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1.
Lancet Respir Med ; 8(5): 482-492, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32380068

RESUMO

BACKGROUND: African ancestry is associated with a higher prevalence and greater severity of asthma than European ancestries, yet genetic studies of the most common locus associated with childhood-onset asthma, 17q12-21, in African Americans have been inconclusive. The aim of this study was to leverage both the phenotyping of the Children's Respiratory and Environmental Workgroup (CREW) birth cohort consortium, and the reduced linkage disequilibrium in African Americans, to fine map the 17q12-21 locus. METHODS: We first did a genetic association study and meta-analysis using 17q12-21 tag single-nucleotide polymorphisms (SNPs) for childhood-onset asthma in 1613 European American and 870 African American children from the CREW consortium. Nine tag SNPs were selected based on linkage disequilibrium patterns at 17q12-21 and their association with asthma, considering the effect allele under an additive model (0, 1, or 2 effect alleles). Results were meta-analysed with publicly available summary data from the EVE consortium (on 4303 European American and 3034 African American individuals) for seven of the nine SNPs of interest. Subsequently, we tested for expression quantitative trait loci (eQTLs) among the SNPs associated with childhood-onset asthma and the expression of 17q12-21 genes in resting peripheral blood mononuclear cells (PBMCs) from 85 African American CREW children and in upper airway epithelial cells from 246 African American CREW children; and in lower airway epithelial cells from 44 European American and 72 African American adults from a case-control study of asthma genetic risk in Chicago (IL, USA). FINDINGS: 17q12-21 SNPs were broadly associated with asthma in European Americans. Only two SNPs (rs2305480 in gasdermin-B [GSDMB] and rs8076131 in ORMDL sphingolipid biosynthesis regulator 3 [ORMDL3]) were associated with asthma in African Americans, at a Bonferroni-corrected threshold of p<0·0055 (for rs2305480_G, odds ratio [OR] 1·36 [95% CI 1·12-1·65], p=0·0014; and for rs8076131_A, OR 1·37 [1·13-1·67], p=0·0010). In upper airway epithelial cells from African American children, genotype at rs2305480 was the most significant eQTL for GSDMB (eQTL effect size [ß] 1·35 [95% CI 1·25-1·46], p<0·0001), and to a lesser extent showed an eQTL effect for post-GPI attachment to proteins phospholipase 3 (ß 1·15 [1·08-1·22], p<0·0001). No SNPs were eQTLs for ORMDL3. By contrast, in PBMCs, the five core SNPs were associated only with expression of GSDMB and ORMDL3. Genotype at rs12936231 (in zona pellucida binding protein 2) showed the strongest associations across both genes (for GSDMB, eQTLß 1·24 [1·15-1·32], p<0·0001; and for ORMDL3 (ß 1·19 [1·12-1·24], p<0·0001). The eQTL effects of rs2305480 on GSDMB expression were replicated in lower airway cells from African American adults (ß 1·29 [1·15-1·44], p<0·0001). INTERPRETATION: Our study suggests that SNPs regulating GSDMB expression in airway epithelial cells have a major role in childhood-onset asthma, whereas SNPs regulating the expression levels of 17q12-21 genes in resting blood cells are not central to asthma risk. Our genetic and gene expression data in African Americans and European Americans indicated GSDMB to be the leading candidate gene at this important asthma locus. FUNDING: National Institutes of Health, Office of the Director.

