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1.
Am J Hum Genet ; 2022 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-35568032

RESUMO

Metabolite levels measured in the human population are endophenotypes for biological processes. We combined sequencing data for 3,924 (whole-exome sequencing, WES, discovery) and 2,805 (whole-genome sequencing, WGS, replication) donors from a prospective cohort of blood donors in England. We used multiple approaches to select and aggregate rare genetic variants (minor allele frequency [MAF] < 0.1%) in protein-coding regions and tested their associations with 995 metabolites measured in plasma by using ultra-high-performance liquid chromatography-tandem mass spectrometry. We identified 40 novel associations implicating rare coding variants (27 genes and 38 metabolites), of which 28 (15 genes and 28 metabolites) were replicated. We developed algorithms to prioritize putative driver variants at each locus and used mediation and Mendelian randomization analyses to test directionality at associations of metabolite and protein levels at the ACY1 locus. Overall, 66% of reported associations implicate gene targets of approved drugs or bioactive drug-like compounds, contributing to drug targets' validating efforts.

2.
Hum Mol Genet ; 31(3): 347-361, 2022 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-34553764

RESUMO

Platelets play a key role in thrombosis and hemostasis. Platelet count (PLT) and mean platelet volume (MPV) are highly heritable quantitative traits, with hundreds of genetic signals previously identified, mostly in European ancestry populations. We here utilize whole genome sequencing (WGS) from NHLBI's Trans-Omics for Precision Medicine initiative (TOPMed) in a large multi-ethnic sample to further explore common and rare variation contributing to PLT (n = 61 200) and MPV (n = 23 485). We identified and replicated secondary signals at MPL (rs532784633) and PECAM1 (rs73345162), both more common in African ancestry populations. We also observed rare variation in Mendelian platelet-related disorder genes influencing variation in platelet traits in TOPMed cohorts (not enriched for blood disorders). For example, association of GP9 with lower PLT and higher MPV was partly driven by a pathogenic Bernard-Soulier syndrome variant (rs5030764, p.Asn61Ser), and the signals at TUBB1 and CD36 were partly driven by loss of function variants not annotated as pathogenic in ClinVar (rs199948010 and rs571975065). However, residual signal remained for these gene-based signals after adjusting for lead variants, suggesting that additional variants in Mendelian genes with impacts in general population cohorts remain to be identified. Gene-based signals were also identified at several genome-wide association study identified loci for genes not annotated for Mendelian platelet disorders (PTPRH, TET2, CHEK2), with somatic variation driving the result at TET2. These results highlight the value of WGS in populations of diverse genetic ancestry to identify novel regulatory and coding signals, even for well-studied traits like platelet traits.


Assuntos
Estudo de Associação Genômica Ampla , Medicina de Precisão , Plaquetas , Humanos , National Heart, Lung, and Blood Institute (U.S.) , Fenótipo , Polimorfismo de Nucleotídeo Único , Medicina de Precisão/métodos , Estados Unidos
3.
Nutrients ; 13(11)2021 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-34836419

RESUMO

Salicylic acid (SA) has observationally been shown to decrease colorectal cancer (CRC) risk. Aspirin (acetylsalicylic acid, that rapidly deacetylates to SA) is an effective primary and secondary chemopreventive agent. Through a Mendelian randomization (MR) approach, we aimed to address whether levels of SA affected CRC risk, stratifying by aspirin use. A two-sample MR analysis was performed using GWAS summary statistics of SA (INTERVAL and EPIC-Norfolk, N = 14,149) and CRC (CCFR, CORECT, GECCO and UK Biobank, 55,168 cases and 65,160 controls). The DACHS study (4410 cases and 3441 controls) was used for replication and stratification of aspirin-use. SNPs proxying SA were selected via three methods: (1) functional SNPs that influence the activity of aspirin-metabolising enzymes; (2) pathway SNPs present in enzymes' coding regions; and (3) genome-wide significant SNPs. We found no association between functional SNPs and SA levels. The pathway and genome-wide SNPs showed no association between SA and CRC risk (OR: 1.03, 95% CI: 0.84-1.27 and OR: 1.08, 95% CI: 0.86-1.34, respectively). Results remained unchanged upon aspirin use stratification. We found little evidence to suggest that an SD increase in genetically predicted SA protects against CRC risk in the general population and upon stratification by aspirin use.


