RESUMO
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.
RESUMO
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.
Assuntos
COVID-19 , Regiões Determinantes de Complementaridade , SARS-CoV-2 , Índice de Gravidade de Doença , Humanos , COVID-19/genética , COVID-19/imunologia , COVID-19/virologia , Masculino , Pessoa de Meia-Idade , Feminino , SARS-CoV-2/imunologia , SARS-CoV-2/genética , SARS-CoV-2/patogenicidade , Adulto , Idoso , Regiões Determinantes de Complementaridade/genética , Regiões Determinantes de Complementaridade/imunologia , Espanha , Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , AlelosRESUMO
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.
Assuntos
Compostos Benzidrílicos , Fator Neurotrófico Derivado do Encéfalo , Cognição , Disruptores Endócrinos , Fenóis , Polimorfismo de Nucleotídeo Único , Humanos , Criança , Fenóis/efeitos adversos , Compostos Benzidrílicos/efeitos adversos , Feminino , Masculino , Espanha , Cognição/efeitos dos fármacos , Disruptores Endócrinos/efeitos adversos , Fator Neurotrófico Derivado do Encéfalo/genética , Exposição Dietética/efeitos adversos , Receptores de Ocitocina/genética , Proteína 25 Associada a Sinaptossoma/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Receptor 5-HT2A de Serotonina/genética , Receptor trkB/genética , Alelos , Genótipo , Glicoproteínas de MembranaRESUMO
BACKGROUND AND OBJECTIVES: There is growing interest in the potential of telemedicine (TM) as an alternative to physical consultation. Although numerous studies prove the benefits of TM in rheumatology, there are no recommendations on its implementation in Spain. The aim of this study was to analyze the application of TM in rheumatology consultations in Spain. MATERIALS AND METHODS: Qualitative, cross-sectional, multicenter study with Delphi methodology in two rounds of queries. A structured ad hoc questionnaire was designed that included statements on teleconsultation, nursing teleconsultation, telecare, telerehabilitation, teleradiology, telehealth tele-education, main barriers, advantages and disadvantages of telehealth tele-education and TM in rheumatoid arthritis. The participants were rheumatology specialists practicing in Spain. RESULTS: The participating rheumatologists (Nâ¯=â¯80) had a mean age of 42.4 (±9.0) years, with 12.6 (±8.4) years of experience. Some of the aspects of TM that obtained the greatest consensus were: TM is useful for follow-up of some patients, to help determine if a face-to-face consultation is necessary, or to assist patients with rheumatoid arthritis if they present low activity or in remission; certain patients, such as those in their first consultation or those who present digital barriers or cognitive deterioration, should be seen face-to-face; TM presents some technical and patient access barriers; TM can be useful in nursing and in continued medical education. CONCLUSIONS: TM can be beneficial for the treatment and follow-up of patients with rheumatic diseases, as well as for alleviating the face-to-face care burden in rheumatology.
Assuntos
Técnica Delphi , Reumatologia , Telemedicina , Humanos , Estudos Transversais , Adulto , Feminino , Masculino , Espanha , Pessoa de Meia-Idade , Consenso , Artrite Reumatoide , Pesquisa Qualitativa , Inquéritos e QuestionáriosRESUMO
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 4â¯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.