2.
Retrovirology ; 17(1): 3, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31918727

RESUMO

The HIV accessory protein Nef downregulates the viral entry receptor CD4, the Human Leukocyte Antigen (HLA)-A and -B molecules, the Serine incorporator 5 (SERINC5) protein and other molecules from the infected cell surface, thereby promoting viral infectivity, replication and immune evasion. The nef locus also represents one of the most genetically variable regions in the HIV genome, and nef sequences undergo substantial evolution within a single individual over the course of infection. Few studies however have simultaneously characterized the impact of within-host nef sequence evolution on Nef protein function over prolonged timescales. Here, we isolated 50 unique Nef clones by single-genome amplification over an 11-year period from the plasma of an individual who was largely naïve to antiretroviral treatment during this time. Together, these clones harbored nonsynonymous substitutions at 13% of nef's codons. We assessed their ability to downregulate cell-surface CD4, HLA and SERINC5 and observed that all three Nef functions declined modestly over time, where the reductions in CD4 and HLA downregulation (an average of 0.6% and 2.0% per year, respectively) achieved statistical significance. The results from this case study support all three Nef activities as being important to maintain throughout untreated HIV infection, but nevertheless suggest that, despite nef's mutational plasticity, within-host viral evolution can compromise Nef function, albeit modestly, over prolonged periods.

3.
Ann Am Thorac Soc ; 17(1): 72-80, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31437013

RESUMO

Rationale: The decision whether to initiate or forgo long-term ventilation for children can be difficult and impactful. However, little has been published on the informational and decisional needs of families facing this decision.Objectives: To assess what families with children with chronic respiratory failure and life-limiting conditions need and want for informed decision-making.Methods: English- and Spanish-speaking parents who were facing (contemporaneous decision makers) or had previously faced (former decision makers) a decision regarding invasive or noninvasive long-term ventilation for their children were recruited using convenience sampling. Patients who were older and cognitively capable also were invited to participate. We performed semistructured interviews using an open-ended interview guide developed de novo to assess parents' decisional needs and experiences. Qualitative data analysis used a thematic approach based on framework analysis, and thematic saturation was a goal.Results: A sample of 44 parents and 2 patients from 43 families was interviewed. All contemporaneous decision makers (n = 28) favored or believed that they would choose long-term ventilation. Fifteen of 16 former decision makers chose long-term ventilation. Thematic saturation was achieved from the perspective of parents who favored or chose long-term ventilation. Four domains were identified: parents' emotional and psychological experiences with decision-making, parents' informational needs, parents' communication and decision support needs, and parents' views on the option not to initiate long-term ventilation. For most parents, making a decision regarding long-term ventilation was stressful, even though they articulated goals and values that could/did guide their decision-making. In general, parents wanted comprehensive information, including what life would be like at home for the child and the family. They wanted their medical providers to be honest, tactful, patient, and supportive. Parents reported that they felt being presented with the option not to initiate was acceptable.Conclusions: In this study, we identified specific informational and decision-making needs regarding long-term ventilation that parents facing decisions feel are important. These data suggest that providers should present families with comprehensive, balanced information on the impact of long-term ventilation and, when the child has a profoundly serious and life-limiting condition, explore the option not to initiate long-term ventilation.

4.
J Virol ; 94(5)2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-31776273

RESUMO

The HIV reservoir, which comprises diverse proviruses integrated into the genomes of infected, primarily CD4+ T cells, is the main barrier to developing an effective HIV cure. Our understanding of the genetics and dynamics of proviruses persisting within distinct CD4+ T cell subsets, however, remains incomplete. Using single-genome amplification, we characterized subgenomic proviral sequences (nef region) from naive, central memory, transitional memory, and effector memory CD4+ T cells from five HIV-infected individuals on long-term combination antiretroviral therapy (cART) and compared these to HIV RNA sequences isolated longitudinally from archived plasma collected prior to cART initiation, yielding HIV data sets spanning a median of 19.5 years (range, 10 to 20 years) per participant. We inferred a distribution of within-host phylogenies for each participant, from which we characterized proviral ages, phylogenetic diversity, and genetic compartmentalization between CD4+ T cell subsets. While three of five participants exhibited some degree of proviral compartmentalization between CD4+ T cell subsets, combined analyses revealed no evidence that any particular CD4+ T cell subset harbored the longest persisting, most genetically diverse, and/or most genetically distinctive HIV reservoir. In one participant, diverse proviruses archived within naive T cells were significantly younger than those in memory subsets, while for three other participants we observed no significant differences in proviral ages between subsets. In one participant, "old" proviruses were recovered from all subsets, and included one sequence, estimated to be 21.5 years old, that dominated (>93%) their effector memory subset. HIV eradication strategies will need to overcome within- and between-host genetic complexity of proviral landscapes, possibly via personalized approaches.IMPORTANCE The main barrier to HIV cure is the ability of a genetically diverse pool of proviruses, integrated into the genomes of infected CD4+ T cells, to persist despite long-term suppressive combination antiretroviral therapy (cART). CD4+ T cells, however, constitute a heterogeneous population due to their maturation across a developmental continuum, and the genetic "landscapes" of latent proviruses archived within them remains incompletely understood. We applied phylogenetic techniques, largely novel to HIV persistence research, to reconstruct within-host HIV evolutionary history and characterize proviral diversity in CD4+ T cell subsets in five individuals on long-term cART. Participants varied widely in terms of proviral burden, genetic diversity, and age distribution between CD4+ T cell subsets, revealing that proviral landscapes can differ between individuals and between infected cell types within an individual. Our findings expose each within-host latent reservoir as unique in its genetic complexity and support personalized strategies for HIV eradication.