Assuntos
Aspirina/uso terapêutico , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Ácido Salicílico/sangue , Estudos de Casos e Controles , Neoplasias Colorretais/sangue , Neoplasias Colorretais/prevenção & controle , Dieta , Feminino , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Masculino , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Ácido Salicílico/administração & dosagem
4.
Am J Hum Genet ; 108(10): 1836-1851, 2021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34582791

RESUMO

Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs.


Assuntos
Asma/epidemiologia , Biomarcadores/metabolismo , Dermatite Atópica/epidemiologia , Leucócitos/patologia , Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Locos de Características Quantitativas , Asma/genética , Asma/metabolismo , Asma/patologia , Dermatite Atópica/genética , Dermatite Atópica/metabolismo , Dermatite Atópica/patologia , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , National Heart, Lung, and Blood Institute (U.S.) , Fenótipo , Prognóstico , Proteoma/análise , Proteoma/metabolismo , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Reino Unido/epidemiologia , Estados Unidos/epidemiologia , Sequenciamento Completo do Genoma
5.
PLoS Med ; 18(9): e1003786, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34543281

RESUMO

BACKGROUND: Excess bodyweight and related metabolic perturbations have been implicated in kidney cancer aetiology, but the specific molecular mechanisms underlying these relationships are poorly understood. In this study, we sought to identify circulating metabolites that predispose kidney cancer and to evaluate the extent to which they are influenced by body mass index (BMI). METHODS AND FINDINGS: We assessed the association between circulating levels of 1,416 metabolites and incident kidney cancer using pre-diagnostic blood samples from up to 1,305 kidney cancer case-control pairs from 5 prospective cohort studies. Cases were diagnosed on average 8 years after blood collection. We found 25 metabolites robustly associated with kidney cancer risk. In particular, 14 glycerophospholipids (GPLs) were inversely associated with risk, including 8 phosphatidylcholines (PCs) and 2 plasmalogens. The PC with the strongest association was PC ae C34:3 with an odds ratio (OR) for 1 standard deviation (SD) increment of 0.75 (95% confidence interval [CI]: 0.68 to 0.83, p = 2.6 × 10-8). In contrast, 4 amino acids, including glutamate (OR for 1 SD = 1.39, 95% CI: 1.20 to 1.60, p = 1.6 × 10-5), were positively associated with risk. Adjusting for BMI partly attenuated the risk association for some-but not all-metabolites, whereas other known risk factors of kidney cancer, such as smoking and alcohol consumption, had minimal impact on the observed associations. A mendelian randomisation (MR) analysis of the influence of BMI on the blood metabolome highlighted that some metabolites associated with kidney cancer risk are influenced by BMI. Specifically, elevated BMI appeared to decrease levels of several GPLs that were also found inversely associated with kidney cancer risk (e.g., -0.17 SD change [ßBMI] in 1-(1-enyl-palmitoyl)-2-linoleoyl-GPC (P-16:0/18:2) levels per SD change in BMI, p = 3.4 × 10-5). BMI was also associated with increased levels of glutamate (ßBMI: 0.12, p = 1.5 × 10-3). While our results were robust across the participating studies, they were limited to study participants of European descent, and it will, therefore, be important to evaluate if our findings can be generalised to populations with different genetic backgrounds. CONCLUSIONS: This study suggests a potentially important role of the blood metabolome in kidney cancer aetiology by highlighting a wide range of metabolites associated with the risk of developing kidney cancer and the extent to which changes in levels of these metabolites are driven by BMI-the principal modifiable risk factor of kidney cancer.


Assuntos
Índice de Massa Corporal , Neoplasias Renais/sangue , Metaboloma , Obesidade/sangue , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Europa (Continente)/epidemiologia , Feminino , Humanos , Incidência , Neoplasias Renais/diagnóstico , Neoplasias Renais/epidemiologia , Neoplasias Renais/genética , Masculino , Análise da Randomização Mendeliana , Metabolômica , Pessoa de Meia-Idade , Obesidade/diagnóstico , Obesidade/epidemiologia , Obesidade/genética , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Vitória/epidemiologia
6.
BMJ Open Qual ; 10(3)2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34535456