Assuntos
Poluentes Ambientais , Estresse Oxidativo , Antígeno Prostático Específico , Neoplasias da Próstata , Xenobióticos , Masculino , Humanos , Neoplasias da Próstata/genética , Estresse Oxidativo/efeitos dos fármacos , Pessoa de Meia-Idade , Idoso , Poluentes Ambientais/urina , Poluentes Ambientais/toxicidade , Antígeno Prostático Específico/sangue , Estudos de Casos e Controles , Exposição Ambiental/efeitos adversos , Glutationa Transferase/genéticaAssuntos
Multiômica , Neoplasias da Próstata , Masculino , Humanos , Genômica , Neoplasias da Próstata/genéticaRESUMO
The valorization of fruit and vegetable residues (such as carrot discard) and their microbial conversion into 2,3-butanediol (BDO) can be considered as a very interesting way to reduce food waste and sustainably originate high value-added products. This work analyzes the valorization of carrot discard as feedstock for 2,3-butanediol (BDO) production by Paenibacillus polymyxa DSM 365. The influences of stirring and the presence of tryptone (nitrogen source) are studied. Furthermore, in order to evaluate the influence of the pre-culture medium (nitrogen source, nutrients, and pH) and the substrate, fermentation assays in simple and mixture semi-defined media (glucose, fructose, and/or galactose) were also carried out. As a result, 18.8 g/L BDO, with a BDO yield of 0.43 g/g (86% of its theoretical value), could be obtained from carrot discard enzymatic hydrolysate at 100 rpm, no tryptone, and pre-culture Häßler medium. No hydrothermal pre-treatment was necessary for BDO production from carrot discard, which increases the profitability of the process. Therefore, 18.8 g BDO, as well as 2.5 g ethanol and 2.1 g acetoin by-products, could be obtained from 100 g of carrot discard (dry matter).
RESUMO
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.
Assuntos
Inteligência Artificial , Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/genética , Sensibilidade e Especificidade , Expressão GênicaRESUMO
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.
Assuntos
Antioxidantes , Neoplasias da Próstata , Masculino , Humanos , Xenobióticos , Glutationa S-Transferase pi/genética , Genótipo , Neoplasias da Próstata/genética , Polimorfismo de Nucleotídeo Único , Predisposição Genética para Doença , Estudos de Casos e Controles , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética , Arildialquilfosfatase/genéticaRESUMO
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.
Assuntos
COVID-19 , Feminino , Humanos , COVID-19/genética , Enzima de Conversão de Angiotensina 2/genética , SARS-CoV-2/genética , Marcadores Genéticos , Bases de Dados Factuais , Serina Endopeptidases/genética , Proteínas de Resistência a MyxovirusRESUMO
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.
Assuntos
Metais Pesados , Metais , Humanos , Criança , Cobre , Genótipo , Polimorfismo de Nucleotídeo Único , Peso Corporal , Metais Pesados/urinaRESUMO
This work studied the effects of the inclusion of Purple Garlic Powder (PGP) and Oregano Essential Oil (OEO) in the feed, at different doses and combinations, on intestinal health and the growth performance of 140 and 3000 piglets, respectively, weaned at 21 days of age. Seven dietary treatments were used: a negative control group (basal diet), a positive control group with ZnO (3000 mg/Kg of feed), two groups with OEO at 0.4% and 1.2% respectively, two groups with PGP at 0.4% and 2% respectively and one group with OEO at 1.2% combined with PGP at 2%. Only the positive control group received ZnO in the diet. Each group of piglets received the treatment for seven weeks, from weaning, and were later sacrificed to obtain jejunum and ileum samples for counting of goblet cells, intraepithelial lymphocytes, and IgA-producing cells. The growth performance were measured at the beginning and at the end of the seven weeks. In jejunum and ileum, the number of goblet cells increased in the groups with ZnO, PGP 2%, OEO 1.2% and PGP 2% + OEO 1.2%, presenting significant differences with the rest of the groups. The results obtained for the intraepithelial lymphocyte count were in line with those obtained for the count of goblet cells. Regarding IgA-producing cells, the groups that showed significantly favourable results in the jejunum and ileum were OEO 1.2%, PGP 2% and their combination, but the groups that showed the most similar means to ZnO were the OEO 0.4% and the PGP 0.4%. Regarding the growth performance, PGP 2%, OEO 1.2% and their combination had similar results to ZnO. The intestinal health of piglets could be improved, without harming the growth performance, by means of the supplementation of PGP 2%, OEO 1.2% and PGP 2% + OEO 1.2% offering a natural alternative to the use of ZnO.