5.
Breast Cancer Res ; 21(1): 96, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31429809

RESUMO

BACKGROUND: The long time from exposure to potentially harmful chemicals until breast cancer occurrence poses challenges for designing etiologic studies and for implementing successful prevention programs. Growing evidence from animal and human studies indicates that distinct time periods of heightened susceptibility to endocrine disruptors exist throughout the life course. The influence of environmental chemicals on breast cancer risk may be greater during several windows of susceptibility (WOS) in a woman's life, including prenatal development, puberty, pregnancy, and the menopausal transition. These time windows are considered as specific periods of susceptibility for breast cancer because significant structural and functional changes occur in the mammary gland, as well as alterations in the mammary micro-environment and hormone signaling that may influence risk. Breast cancer research focused on these breast cancer WOS will accelerate understanding of disease etiology and prevention. MAIN TEXT: Despite the plausible heightened mechanistic influences of environmental chemicals on breast cancer risk during time periods of change in the mammary gland's structure and function, most human studies of environmental chemicals are not focused on specific WOS. This article reviews studies conducted over the past few decades that have specifically addressed the effect of environmental chemicals and metals on breast cancer risk during at least one of these WOS. In addition to summarizing the broader evidence-base specific to WOS, we include discussion of the NIH-funded Breast Cancer and the Environment Research Program (BCERP) which included population-based and basic science research focused on specific WOS to evaluate associations between breast cancer risk and particular classes of endocrine-disrupting chemicals-including polycyclic aromatic hydrocarbons, perfluorinated compounds, polybrominated diphenyl ethers, and phenols-and metals. We outline ways in which ongoing transdisciplinary BCERP projects incorporate animal research and human epidemiologic studies in close partnership with community organizations and communication scientists to identify research priorities and effectively translate evidence-based findings to the public and policy makers. CONCLUSIONS: An integrative model of breast cancer research is needed to determine the impact and mechanisms of action of endocrine disruptors at different WOS. By focusing on environmental chemical exposure during specific WOS, scientists and their community partners may identify when prevention efforts are likely to be most effective.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etiologia , Exposição Ambiental/efeitos adversos , Animais , Neoplasias da Mama/prevenção & controle , Suscetibilidade a Doenças , Feminino , Humanos , Exposição Materna/efeitos adversos , Menopausa , Gravidez , Puberdade , Pesquisa , Fatores de Risco , Fatores de Tempo
6.
Environ Res ; 177: 108595, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31352299