RESUMO

Early mobilisation following cardiac surgery is vital for improved patient outcomes, as it has a positive effect on a patient's physical and psychological recovery following surgery. We observed that patients admitted to the cardiothoracic intensive care unit (CTICU) following cardiac surgery had only bed exercises and were confined to bed until the chest tubes were removed, which may have delayed patients achieving functional independence. Therefore, the CTICU team implemented a quality improvement (QI) project aimed at the early mobilisation of patients after cardiac surgery.A retrospective analysis was undertaken to define the current mobilisation practices in the CTICU. The multidisciplinary team identified various practice gaps and tested several changes that led to the implementation of a successful early mobility programme. The tests were carried out and reported using rapid cycle changes. A model for improvement methodology was used to run the project. The outcomes of the project were analysed using standard 'run chart rules' to detect changes in outcomes over time and Welch's t-test to assess the significance of these outcomes.This project was implemented in 2015. Patient compliance with early activity and mobilisation gradually reached 95% in 2016 and was sustained over the next 3 years. After the programme was implemented, the mean hours required for initiating out-of-bed-mobilisation was reduced from 22.77 hours to 11.74 hours. Similarly, functional independence measures and intensive care unit mobility scores also showed a statistically significant (p<0.005) improvement in patient transfers out of the CTICU.Implementing an early mobility programme for post-cardiac surgery patients is both safe and feasible. This QI project allowed for early activity and mobilisation, a substantial reduction in the number of hours required for initiating out-of-bed mobilisation following cardiac surgery, and facilitated the achievement of early ambulation and functional milestones in our patients.


Assuntos
Estado Funcional , Melhoria de Qualidade , Deambulação Precoce , Humanos , Unidades de Terapia Intensiva , Estudos Retrospectivos
7.
Revista Pesquisa em Fisioterapia ; 11(4): 702-710, 20210802. ilus, tab
Artigo em Inglês, Português | LILACS-Express | LILACS | ID: biblio-1348974

RESUMO

INTRODUÇÃO: A pandemia COVID-19 trouxe um impacto relativamente significativo no mundo. A Malásia implementou uma estratégia de isolamento social em todo o país para nivelar a curva da epidemia. À medida que os limites ao movimento e à interação social entraram em vigor, mais indivíduos parecem menos ativos fisicamente. OBJETIVO: determinar as barreiras percebidas para a atividade física entre jovens adultos da Malásia durante a pandemia de COVID-19. MÉTODOS E MATERIAIS: Total de 217 participantes incluídos na faixa etária de 18 a 40 anos participaram voluntariamente deste estudo. Os participantes foram excluídos se não fossem malaios e apresentassem quaisquer problemas psicológicos e deficiência física que impedissem a atividade física. O questionário Barrier to Being Active (BBAQ) foi distribuído por várias plataformas de mídia social de janeiro de 2021 a maio de 2021. Os dados categóricos foram apresentados usando frequência simples e absoluta na distribuição de perfis sociodemográficos e respostas do BBAQ. Qui-quadrado de Pearson com nível de confiança de 95%, p <0,05 foi utilizado como nível de significância para analisar a associação entre gênero e barreiras. RESULTADOS: A barreira relatada pelos participantes foi "falta de força de vontade" 136 (62,7%), seguida de "falta de energia" 117 (53,9%), "falta de recursos" 113 (52,1%), "falta de tempo", 109 (50,2%), "influência social" 100 (46,1%), "falta de habilidade" 48 (22,1%) e "medo de se machucar" 40 (18,4%). Não houve relação significativa entre gênero e barreira à atividade física entre jovens adultos da Malásia. CONCLUSÃO: A "falta de energia", "falta de força de vontade" e "falta de recursos" foram as barreiras mais percebidas para a atividade física entre jovens adultos da Malásia durante o confinamento por causa da COVID-19. Não houve associação significativa entre as barreiras de atividade física e o gênero.


