved in brain development, synaptic plasticity, and neurotransmission (BDNF, NTRK2, HTR2A, MTHFR, OXTR, SLC6A2, and SNAP25) were genotyped. Then, dietary exposure to bisphenols (BPA plus BPS) was estimated and cognitive functions were assessed using the WISC-V Spanish form. RESULTS: BDNF rs11030101-T and SNAP25 rs363039-A allele carriers scored better on the fluid reasoning domain, except for those inheriting the BDNF rs6265-A allele, who had lower scores. Secondly, relevant SNP-bisphenol interactions existed in verbal comprehension (NTRK2 rs10868235 (p-int = 0.043)), working memory (HTR2A rs7997012 (p-int = 0.002), MTHFR rs1801133 (p-int = 0.026), and OXTR rs53576 (p-int = 0.030)) and fluid reasoning (SLC6A2 rs998424 (p-int = 0.004)). CONCLUSIONS: Our findings provide the first proof that exploring the synergistic or additive effects between genetic variability and bisphenol exposure on cognitive function could lead to a better understanding of the multifactorial and polygenic aetiology of NDDs.

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.

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.

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.

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.

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 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.

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.

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.

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.

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.

Genetic Polymorphisms Affecting Ranibizumab Response in High Myopia Patients.

High myopia is an ophthalmic pathology that affects half of the young adults in the United States and Europe and it is predicted that a third of the world's population could be nearsighted at the end of this decade. It is characterized by at least 6 diopters or axial length > 26 mm and, choroidal neovascularization (CNV) in 5 to 11% of cases. Ranibizumab is a recombinant humanized monoclonal antibody fragment. It is an anti-vascular endothelial growth factor (anti-VEGF) drug used in the treatment of CNV. Many genetic polymorphisms have been associated with interindividual differences in the response to ranibizumab, but these associations were not yet assessed among patients with high myopia and CNV. We performed a retrospective study assessing the association of genetic polymorphisms with response to ranibizumab in patients with CNV secondary to high myopia (mCNV). We included genetic polymorphisms previously associated with the response to drugs used in CNV patients (bevacizumab, ranibizumab, aflibercept, and photodynamic therapy (PDT)). We also included genetic variants in the VEGFA gene. Based on our results, ARMS2 (rs10490924) and CFH (rs1061170) are associated with response to ranibizumab in high myopia patients; and, included VEGFA genetic polymorphisms are not associated with ranibizumab response in our population but might be related to a higher risk of CNV.

Pharmacogenetic polymorphisms affecting bisoprolol response.

ß-blockers are commonly prescribed to treat multiple cardiovascular (CV) diseases, but, frequently, adverse drug reactions and intolerance limit their use in clinical practice. Interindividual variability in response to ß-blockers may be explained by genetic differences. In fact, pharmacogenetic interactions for some of these drugs have been widely studied, such as metoprolol. But studies that explore genetic variants affecting bisoprolol response are inconclusive, limited or confusing because of mixed results with other ß-Blockers, different genetic polymorphisms observed, endpoint studied etc. Because of this, we performed a systematic review in order to find relevant genetic variants affecting bisoprolol response. We have found genetic polymorphism in several genes, but most of the studies focused in ADRB variants. The ADRB1 Arg389Gly (rs1801253) was the most studied genetic polymorphism and it seems to influence the response to bisoprolol, although studies are inconclusive. Even, we performed a meta-analysis about its influence on systolic/diastolic blood pressure in patients treated with bisoprolol, but this did not show statistically significant results. In conclusion, many genetic polymorphisms have been assessed about their influence on patients´ response to bisoprolol and the ADRB1 Arg389Gly (rs1801253) seems the most relevant genetic polymorphism in this regard but results have not been confirmed with a meta-analysis. Our results support the need of further studies about the impact of genetic variants on bisoprolol response, considering different genetic polymorphisms and conducting single and multiple SNPs analysis, including other clinical parameters related to bisoprolol response in a multivariate study.

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.