RESUMO

There is evidence that exposures to polycyclic aromatic hydrocarbons (PAH) and fine particles in air pollution are associated with higher childhood body mass index (BMI). Birth cohort analyses of prenatal exposures to PAH and child BMI Z-scores from age 5-14 years were conducted. African-American and Hispanic children born in the Bronx or Northern Manhattan, New York (1998-2006), whose mothers underwent personal air monitoring for airborne PAH exposure during pregnancy, were followed up with measurements of height and weight at approximate ages 5, 7, 9, 10, 11, 12.5 and 13.5 years. Multivariable generalized estimating equation analyses were used to relate prenatal airborne PAH exposures to child BMI Z-scores through time. The analyses adjusted for many known risk factors for childhood obesity and included interactions terms between age and exposure tertiles and age squared and exposure tertiles. In total, 535 children had at least one height and weight measure during follow-up. The prevalence of obesity was 20.6% at age 5 and increased across follow-ups until age 11 when it was 33.0%. At age 5, BMI Z-scores were significantly greater for children in the third tertile of exposure relative to the first tertile (0.35 Z-score units, 95% CI 0.09, 0.61, p = 0.007) and were non-significantly higher for the second tertile of exposure compared to the first tertile (0.25 Z-score units, 95% CI -0.02, 0.52, P = 0.075). The trajectories of BMI Z-scores by tertiles of exposure converged as the children aged, such that by age 11 years the estimated mean BMI Z-scores associated with each tertile of exposure were not different. Prenatal exposures to airborne PAH were associated with higher childhood BMI Z-scores at a young age, but growth trajectories converged by age 11 years. Accordingly, highly exposed children spend a greater proportion of their childhood with higher BMI Z-scores.

7.
J Virol ; 93(17)2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31189714

RESUMO

HIV's ability to persist during suppressive antiretroviral therapy is the main barrier to cure. Immune-privileged tissues, such as the testes, may constitute distinctive sites of HIV persistence, but this has been challenging to study in humans. We analyzed the proviral burden and genetics in the blood and testes of 10 individuals on suppressive therapy who underwent elective gender-affirming surgery. HIV DNA levels in matched blood and testes were quantified by quantitative PCR, and subgenomic proviral sequences (nef region) were characterized from single templates. HIV diversity, compartmentalization, and immune escape burden were assessed using genetic and phylogenetic approaches. Diverse proviruses were recovered from the blood (396 sequences; 354 nef-intact sequences) and testes (326 sequences; 309 nef-intact sequences) of all participants. Notably, the frequency of identical HIV sequences varied markedly between and within individuals. Nevertheless, proviral loads, within-host unique HIV sequence diversity, and the immune escape burden correlated positively between blood and testes. When all intact nef sequences were evaluated, 60% of participants exhibited significant blood-testis genetic compartmentalization, but none did so when the evaluation was restricted to unique sequences per site, suggesting that compartmentalization, when present, is attributable to the clonal expansion of HIV-infected cells. Our observations confirm the testes as a site of HIV persistence and suggest that individuals with larger and more diverse blood reservoirs will have larger and more diverse testis reservoirs. Furthermore, while the testis microenvironment may not be sufficiently unique to facilitate the seeding of unique viral populations therein, differential clonal expansion dynamics may be at play, which may complicate HIV eradication.IMPORTANCE Two key questions in HIV reservoir biology are whether immune-privileged tissues, such as the testes, harbor distinctive proviral populations during suppressive therapy and, if so, by what mechanism. While our results indicated that blood-testis HIV genetic compartmentalization was reasonably common (60%), it was always attributable to differential frequencies of identical HIV sequences between sites. No blood-tissue data set retained evidence of compartmentalization when only unique HIV sequences per site were considered; moreover, HIV immune escape mutation burdens were highly concordant between sites. We conclude that the principal mechanism by which blood and testis reservoirs differ is not via seeding of divergent HIV sequences therein but, rather, via differential clonal expansion of latently infected cells. Thus, while viral diversity and escape-related barriers to HIV eradication are of a broadly similar magnitude across the blood and testes, clonal expansion represents a challenge. The results support individualized analysis of within-host reservoir diversity to inform curative approaches.