INTRODUCTION: The COVID-19 pandemic has had a relatively significant impact on the world. Malaysia implemented a countrywide social isolation strategy to flatten the epidemic curve. As limits on movement and social interaction have come into force, more individuals appear less physically active. OBJECTIVE: To determine the perceived barriers to physical activity among Malaysian young adults during the COVID-19 Pandemic. METHODS AND MATERIALS: A total of 217 participants included with age group from 18-40 years old voluntarily participated in this study. Participants were excluded if they were non-Malaysian and had any psychological problems and physical impairment that hindered physical activity. The barrier to Being Active quiz (BBAQ) questionnaire was circulated through various social media platforms from January 2021 to May 2021. Categorical data were presented using simple and absolute frequency on the distribution of sociodemographic profiles and BBAQ responses. Pearson Chi-square with 95% confidence level, p<0.05, was used as the significant level to analyze the association between gender and barriers. RESULTS: The barrier reported by the participants was "lack of willpower" 136 (62.7%), followed by "lack of energy" 117(53.9%), "lack of resource" 113(52.1%), "Lack of time," 109(50.2%), "social influence" 100(46.1%), "lack of skill" 48(22.1%) and "fear of injury" 40(18.4%). There was no significant relationship between gender and Barrier to Physical Activity among Malaysian young adults. CONCLUSION: The "lack of energy," "lack of willpower," and "lack of resource" were the most perceived barriers to physical activity among Malaysian young adults during COVID-19 lockdown, and there was no significant association between physical activity barriers and gender.

9.
Nat Med ; 27(4): 668-676, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33837377

RESUMO

Drug repurposing provides a rapid approach to meet the urgent need for therapeutics to address COVID-19. To identify therapeutic targets relevant to COVID-19, we conducted Mendelian randomization analyses, deriving genetic instruments based on transcriptomic and proteomic data for 1,263 actionable proteins that are targeted by approved drugs or in clinical phase of drug development. Using summary statistics from the Host Genetics Initiative and the Million Veteran Program, we studied 7,554 patients hospitalized with COVID-19 and >1 million controls. We found significant Mendelian randomization results for three proteins (ACE2, P = 1.6 × 10-6; IFNAR2, P = 9.8 × 10-11 and IL-10RB, P = 2.3 × 10-14) using cis-expression quantitative trait loci genetic instruments that also had strong evidence for colocalization with COVID-19 hospitalization. To disentangle the shared expression quantitative trait loci signal for IL10RB and IFNAR2, we conducted phenome-wide association scans and pathway enrichment analysis, which suggested that IFNAR2 is more likely to play a role in COVID-19 hospitalization. Our findings prioritize trials of drugs targeting IFNAR2 and ACE2 for early management of COVID-19.


Assuntos
COVID-19/genética , Reposicionamento de Medicamentos , Análise da Randomização Mendeliana/métodos , SARS-CoV-2 , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/fisiologia , COVID-19/tratamento farmacológico , Estudo de Associação Genômica Ampla , Humanos , Subunidade beta de Receptor de Interleucina-10/genética , Subunidade beta de Receptor de Interleucina-10/fisiologia , Locos de Características Quantitativas , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/fisiologia
10.
Am J Hum Genet ; 108(5): 874-893, 2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-33887194

RESUMO

Whole-genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci, which have not been reported previously. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, and G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3 bp indel p.Lys2169del (g.88717175_88717177TCT[4]) (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis (MIM: 194380), associated with higher mean corpuscular hemoglobin concentration (MCHC). In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders.


Assuntos
Eritrócitos/metabolismo , Eritrócitos/patologia , Estudo de Associação Genômica Ampla , National Heart, Lung, and Blood Institute (U.S.)/organização & administração , Fenótipo , Adulto , Idoso , Cromossomos Humanos Par 16/genética , Conjuntos de Dados como Assunto , Feminino , Edição de Genes , Variação Genética/genética , Células HEK293 , Humanos , Masculino , Pessoa de Meia-Idade , Controle de Qualidade , Reprodutibilidade dos Testes , Estados Unidos
12.
Commun Biol ; 4(1): 156, 2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33536631

RESUMO

Iron is essential for many biological functions and iron deficiency and overload have major health implications. We performed a meta-analysis of three genome-wide association studies from Iceland, the UK and Denmark of blood levels of ferritin (N = 246,139), total iron binding capacity (N = 135,430), iron (N = 163,511) and transferrin saturation (N = 131,471). We found 62 independent sequence variants associating with iron homeostasis parameters at 56 loci, including 46 novel loci. Variants at DUOX2, F5, SLC11A2 and TMPRSS6 associate with iron deficiency anemia, while variants at TF, HFE, TFR2 and TMPRSS6 associate with iron overload. A HBS1L-MYB intergenic region variant associates both with increased risk of iron overload and reduced risk of iron deficiency anemia. The DUOX2 missense variant is present in 14% of the population, associates with all iron homeostasis biomarkers, and increases the risk of iron deficiency anemia by 29%. The associations implicate proteins contributing to the main physiological processes involved in iron homeostasis: iron sensing and storage, inflammation, absorption of iron from the gut, iron recycling, erythropoiesis and bleeding/menstruation.


