RESUMO
Latin America continues to be severely underrepresented in genomics research, and fine-scale genetic histories and complex trait architectures remain hidden owing to insufficient data1. To fill this gap, the Mexican Biobank project genotyped 6,057 individuals from 898 rural and urban localities across all 32 states in Mexico at a resolution of 1.8 million genome-wide markers with linked complex trait and disease information creating a valuable nationwide genotype-phenotype database. Here, using ancestry deconvolution and inference of identity-by-descent segments, we inferred ancestral population sizes across Mesoamerican regions over time, unravelling Indigenous, colonial and postcolonial demographic dynamics2-6. We observed variation in runs of homozygosity among genomic regions with different ancestries reflecting distinct demographic histories and, in turn, different distributions of rare deleterious variants. We conducted genome-wide association studies (GWAS) for 22 complex traits and found that several traits are better predicted using the Mexican Biobank GWAS compared to the UK Biobank GWAS7,8. We identified genetic and environmental factors associating with trait variation, such as the length of the genome in runs of homozygosity as a predictor for body mass index, triglycerides, glucose and height. This study provides insights into the genetic histories of individuals in Mexico and dissects their complex trait architectures, both crucial for making precision and preventive medicine initiatives accessible worldwide.
Assuntos
Bancos de Espécimes Biológicos , Genética Médica , Genoma Humano , Genômica , Hispânico ou Latino , Humanos , Glicemia/genética , Glicemia/metabolismo , Estatura/genética , Índice de Massa Corporal , Interação Gene-Ambiente , Marcadores Genéticos/genética , Estudo de Associação Genômica Ampla , Hispânico ou Latino/classificação , Hispânico ou Latino/genética , Homozigoto , México , Fenótipo , Triglicerídeos/sangue , Triglicerídeos/genética , Reino Unido , Genoma Humano/genéticaRESUMO
Infectious agents contribute significantly to the global burden of diseases through both acute infection and their chronic sequelae. We leveraged the UK Biobank to identify genetic loci that influence humoral immune response to multiple infections. From 45 genome-wide association studies in 9,611 participants from UK Biobank, we identified NFKB1 as a locus associated with quantitative antibody responses to multiple pathogens, including those from the herpes, retro-, and polyoma-virus families. An insertion-deletion variant thought to affect NFKB1 expression (rs28362491), was mapped as the likely causal variant and could play a key role in regulation of the immune response. Using 121 infection- and inflammation-related traits in 487,297 UK Biobank participants, we show that the deletion allele was associated with an increased risk of infection from diverse pathogens but had a protective effect against allergic disease. We propose that altered expression of NFKB1, as a result of the deletion, modulates hematopoietic pathways and likely impacts cell survival, antibody production, and inflammation. Taken together, we show that disruptions to the tightly regulated immune processes may tip the balance between exacerbated immune responses and allergy, or increased risk of infection and impaired resolution of inflammation.
Assuntos
Predisposição Genética para Doença , Hipersensibilidade , Inflamação , Humanos , Estudo de Associação Genômica Ampla , Hipersensibilidade/genética , Inflamação/genética , Subunidade p50 de NF-kappa B/genética , Biobanco do Reino UnidoRESUMO
Genetic studies of disease progression can be used to identify factors that may influence survival or prognosis, which may differ from factors that influence on disease susceptibility. Studies of disease progression feed directly into therapeutics for disease, whereas studies of incidence inform prevention strategies. However, studies of disease progression are known to be affected by collider (also known as "index event") bias since the disease progression phenotype can only be observed for individuals who have the disease. This applies equally to observational and genetic studies, including genome-wide association studies and Mendelian randomisation (MR) analyses. In this paper, our aim is to review several statistical methods that can be used to detect and adjust for index event bias in studies of disease progression, and how they apply to genetic and MR studies using both individual- and summary-level data. Methods to detect the presence of index event bias include the use of negative controls, a comparison of associations between risk factors for incidence in individuals with and without the disease, and an inspection of Miami plots. Methods to adjust for the bias include inverse probability weighting (with individual-level data), or Slope-Hunter and Dudbridge et al.'s index event bias adjustment (when only summary-level data are available). We also outline two approaches for sensitivity analysis. We then illustrate how three methods to minimise bias can be used in practice with two applied examples. Our first example investigates the effects of blood lipid traits on mortality from coronary heart disease, while our second example investigates genetic associations with breast cancer mortality.