Assuntos
Alho , Óleos Voláteis , Origanum , Óxido de Zinco , Animais , Suínos , Suplementos Nutricionais , Óleos Voláteis/farmacologia , Pós , Desmame , Óxido de Zinco/farmacologia , Fazendas , Imunoglobulina A , Ração Animal/análiseRESUMO
Current evidence highlights the importance of the genetic component in obesity and neurodevelopmental disorders (attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD) and intellectual disability (ID)), given that these diseases have reported an elevated heritability. Additionally, environmental stressors, such as endocrine disrupting chemicals (EDCs) have been classified as obesogens, neuroendocrine disruptors, and microbiota disrupting chemicals (MDCs). For this reason, the importance of this work lies in examining two possible biological mechanistic pathways linking obesity and neurodevelopmental/behavioural disorders: EDCs - gene and EDCs - microbiota interactions. First, we summarise the shared mechanisms of action of EDCs and the common genetic profile in the bidirectional link between obesity and neurodevelopment. In relation to interaction models, evidence from the reviewed studies reveals significant interactions between pesticides/heavy metals and gene polymorphisms of detoxifying and neurotransmission systems and metal homeostasis on cognitive development, ASD and ADHD symptomatology. Nonetheless, available literature about obesity is quite limited. Importantly, EDCs have been found to induce gut microbiota changes through gut-brain-microbiota axis conferring susceptibility to obesity and neurodevelopmental disorders. In view of the lack of studies assessing the impact of EDCs - gene interactions and EDCs - mediated dysbiosis jointly in obesity and neurodevelopment, we support considering genetics, EDCs exposure, and microbiota as interactive factors rather than individual contributors to the risk for developing obesity and neurodevelopmental disabilities at the same time.
Assuntos
Transtorno do Espectro Autista , Disruptores Endócrinos , Microbioma Gastrointestinal , Metais Pesados , Praguicidas , Humanos , Disruptores Endócrinos/toxicidade , Transtorno do Espectro Autista/induzido quimicamente , Obesidade/induzido quimicamente , Exposição AmbientalRESUMO
This study examines (a) the influence of exercise, lifestyle behavior components (sedentary time, physical activity, and sleep and dietary patterns), and physical fitness on maternal weight gain, postpartum weight retention, and excessive gestational weight gain and (b) whether exercise protects against the adverse effects of impaired metabolism and nonoptimal body composition related to excessive gestational weight gain. Subjects were assigned to either a supervised concurrent (aerobic + resistance) exercise program followed 3 days/week (n = 47) or a control group (n = 54). Sedentary time, physical activity, sleep and dietary patterns (assessed by accelerometry and questionnaires), muscle strength (handgrip test), and cardiorespiratory fitness (Bruce test) were determined at gestational Weeks 16 and 33 (early-middle and late pregnancy, respectively), and at 6 weeks postpartum. Weight gain and weight retention were calculated using recorded weights at prepregnancy, early-middle, and late pregnancy, and at 6 weeks postpartum. Birth complications, maternal postpartum body composition, cardiometabolic, and inflammatory markers in maternal and umbilical cord arterial and venous blood, and in colostrum, and mature milk were also recorded. The exercise intervention reduced late weight gain (B = -2.7, SE = 0.83, p = .003) and weight retention (B = -2.85, SE = 1.3, p = .03), independent of any lifestyle behavior component or physical fitness, but did not prevent excessive weight gain. Increasing cardiorespiratory fitness, muscle strength, and sleep duration were associated with a smaller mean weight gain and lower excessive weight gain values (p < .05). Among the participants who experienced excessive weight gain, those who were exercisers had a lower body mass index and systemic tumor necrosis factor-alpha concentration, lower umbilical cord venous tumor necrosis factor-alpha and arterial interferon gamma levels, higher cord arterial interleukin-10 levels, and improved placental function compared with controls (p < .05). In summary, exercise may help optimize gestational weight gain and weight retention, and may attenuate the impaired phenotype related to excessive weight gain. Increasing cardiorespiratory fitness, muscle strength, and sleep duration might help to prevent excessive weight gain during pregnancy.