Assuntos
Anemia Ferropriva/genética , Loci Gênicos , Variação Genética , Sobrecarga de Ferro/genética , Ferro/sangue , Anemia Ferropriva/sangue , Anemia Ferropriva/diagnóstico , Biomarcadores/sangue , Dinamarca , Ferritinas/sangue , Estudo de Associação Genômica Ampla , Genótipo , Homeostase , Humanos , Islândia , Sobrecarga de Ferro/sangue , Sobrecarga de Ferro/diagnóstico , Fenótipo , Medição de Risco , Fatores de Risco , Transferrina/metabolismo , Reino Unido
13.
Nat Genet ; 53(1): 54-64, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33414548

RESUMO

In cross-platform analyses of 174 metabolites, we identify 499 associations (P < 4.9 × 10-10) characterized by pleiotropy, allelic heterogeneity, large and nonlinear effects and enrichment for nonsynonymous variation. We identify a signal at GLP2R (p.Asp470Asn) shared among higher citrulline levels, body mass index, fasting glucose-dependent insulinotropic peptide and type 2 diabetes, with ß-arrestin signaling as the underlying mechanism. Genetically higher serine levels are shown to reduce the likelihood (by 95%) and predict development of macular telangiectasia type 2, a rare degenerative retinal disease. Integration of genomic and small molecule data across platforms enables the discovery of regulators of human metabolism and translation into clinical insights.


Assuntos
Saúde , Metabolismo/genética , Diabetes Mellitus Tipo 2/genética , Oftalmopatias/genética , Frequência do Gene/genética , Loci Gênicos , Pleiotropia Genética , Genoma Humano , Receptor do Peptídeo Semelhante ao Glucagon 2/genética , Glicina/metabolismo , Humanos , Modelos Lineares , Análise da Randomização Mendeliana , Erros Inatos do Metabolismo/genética , Metaboloma/genética , Mutação de Sentido Incorreto/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Telangiectasia Retiniana/genética , Tamanho da Amostra , Serina/metabolismo
14.
Indian J Crit Care Med ; 24(10): 905-913, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33281313

RESUMO

BACKGROUND: With the Wuhan pandemic spread to India, more than lakhs of population were affected with COVID-19 with varying severities. Physiotherapists participated as frontline workers to contribute to management of patients in COVID-19 in reducing morbidity of these patients and aiding them to road to recovery. With infrastructure and patient characteristics different from the West and lack of adequate evidence to existing practices, there was a need to formulate a national consensus. MATERIALS AND METHODS: Recommendations were formulated with a systematic literature search and feedback of physiotherapist experiences. Expert consensus was obtained using a modified Delphi method. RESULTS: The intraclass coefficient of agreement between the experts was 0.994, significant at p < 0.001. CONCLUSION: This document offers physiotherapy evidence-based consensus and recommendation to planning physiotherapy workforce, assessment, chest physiotherapy, early mobilization, preparation for discharge planning, and safety for patients and therapist in acutec are COVID 19 setup of India. The recommendations have been integrated in the algorithm and are intended to use by all physiotherapists and other stakeholders in management of patients with COVID-19 in acute care settings. HOW TO CITE THIS ARTICLE: Jiandani MP, Agarwal B, Baxi G, Kale S, Pol T, Bhise A, et al. Evidence-based National Consensus: Recommendations for Physiotherapy Management in COVID-19 in Acute Care Indian Setup. Indian J Crit Care Med 2020;24(10):905-913.

15.
Nat Genet ; 52(12): 1314-1332, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33230300

RESUMO

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10-8), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.