Assuntos
Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Humanos , Viés , Fatores de Risco , Fenótipo , Análise da Randomização Mendeliana/métodos , Progressão da DoençaRESUMO
BACKGROUND: Human papilloma virus infection is known to influence oropharyngeal cancer (OPC) risk, likely via sexual transmission. However, sexual behaviour has been correlated with other risk factors including smoking and alcohol, meaning independent effects are difficult to establish. We aimed to evaluate the causal effect of sexual behaviour on the risk of OPC using Mendelian randomization (MR). METHODS: Genetic variants robustly associated with age at first sex (AFS) and the number of sexual partners (NSP) were used to perform both univariable and multivariable MR analyses with summary data on 2641 OPC cases and 6585 controls, obtained from the largest available genome-wide association studies (GWAS). Given the potential for genetic pleiotropy, we performed a number of sensitivity analyses: (i) MR methods to account for horizontal pleiotropy, (ii) MR of sexual behaviours on positive (cervical cancer and seropositivity for Chlamydia trachomatis) and negative control outcomes (lung and oral cancer), (iii) Causal Analysis Using Summary Effect estimates (CAUSE), to account for correlated and uncorrelated horizontal pleiotropic effects, (iv) multivariable MR analysis to account for the effects of smoking, alcohol, risk tolerance and educational attainment. RESULTS: In univariable MR, we found evidence supportive of an effect of both later AFS (IVW OR = 0.4, 95%CI (0.3, 0.7), per standard deviation (SD), p = < 0.001) and increasing NSP (IVW OR = 2.2, 95%CI (1.3, 3.8) per SD, p = < 0.001) on OPC risk. These effects were largely robust to sensitivity analyses accounting for horizontal pleiotropy. However, negative control analysis suggested potential violation of the core MR assumptions and subsequent CAUSE analysis implicated pleiotropy of the genetic instruments used to proxy sexual behaviours. Finally, there was some attenuation of the univariable MR results in the multivariable models (AFS IVW OR = 0.7, 95%CI (0.4, 1.2), p = 0.21; NSP IVW OR = 0.9, 95%CI (0.5 1.7), p = 0.76). CONCLUSIONS: Despite using genetic variants strongly related sexual behaviour traits in large-scale GWAS, we found evidence for correlated pleiotropy. This emphasizes a need for multivariable approaches and the triangulation of evidence when performing MR of complex behavioural traits.
Assuntos
Análise da Randomização Mendeliana , Neoplasias Orofaríngeas , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana/métodos , Neoplasias Orofaríngeas/epidemiologia , Neoplasias Orofaríngeas/genética , Polimorfismo de Nucleotídeo Único , Comportamento Sexual , Fumar/efeitos adversos , Fumar/epidemiologiaRESUMO
OBJECTIVES: emergency department interventions for frailty (EDIFY) delivers frailty-centric interventions at the emergency department (ED). We evaluated the effectiveness of a multicomponent frailty intervention (MFI) in improving functional outcomes among older persons. DESIGN: a quasi-experimental study. SETTING: a 30-bed ED observation unit within a 1,700-bed acute tertiary hospital. PARTICIPANTS: patients aged ≥65 years, categorised as Clinical Frailty Scale 4-6, and planned for discharge from the unit. METHODS: we compared patients receiving the MFI versus usual-care. Data on demographics, function, frailty, sarcopenia, comorbidities and medications were gathered. Our primary outcome was functional status-Modified Barthel Index (MBI) and Lawton's iADL. Secondary outcomes include hospitalisation, ED re-attendance, mortality, frailty, sarcopenia, polypharmacy and falls. Follow-up assessments were at 3, 6 and 12 months. RESULTS: we recruited 140 participants (mean age 79.7 ± 7.6 years; 47% frail and 73.6% completed the study). Baseline characteristics between groups were comparable (each n = 70). For the intervention group, MBI scores were significantly higher at 6 months (mean: 94.5 ± 11.2 versus 88.5 ± 19.5, P = 0.04), whereas Lawton's iADL scores experienced less decline (change-in-score: 0.0 ± 1.7 versus -1.1 ± 1.8, P = 0.001). Model-based analyses revealed greater odds of maintaining/improving MBI in the intervention group at 6 months [odds ratio (OR) 2.51, 95% confidence interval (CI) 1.04-6.03, P = 0.04] and 12 months (OR 2.98, 95% CI 1.18-7.54, P = 0.02). This was similar for Lawton's iADL at 12 months (OR 4.01, 95% CI 1.70-9.48, P = 0.002). ED re-attendances (rate ratio 0.35, 95% CI 0.13-0.90, P = 0.03) and progression to sarcopenia (OR 0.19, 95% CI 0.04-0.94, P = 0.04) were also lower at 6 months. CONCLUSIONS: the MFI delivered to older persons at the ED can possibly improve functional outcomes and reduce ED re-attendances while attenuating sarcopenia progression.