Assuntos
Ganho de Peso na Gestação , Humanos , Gravidez , Feminino , Interleucina-10 , Fator de Necrose Tumoral alfa , Interferon gama , Força da Mão , Placenta , Aumento de Peso , Exercício Físico/fisiologia , Índice de Massa Corporal , Aptidão Física , SobrepesoRESUMO
In this study, we have evaluated whether 57 genome-wide association studies (GWAS)-identified common variants for type 2 diabetes (T2D) influence the risk of developing prostate cancer (PCa) in a population of 304 Caucasian PCa patients and 686 controls. The association of selected single nucleotide polymorphisms (SNPs) with the risk of PCa was validated through meta-analysis of our data with those from the UKBiobank and FinnGen cohorts, but also previously published genetic studies. We also evaluated whether T2D SNPs associated with PCa risk could influence host immune responses by analysing their correlation with absolute numbers of 91 blood-derived cell populations and circulating levels of 103 immunological proteins and 7 steroid hormones. We also investigated the correlation of the most interesting SNPs with cytokine levels after in vitro stimulation of whole blood, peripheral mononuclear cells (PBMCs), and monocyte-derived macrophages with LPS, PHA, Pam3Cys, and Staphylococcus Aureus. The meta-analysis of our data with those from six large cohorts confirmed that each copy of the FTOrs9939609A, HNF1Brs7501939T, HNF1Brs757210T, HNF1Brs4430796G, and JAZF1rs10486567A alleles significantly decreased risk of developing PCa (p = 3.70 × 10-5, p = 9.39 × 10-54, p = 5.04 × 10-54, p = 1.19 × 10-71, and p = 1.66 × 10-18, respectively). Although it was not statistically significant after correction for multiple testing, we also found that the NOTCH2rs10923931T and RBMS1rs7593730 SNPs associated with the risk of developing PCa (p = 8.49 × 10-4 and 0.004). Interestingly, we found that the protective effect attributed to the HFN1B locus could be mediated by the SULT1A1 protein (p = 0.00030), an arylsulfotransferase that catalyzes the sulfate conjugation of many hormones, neurotransmitters, drugs, and xenobiotic compounds. In addition to these results, eQTL analysis revealed that the HNF1Brs7501939, HNF1Brs757210, HNF1Brs4430796, NOTCH2rs10923931, and RBMS1rs7593730 SNPs influence the risk of PCa through the modulation of mRNA levels of their respective genes in whole blood and/or liver. These results confirm that functional TD2-related variants influence the risk of developing PCa, but also highlight the need of additional experiments to validate our functional results in a tumoral tissue context.
RESUMO
OBJECTIVES: It is widely acknowledged that the experience of pain is promoted by both genetic susceptibility and environmental factors such as engaging in physical activity (PA), and that pain-related cognitions are also important. Thus, the purpose of the present study was to test the association of 64 polymorphisms (34 candidate genes) and the gene-gene, gene-PA and gene-sedentary behaviour interactions with pain and pain-related cognitions in women with FM. METHODS: Saliva samples from 274 women with FM [mean (s.d.) age 51.7 (7.7) years] were collected for extracting DNA. We measured PA and sedentary behaviour by accelerometers for a week, pain with algometry and questionnaires, and pain-related cognitions with questionnaires. To assess the robustness of the results, a meta-analysis was also performed. RESULTS: The rs6311 and rs6313 polymorphisms (5-hydroxytryptamine receptor 2A, HTR2A) were individually related to algometer scores. The interaction of rs4818 (catechol-O-methyltransferase, COMT) and rs1799971 (opioid receptor µ gene, OPRM1) was related to pain catastrophizing. Five gene-behaviour interactions were significant: the interactions of sedentary behaviour with rs1383914 (adrenoceptor alpha 1A, ADRA1A), rs6860 (charged multivesicular body protein 1A, CHMP1A), rs4680 (COMT), rs165599 (COMT) and rs12994338 (SCN9A) on bodily pain subscale of the Short Form 36. Furthermore, the meta-analysis showed an association between rs4680 (COMT) and severity of FM symptoms (codominant model, P-value 0.032). CONCLUSION: The HTR2A gene (individually), COMT and OPRM1 gene-gene interaction, and the interactions of sedentary behaviour with ADRA1A, CHMP1A, COMT and SCN9A genes were associated with pain-related outcomes. Collectively, findings from the present study indicate a modest contribution of genetics and gene-sedentary behaviour interaction to pain and pain catastrophizing in women with FM. Future research should examine whether reducing sedentary behaviour is particularly beneficial for reducing pain in women with genetic susceptibility to pain.