Assuntos
Pressão Sanguínea/genética , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Hipertensão/genética , Fator de Transcrição GATA5/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Mutação/genética , Fosfolipase C beta/genética , Polimorfismo de Nucleotídeo Único/genética
16.
J Assoc Physicians India ; 68(12): 82-89, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33247653

RESUMO

Post COVID-19 sequelae includes breathlessness, weakness, fatigue, decreased exercise tolerance and impaired quality of life. Physiotherapy based rehabilitation program is an essential component for post COVID-19 patients in facilitating maximum functional recovery. Expert consensus statements are available from the developed countries. There is a need for a guidelines to manage post COVID-19 sequelae in Indian context. The objective of this consensus statement is to provide evidence informed guidelines for post COVID-19 physiotherapy management as a component of pulmonary rehabilitation. This consensus statement was developed by expert panel across India. Published literatures were appraised and used to prepare the recommendations. This is the first of its kind of work providing preliminary guidelines for post COVID-19 physiotherapy.


Assuntos
Infecções por Coronavirus , Pandemias , Modalidades de Fisioterapia , Pneumonia Viral , Qualidade de Vida , Terapia Respiratória , Betacoronavirus , COVID-19 , Consenso , Humanos , Índia , Guias de Prática Clínica como Assunto , SARS-CoV-2
17.
Mol Psychiatry ; 25(10): 2392-2409, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-30617275

RESUMO

Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10-8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10-8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10-3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.


Assuntos
Loci Gênicos , Fumar/genética , Bancos de Espécimes Biológicos , Bases de Dados Factuais , Europa (Continente)/etnologia , Exoma , Feminino , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Reino Unido
18.
Bioinformatics ; 35(22): 4851-4853, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31233103

RESUMO

SUMMARY: PhenoScanner is a curated database of publicly available results from large-scale genetic association studies in humans. This online tool facilitates 'phenome scans', where genetic variants are cross-referenced for association with many phenotypes of different types. Here we present a major update of PhenoScanner ('PhenoScanner V2'), including over 150 million genetic variants and more than 65 billion associations (compared to 350 million associations in PhenoScanner V1) with diseases and traits, gene expression, metabolite and protein levels, and epigenetic markers. The query options have been extended to include searches by genes, genomic regions and phenotypes, as well as for genetic variants. All variants are positionally annotated using the Variant Effect Predictor and the phenotypes are mapped to Experimental Factor Ontology terms. Linkage disequilibrium statistics from the 1000 Genomes project can be used to search for phenotype associations with proxy variants. AVAILABILITY AND IMPLEMENTATION: PhenoScanner V2 is available at www.phenoscanner.medschl.cam.ac.uk.


Assuntos
Genoma , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Desequilíbrio de Ligação , Fenótipo , Polimorfismo de Nucleotídeo Único , Software
19.
Nat Commun ; 10(1): 1060, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30837465

RESUMO

Circulating levels of glycine have previously been associated with lower incidence of coronary heart disease (CHD) and type 2 diabetes (T2D) but it remains uncertain if glycine plays an aetiological role. We present a meta-analysis of genome-wide association studies for glycine in 80,003 participants and investigate the causality and potential mechanisms of the association between glycine and cardio-metabolic diseases using genetic approaches. We identify 27 genetic loci, of which 22 have not previously been reported for glycine. We show that glycine is genetically associated with lower CHD risk and find that this may be partly driven by blood pressure. Evidence for a genetic association of glycine with T2D is weaker, but we find a strong inverse genetic effect of hyperinsulinaemia on glycine. Our findings strengthen evidence for a protective effect of glycine on CHD and show that the glycine-T2D association may be driven by a glycine-lowering effect of insulin resistance.


Assuntos
Doença das Coronárias/genética , Diabetes Mellitus Tipo 2/genética , Glicina/sangue , Hiperinsulinismo/genética , Redes e Vias Metabólicas/genética , Doença das Coronárias/sangue , Doença das Coronárias/epidemiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Glicina/metabolismo , Humanos , Hiperinsulinismo/sangue , Hiperinsulinismo/epidemiologia , Incidência , Polimorfismo de Nucleotídeo Único
20.
Nat Genet ; 51(1): 51-62, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30578418

RESUMO

In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.


Assuntos
Pressão Sanguínea/genética , /genética , Adolescente , Animais , Feminino , Expressão Gênica/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Túbulos Renais/fisiologia , Masculino , Camundongos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Transcriptoma/genética , Regulação para Cima/genética
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