Assuntos
Fragilidade , Sarcopenia , Idoso , Idoso de 80 Anos ou mais , Serviço Hospitalar de Emergência , Fragilidade/diagnóstico , Fragilidade/terapia , Avaliação Geriátrica , Hospitalização , Humanos , Sarcopenia/diagnóstico , Sarcopenia/terapiaRESUMO
The reduction in body mass index standard deviation score (BMI-SDS) associated with improvement in biomarkers relating to metabolic health in obese children is unknown. We aimed to establish the change in BMI-SDS associated with improved inflammation, liver function, and insulin resistance to inform clinical guidelines for pediatric weight management interventions and to assess the efficacy of future trials. A large-scale systematic review was conducted to identify relevant studies. Studies of children with a diagnosis of obesity according to defined BMI thresholds, participating in lifestyle interventions to reduce obesity, were included. Studies must have reported baseline (pre-) and postintervention (or change of) BMI-SDS and either fasting glucose, homeostatic model of insulin resistance (HOMA-IR), alanine aminotransferase (ALT), C-reactive protein (CRP), or interleukin-6 (IL-6). A series of meta-regressions were conducted to establish links between BMI-SDS change scores and change in metabolic markers of health. Sixty-eight articles were identified. From the meta-regression analyses, across all study subsets, greater mean falls in all four parameters, (HOMA-IR, Glucose, ALT, and CRP) were observed with greater mean loss of BMI-SDS, but the trends were only statistically significant for HOMA-IR and CRP (P = .003; P = .021). However, we could not find minimum changes in BMI-SDS that would ensure a fall in these outcomes. At this time, we are unable to recommend a definitive value of BMI-SDS reduction needed to improve the markers of metabolic health. Future trials should aim to report additional indices of derived BMI values, which may better reflect changes in actual adiposity.
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Índice de Massa Corporal , Obesidade/terapia , Comportamento de Redução do Risco , Programas de Redução de Peso/normas , Humanos , Obesidade/sangueRESUMO
The major histocompatibility complex (MHC) is a key genomic model region for understanding the evolution of gene families and the co-evolution between host and pathogen. To date, MHC studies have mostly focused on species from major vertebrate lineages. The evolution of MHC classical (Ia) and non-classical (Ib) genes in pigs has attracted interest because of their antigen presentation roles as part of the adaptive immune system. The pig family Suidae comprises over 18 extant species (mostly wild), but only the domestic pig has been extensively sequenced and annotated. To address this, we used a DNA-capture approach, with probes designed from the domestic pig genome, to generate MHC data for 11 wild species of pigs and their closest living family, Tayassuidae. The approach showed good efficiency for wild pigs (~80% reads mapped, ~87× coverage), compared to tayassuids (~12% reads mapped, ~4× coverage). We retrieved 145 MHC loci across both families. Phylogenetic analyses show that the class Ia and Ib genes underwent multiple duplications and diversifications before suids and tayassuids diverged from their common ancestor. The histocompatibility genes mostly form orthologous groups and there is genetic differentiation for most of these genes between Eurasian and sub-Saharan African wild pigs. Tests of selection showed that the peptide-binding region of class Ib genes was under positive selection. These findings contribute to better understanding of the evolutionary history of the MHC, specifically, the class I genes, and provide useful data for investigating the immune response of wild populations against pathogens.