Assuntos
Catecol O-Metiltransferase , Fibromialgia , Catecol O-Metiltransferase/genética , Feminino , Fibromialgia/genética , Predisposição Genética para Doença , Genótipo , Humanos , Estilo de Vida , Pessoa de Meia-Idade , Canal de Sódio Disparado por Voltagem NAV1.7/genética , Dor , Polimorfismo de Nucleotídeo ÚnicoRESUMO
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.
Assuntos
Exposição Dietética , Parabenos , Adolescente , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Índice de Massa Corporal , Estudos Transversais , Exposição Dietética/análise , Humanos , Parabenos/análise , Parabenos/toxicidade , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
Background: Approximately 13.8% and 6.1% of coronavirus disease 2019 (COVID-19) patients require hospitalization and sometimes intensive care unit (ICU) admission, respectively. There is no biomarker to predict which of these patients will develop an aggressive stage that we could improve their quality of life and healthcare management. Our main goal is to include new markers for the classification of COVID-19 patients. Methods: Two tubes of peripheral blood were collected from a total of 66 (n = 34 mild and n = 32 severe) samples (mean age 52 years). Cytometry analysis was performed using a 15-parameter panel included in the Maxpar® Human Monocyte/Macrophage Phenotyping Panel Kit. Cytometry by time-of-flight mass spectrometry (CyTOF) panel was performed in combination with genetic analysis using TaqMan® probes for ACE2 (rs2285666), MX1 (rs469390), and TMPRSS2 (rs2070788) variants. GemStone™ and OMIQ software were used for cytometry analysis. Results: The frequency of CD163+/CD206- population of transitional monocytes (T-Mo) was decreased in the mild group compared to that of the severe one, while T-Mo CD163-/CD206- were increased in the mild group compared to that of the severe one. In addition, we also found differences in CD11b expression in CD14dim monocytes in the severe group, with decreased levels in the female group (p = 0.0412). When comparing mild and severe disease, we also found that CD45- [p = 0.014; odds ratio (OR) = 0.286, 95% CI 0.104-0.787] and CD14dim/CD33+ (p = 0.014; OR = 0.286, 95% CI 0.104-0.787) monocytes were the best options as biomarkers to discriminate between these patient groups. CD33 was also indicated as a good biomarker for patient stratification by the analysis of GemStone™ software. Among genetic markers, we found that G carriers of TMPRSS2 (rs2070788) have an increased risk (p = 0.02; OR = 3.37, 95% CI 1.18-9.60) of severe COVID-19 compared to those with A/A genotype. This strength is further increased when combined with CD45-, T-Mo CD163+/CD206-, and C14dim/CD33+. Conclusions: Here, we report the interesting role of TMPRSS2, CD45-, CD163/CD206, and CD33 in COVID-19 aggressiveness. This strength is reinforced for aggressiveness biomarkers when TMPRSS2 and CD45-, TMPRSS2 and CD163/CD206, and TMPRSS2 and CD14dim/CD33+ are combined.
Assuntos
COVID-19 , Qualidade de Vida , Humanos , Feminino , Pessoa de Meia-Idade , Antígenos CD/metabolismo , Receptores de Superfície Celular/metabolismo , Biomarcadores , Serina Endopeptidases/genética , Lectina 3 Semelhante a Ig de Ligação ao Ácido SiálicoRESUMO
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.