Assuntos
Artiodáctilos/genética , Complexo Principal de Histocompatibilidade/genética , Suínos/genética , Animais , Sequência de Bases , Evolução Biológica , Hibridização Genômica Comparativa/métodos , Evolução Molecular , Genes MHC Classe I , Genoma , Filogenia , Análise de Sequência de DNA/métodosRESUMO
Endogenous retroviruses (ERVs) are one of many families of transposable elements present in vertebrate genomes. We have examined the ERV complement of the freshwater crocodile (Crocodylus johnstoni) in order to investigate the diversity of ERVs present and possibility of ERV or retroviral activity in a diseased individual of this species. Amplification and sequencing of the highly conserved retroviral pro-pol domains revealed high levels of sequence variation in these ERVs. Phylogenetic analyses of these ERVs and those previously identified in other crocodilian species suggest that although many crocodilians share the same ERV lineages, the relative numbers of retroelement insertions from each of these lineages may vary greatly between species. The data generated in this study provide evidence for the presence of a unique and varied complement of ERVs in crocodilians. This study has also demonstrated the presence of species-specific evolution in ancient retroviral infections.
Assuntos
Jacarés e Crocodilos/virologia , Retrovirus Endógenos/genética , Retrovirus Endógenos/isolamento & purificação , Variação Genética , Infecções por Retroviridae/veterinária , Animais , Retrovirus Endógenos/classificação , Evolução Molecular , Dados de Sequência Molecular , Filogenia , Infecções por Retroviridae/virologiaRESUMO
BACKGROUND: Crocodilians are thought to be hosts to a diverse and divergent complement of endogenous retroviruses (ERVs) but a comprehensive investigation is yet to be performed. The recent sequencing of three crocodilian genomes provides an opportunity for a more detailed and accurate representation of the ERV diversity that is present in these species. Here we investigate the diversity, distribution and evolution of ERVs from the genomes of three key crocodilian species, and outline the key processes driving crocodilian ERV proliferation and evolution. RESULTS: ERVs and ERV related sequences make up less than 2% of crocodilian genomes. We recovered and described 45 ERV groups within the three crocodilian genomes, many of which are species specific. We have also revealed a new class of ERV, ERV4, which appears to be common to crocodilians and turtles, and currently has no characterised exogenous counterpart. For the first time, we formally describe the characteristics of this ERV class and its classification relative to other recognised ERV and retroviral classes. This class shares some sequence similarity and sequence characteristics with ERV3, although it is phylogenetically distinct from the other ERV classes. We have also identified two instances of gene capture by crocodilian ERVs, one of which, the capture of a host KIT-ligand mRNA has occurred without the loss of an ERV domain. CONCLUSIONS: This study indicates that crocodilian ERVs comprise a wide variety of lineages, many of which appear to reflect ancient infections. In particular, ERV4 appears to have a limited host range, with current data suggesting that it is confined to crocodilians and some lineages of turtles. Also of interest are two ERV groups that demonstrate evidence of host gene capture. This study provides a framework to facilitate further studies into non-mammalian vertebrates and highlights the need for further studies into such species.
Assuntos
Jacarés e Crocodilos/genética , Jacarés e Crocodilos/virologia , Retrovirus Endógenos/classificação , Retrovirus Endógenos/genética , Evolução Molecular , Variação Genética , Genoma , Animais , Análise por Conglomerados , Biologia Computacional , Filogenia , Recombinação Genética , Homologia de Sequência , Tartarugas/virologiaRESUMO
INTRODUCTION: The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has posed unprecedented global health challenges since its emergence in December 2019. The rapid availability of vaccines has been estimated to save millions of lives, but there is variation in how individuals respond to vaccines, influencing their effectiveness at an individual, and population level. AREAS COVERED: This review focuses on human genetic factors influencing the immune response and effectiveness of vaccines, highlighting the importance of associations across the HLA locus. Genome-Wide Association Studies (GWAS) and other genetic association analyses have identified statistically significant associations between specific HLA alleles including HLA-DRB1*13, DBQ1*06, and A*03 impacting antibody responses and the risk of breakthrough infections post-vaccination. Relationships between these associations and potential mechanisms and links with risks of natural infection or disease are explored, and this review concludes by emphasizing how understanding the mechanisms of these genetic determinants may inform the development of tailored vaccination strategies. EXPERT OPINION: Although complex, we believe these findings from the SARS-CoV2 pandemic offer a unique opportunity to understand the relationships between HLA and infection and vaccine response, with a goal of optimizing individual protection against COVID-19 in the ongoing pandemic, and possibly influencing wider vaccine development in the future.
Assuntos
Vacinas contra COVID-19 , COVID-19 , Estudo de Associação Genômica Ampla , Antígenos HLA , SARS-CoV-2 , Humanos , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , COVID-19/imunologia , COVID-19/genética , SARS-CoV-2/imunologia , Antígenos HLA/genética , Antígenos HLA/imunologia , Alelos , Vacinação , Eficácia de VacinasRESUMO
How human genetic variation contributes to vaccine effectiveness in infants is unclear, and data are limited on these relationships in populations with African ancestries. We undertook genetic analyses of vaccine antibody responses in infants from Uganda (n = 1391), Burkina Faso (n = 353) and South Africa (n = 755), identifying associations between human leukocyte antigen (HLA) and antibody response for five of eight tested antigens spanning pertussis, diphtheria and hepatitis B vaccines. In addition, through HLA typing 1,702 individuals from 11 populations of African ancestry derived predominantly from the 1000 Genomes Project, we constructed an imputation resource, fine-mapping class II HLA-DR and DQ associations explaining up to 10% of antibody response variance in our infant cohorts. We observed differences in the genetic architecture of pertussis antibody response between the cohorts with African ancestries and an independent cohort with European ancestry, but found no in silico evidence of differences in HLA peptide binding affinity or breadth. Using immune cell expression quantitative trait loci datasets derived from African-ancestry samples from the 1000 Genomes Project, we found evidence of differential HLA-DRB1 expression correlating with inferred protection from pertussis following vaccination. This work suggests that HLA-DRB1 expression may play a role in vaccine response and should be considered alongside peptide selection to improve vaccine design.
Assuntos
Cadeias HLA-DRB1 , Humanos , Cadeias HLA-DRB1/genética , Cadeias HLA-DRB1/imunologia , Lactente , População Negra/genética , Vacinas contra Hepatite B/imunologia , Locos de Características Quantitativas , Masculino , Feminino , Uganda , Formação de Anticorpos/genética , Formação de Anticorpos/imunologia , Vacina contra Coqueluche/imunologia , Vacina contra Coqueluche/genética , Vacinação , Coqueluche/prevenção & controle , Coqueluche/imunologia , Coqueluche/genéticaRESUMO
Cities all over the world are edging further into the ocean. Coastal reclamation is a global conservation issue with implications for ocean life, ecosystems, and human well-being. Using Malaysia as a case study, the coastal reclamation trends over three decades (1991-2021) were mapped using Landsat images and Normalized Difference Water Index (NDWI) via the Google Earth Engine platform. The changes in drivers and impacts of these coastal expansions throughout the decades were also reviewed. Twelve out of the 14 states in Malaysia had planned, active, or completed reclamations on their shorelines. Between 1991 and 2021, an absolute area of 82.64 km2 has been or will be reclaimed should all the projects be completed. The most reported driver for coastal expansion in Malaysia is for development and modernization (41 %), followed by rise in human population (20 %), monetary gains from the development of prime land (15 %), and agriculture and aquaculture activities (9 %). Drivers such as reduction of construction costs, financial advantage of prime land, oil and gas, advancement of technology, and tourism (Malaysia My Second Home (MM2H)) had only started occurring within the last decade, while others have been documented since the 1990's. Pollution is the most reported impact (24 %) followed by disruption of livelihoods, sources of income and human well-being (21 %), destruction of natural habitats (17 %), decrease in biodiversity (11 %), changes in landscapes (10 %), erosion / accretion (8 %), threat to tourism industry (6 %), and exposure to wave surges (3 %). Of these, changes in landscape, shoreline alignment, seabed contour, and coastal groundwater, as well as wave surges had only started to surface as impacts in the last two decades. Efforts to protect existing natural coastal and marine ecosystems, restore degraded ones, and fund endeavours that emphasize nature is needed to support sustainable development goals for the benefit of future generations.
Assuntos
Conservação dos Recursos Naturais , Ecossistema , Humanos , Conservação dos Recursos Naturais/métodos , Malásia , Biodiversidade , Poluição AmbientalRESUMO
Hepatitis B virus (HBV) vaccine escape mutants (VEM) are increasingly described, threatening progress in control of this virus worldwide. Here we studied the relationship between host genetic variation, vaccine immunogenicity and viral sequences implicating VEM emergence. In a cohort of 1,096 Bangladeshi children, we identified human leukocyte antigen (HLA) variants associated with response vaccine antigens. Using an HLA imputation panel with 9,448 south Asian individuals DPB1*04:01 was associated with higher HBV antibody responses (p=4.5×10-30). The underlying mechanism is a result of higher affinity binding of HBV surface antigen epitopes to DPB1*04:01 dimers. This is likely a result of evolutionary pressure at the HBV surface antigen 'a-determinant' segment incurring VEM specific to HBV. Prioritizing pre-S isoform HBV vaccines may tackle the rise of HBV vaccine evasion.
RESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine immunogenicity varies between individuals, and immune responses correlate with vaccine efficacy. Using data from 1,076 participants enrolled in ChAdOx1 nCov-19 vaccine efficacy trials in the United Kingdom, we found that inter-individual variation in normalized antibody responses against SARS-CoV-2 spike and its receptor-binding domain (RBD) at 28 days after first vaccination shows genome-wide significant association with major histocompatibility complex (MHC) class II alleles. The most statistically significant association with higher levels of anti-RBD antibody was HLA-DQB1*06 (P = 3.2 × 10-9), which we replicated in 1,677 additional vaccinees. Individuals carrying HLA-DQB1*06 alleles were less likely to experience PCR-confirmed breakthrough infection during the ancestral SARS-CoV-2 virus and subsequent Alpha variant waves compared to non-carriers (hazard ratio = 0.63, 0.42-0.93, P = 0.02). We identified a distinct spike-derived peptide that is predicted to bind differentially to HLA-DQB1*06 compared to other similar alleles, and we found evidence of increased spike-specific memory B cell responses in HLA-DQB1*06 carriers at 84 days after first vaccination. Our results demonstrate association of HLA type with Coronavirus Disease 2019 (COVID-19) vaccine antibody response and risk of breakthrough infection, with implications for future vaccine design and implementation.
Assuntos
Infecções Irruptivas , Vacinas contra COVID-19 , COVID-19 , Antígenos de Histocompatibilidade Classe II , Imunogenicidade da Vacina , Humanos , Alelos , Anticorpos Antivirais , ChAdOx1 nCoV-19 , COVID-19/genética , COVID-19/prevenção & controle , Vacinas contra COVID-19/imunologia , SARS-CoV-2 , VacinaçãoRESUMO
Certain infectious agents are recognised causes of cancer and other chronic diseases. To understand the pathological mechanisms underlying such relationships, here we design a Multiplex Serology platform to measure quantitative antibody responses against 45 antigens from 20 infectious agents including human herpes, hepatitis, polyoma, papilloma, and retroviruses, as well as Chlamydia trachomatis, Helicobacter pylori and Toxoplasma gondii, then assayed a random subset of 9695 UK Biobank participants. We find seroprevalence estimates consistent with those expected from prior literature and confirm multiple associations of antibody responses with sociodemographic characteristics (e.g., lifetime sexual partners with C. trachomatis), HLA genetic variants (rs6927022 with Epstein-Barr virus (EBV) EBNA1 antibodies) and disease outcomes (human papillomavirus-16 seropositivity with cervical intraepithelial neoplasia, and EBV responses with multiple sclerosis). Our accessible dataset is one of the largest incorporating diverse infectious agents in a prospective UK cohort offering opportunities to improve our understanding of host-pathogen-disease relationships with significant clinical and public health implications.
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Infecções por Vírus Epstein-Barr , Neoplasias do Colo do Útero , Bancos de Espécimes Biológicos , Feminino , Herpesvirus Humano 4/genética , Humanos , Estudos Prospectivos , Estudos Soroepidemiológicos , Reino Unido/epidemiologiaRESUMO
The burden of infections on an individual and public health is profound. Many observational studies have shown a link between infections and the pathogenesis of disease; however a greater understanding of the role of host genetics is essential. Children from the longitudinal birth cohort, the Avon Longitudinal Study of Parents and Children, had 14 antibodies measured in plasma at age 7: Alpha-casein protein, beta-casein protein, cytomegalovirus, Epstein-Barr virus, feline herpes virus, Helicobacter pylori, herpes simplex virus 1, influenza virus subtype H1N1, influenza virus subtype H3N2, measles virus, Saccharomyces cerevisiae, Theiler's virus, Toxoplasma gondii, and SAG1 protein domain, a surface antigen of Toxoplasma gondii measured for greater precision. We performed genome-wide association analyses of antibody levels against these 14 infections (N = 357 - 5010) and identified three genome-wide signals (P < 5×10-8), two associated with measles virus antibodies and one with Toxoplasma gondii antibodies. In an association analysis focused on the human leukocyte antigen (HLA) region of the genome, we further detected 15 HLA alleles at a two-digit resolution and 23 HLA alleles at a four-digit resolution associated with five antibodies, with eight HLA alleles associated with Epstein-Barr virus antibodies showing strong evidence of replication in UK Biobank. We discuss how our findings from antibody levels complement other studies using self-reported phenotypes in understanding the architecture of host genetics related to infections.
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Infecções Bacterianas/genética , Toxoplasmose/genética , Viroses/genética , Adolescente , Anticorpos Antibacterianos/sangue , Anticorpos Antiprotozoários/sangue , Anticorpos Antivirais/sangue , Antígenos de Protozoários/genética , Antígenos de Protozoários/imunologia , Bactérias/imunologia , Infecções Bacterianas/sangue , Infecções Bacterianas/imunologia , Caseínas/genética , Caseínas/imunologia , Criança , Estudo de Associação Genômica Ampla , Antígenos HLA/genética , Humanos , Estudos Longitudinais , Polimorfismo de Nucleotídeo Único , Proteínas de Protozoários/genética , Proteínas de Protozoários/imunologia , Toxoplasma/imunologia , Toxoplasmose/sangue , Toxoplasmose/imunologia , Viroses/sangue , Viroses/imunologia , Vírus/imunologiaRESUMO
OBJECTIVE: To determine the benefits and harms of pre-admission interventions (prehabilitation) on postoperative outcomes in patients undergoing major elective surgery. DESIGN: Systematic review and meta-analysis of randomised controlled trials (RCTs) (published or unpublished). We searched Medline, Embase, CENTRAL, DARE, HTA and NHS EED, The Cochrane Library, CINAHL, PsychINFO and ISI Web of Science (June 2020). SETTING: Secondary care. PARTICIPANTS: Patients (≥18 years) undergoing major elective surgery (curative or palliative). INTERVENTIONS: Any intervention administered in the preoperative period with the aim of improving postoperative outcomes. OUTCOMES AND MEASURES: Primary outcomes were 30-day mortality, hospital length of stay (LoS) and postoperative complications. Secondary outcomes included LoS in intensive care unit or high dependency unit, perioperative morbidity, hospital readmission, postoperative pain, heath-related quality of life, outcomes specific to the intervention, intervention-specific adverse events and resource use. REVIEW METHODS: Two authors independently extracted data from eligible RCTs and assessed risk of bias and the certainty of evidence using Grading of Recommendations, Assessment, Development and Evaluation. Random-effects meta-analyses were used to pool data across trials. RESULTS: 178 RCTs including eight types of intervention were included. Inspiratory muscle training (IMT), immunonutrition and multimodal interventions reduced hospital LoS (mean difference vs usual care: -1.81 days, 95% CI -2.31 to -1.31; -2.11 days, 95% CI -3.07 to -1.15; -1.67 days, 95% CI -2.31 to -1.03, respectively). Immunonutrition reduced infective complications (risk ratio (RR) 0.64 95% CI 0.40 to 1.01) and IMT, and exercise reduced postoperative pulmonary complications (RR 0.55, 95% CI 0.38 to 0.80, and RR 0.54, 95% CI 0.39 to 0.75, respectively). Smoking cessation interventions reduced wound infections (RR 0.28, 95% CI 0.12 to 0.64). CONCLUSIONS: Some prehabilitation interventions may reduce postoperative LoS and complications but the quality of the evidence was low. PROSPERO REGISTRATION NUMBER: CRD42015019191.
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Procedimentos Cirúrgicos Eletivos , Exercício Pré-Operatório , Exercício Físico , Humanos , Tempo de Internação , Complicações Pós-Operatórias/prevenção & controleRESUMO
BACKGROUND: The number of gluten-free diet followers without celiac disease (CD) is increasing. However, little is known about the characteristics of these individuals. OBJECTIVES: We address this issue by investigating a wide range of genetic and phenotypic characteristics in association with following a gluten-free diet. METHODS: The cross-sectional association between lifestyle and health-related characteristics and following a gluten-free diet was investigated in 124,447 women and men aged 40-69 y from the population-based UK Biobank study. A genome-wide association study (GWAS) of following a gluten-free diet was performed. RESULTS: A total of 1776 (1.4%) participants reported following a gluten-free diet. Gluten-free diet followers were more likely to be women, nonwhite, highly educated, living in more socioeconomically deprived areas, former smokers, have lost weight in the past year, have poorer self-reported health, and have made dietary changes as a result of illness. Conversely, these individuals were less likely to consume alcohol daily, be overweight or obese, have hypertension, or use cholesterol-lowering medication. Participants with hospital inpatient diagnosed blood and immune mechanism disorders (OR: 1.62; 95% CI: 1.18, 2.21) and non-CD digestive system diseases (OR: 1.58; 95% CI: 1.42, 1.77) were more likely to follow a gluten-free diet. The GWAS demonstrated that no genetic variants were associated with being a gluten-free diet follower. CONCLUSIONS: Gluten-free diet followers have a better cardiovascular risk profile than non-gluten-free diet followers but poorer self-reported health and a higher prevalence of blood and immune disorders and digestive conditions. Reasons for following a gluten-free diet warrant further investigation.
Assuntos
Dieta Livre de Glúten , Estudo de Associação Genômica Ampla , Estilo de Vida , Adulto , Idoso , Coleta de Dados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reino UnidoRESUMO
OBJECTIVES: The EDIFY program was developed to deliver early geriatric specialist interventions at the emergency department (ED) to reduce the number of acute admissions by identifying patients for safe discharge or transfer to low-acuity care settings. We evaluated the effectiveness of EDIFY in reducing potentially avoidable acute admissions. DESIGN: A quasi-experimental study. SETTING: ED of a 1700-bed tertiary hospital. PARTICIPANTS: ED patients aged ≥85 years. MEASUREMENTS: We compared EDIFY interventions versus standard care. Patients with plans for acute admission were screened and recruited. Data on demographics, premorbid function, frailty status, comorbidities, and acute illness severity were gathered. We examined the primary outcome of "successful acute admission avoidance" among the intervention group, which was defined as no ED attendance within 72 hours of discharge from ED, no transfer to an acute ward from subacute-care units (SCU) within 72-hours, or no transfer to an acute ward from the short-stay unit (SSU). Secondary outcomes were rehospitalization, ED re-attendance, institutionalization, functional decline, mortality, and frailty transitions at 1, 3, and 6 months. RESULTS: We recruited 100 participants (mean age 90.0 ± 4.1 years, 66.0% women). There were no differences in baseline characteristics between intervention (n = 43) and nonintervention (n = 57) groups. Thirty-five (81.4%) participants in the intervention group successfully avoided an acute admission (20.9% home, 23.3% SCU, and 44.2% SSU). All participants in the nonintervention group were hospitalized. There were no differences in rehospitalization, ED re-attendance, institutionalization and mortality over the study period. Additionally, we observed a higher rate of progression to a poorer frailty category at all time points among the nonintervention group (1, 3, and 6 months: all P < .05). CONCLUSIONS AND IMPLICATIONS: Results from our single-center study suggest that early geriatric specialist interventions at the ED can reduce potentially avoidable acute admissions without escalating the risk of rehospitalization, ED re-attendance, or mortality, and with possible benefit in attenuating frailty progression.
Assuntos
Fragilidade , Idoso , Idoso de 80 Anos ou mais , Serviço Hospitalar de Emergência , Feminino , Fragilidade/terapia , Avaliação Geriátrica , Hospitalização , Humanos , Masculino , Alta do PacienteRESUMO
Current Genome-Wide Association Studies (GWAS) rely on genotype imputation to increase statistical power, improve fine-mapping of association signals, and facilitate meta-analyses. Due to the complex demographic history of Latin America and the lack of balanced representation of Native American genomes in current imputation panels, the discovery of locally relevant disease variants is likely to be missed, limiting the scope and impact of biomedical research in these populations. Therefore, the necessity of better diversity representation in genomic databases is a scientific imperative. Here, we expand the 1,000 Genomes reference panel (1KGP) with 134 Native American genomes (1KGP + NAT) to assess imputation performance in Latin American individuals of mixed ancestry. Our panel increased the number of SNPs above the GWAS quality threshold, thus improving statistical power for association studies in the region. It also increased imputation accuracy, particularly in low-frequency variants segregating in Native American ancestry tracts. The improvement is subtle but consistent across countries and proportional to the number of genomes added from local source populations. To project the potential improvement with a higher number of reference genomes, we performed simulations and found that at least 3,000 Native American genomes are needed to equal the imputation performance of variants in European ancestry tracts. This reflects the concerning imbalance of diversity in current references and highlights the contribution of our work to reducing it while complementing efforts to improve global equity in genomic research.