8.
J Allergy Clin Immunol ; 144(2): 381-392, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31247266

RESUMO

Many notable advances in drug allergy, urticaria, angioedema, and anaphylaxis were reported in 2018. Broad-spectrum antibiotic use and, consequently, antibiotic resistance are widespread, and algorithms to clarify ß-lactam allergy and optimize antibiotic use were described. Meaningful data emerged on the pathogenesis of delayed drug hypersensitivity reactions. Progress not only in defining biomarkers but also in understanding the effect on quality of life and developing better treatments has been made for patients with chronic idiopathic urticaria. Patients with hereditary angioedema (HAE) have gained additional access to highly efficacious therapies, with associated improvements in quality of life, and some progress was made in our understanding of recurrent angioedema in patients with normal laboratory results. Guidelines have defined clear goals to help providers optimize therapies in patients with HAE. The epidemiology and triggers of anaphylaxis and the mechanisms underlying anaphylaxis were elucidated further. In summary, these disorders (and labels) cause substantial burdens for individual persons and even society. Fortunately, publications in 2018 have informed on advancements in diagnosis and management and have provided better understanding of mechanisms that potentially could yield new therapies. This progress should lead to better health outcomes and paths forward in patients with drug allergy, urticaria, HAE, and anaphylaxis.

10.
J Virol ; 93(6)2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30602611

RESUMO

The HIV accessory protein Nef modulates key immune evasion and pathogenic functions, and its encoding gene region exhibits high sequence diversity. Given the recent identification of early HIV-specific adaptive immune responses as novel correlates of HIV reservoir size, we hypothesized that viral factors that facilitate the evasion of such responses-namely, Nef genetic and functional diversity-might also influence reservoir establishment and/or persistence. We isolated baseline plasma HIV RNA-derived nef clones from 30 acute/early-infected individuals who participated in a clinical trial of early combination antiretroviral therapy (cART) (<6 months following infection) and assessed each Nef clone's ability to downregulate CD4 and human leukocyte antigen (HLA) class I in vitro We then explored the relationships between baseline clinical, immunological, and virological characteristics and the HIV reservoir size measured 48 weeks following initiation of suppressive cART (where the reservoir size was quantified in terms of the proviral DNA loads as well as the levels of replication-competent HIV in CD4+ T cells). Maximal within-host Nef-mediated downregulation of HLA, but not CD4, correlated positively with post-cART proviral DNA levels (Spearman's R = 0.61, P = 0.0004) and replication-competent reservoir sizes (Spearman's R = 0.36, P = 0.056) in univariable analyses. Furthermore, the Nef-mediated HLA downregulation function was retained in final multivariable models adjusting for established clinical and immunological correlates of reservoir size. Finally, HIV subtype B-infected persons (n = 25) harbored significantly larger viral reservoirs than non-subtype B-infected persons (2 infected with subtype CRF01_AE and 3 infected with subtype G). Our results highlight a potentially important role of viral factors-in particular, HIV subtype and accessory protein function-in modulating viral reservoir establishment and persistence.IMPORTANCE While combination antiretroviral therapies (cART) have transformed HIV infection into a chronic manageable condition, they do not act upon the latent HIV reservoir and are therefore not curative. As HIV cure or remission should be more readily achievable in individuals with smaller HIV reservoirs, achieving a deeper understanding of the clinical, immunological, and virological determinants of reservoir size is critical to eradication efforts. We performed a post hoc analysis of 30 participants of a clinical trial of early cART who had previously been assessed in detail for their clinical, immunological, and reservoir size characteristics. We observed that the HIV subtype and autologous Nef-mediated HLA downregulation function correlated with the viral reservoir size measured approximately 1 year post-cART initiation. Our findings highlight virological characteristics-both genetic and functional-as possible novel determinants of HIV reservoir establishment and persistence.


Assuntos
Infecções por HIV/imunologia , HIV/imunologia , Evasão da Resposta Imune/imunologia , Produtos do Gene nef do Vírus da Imunodeficiência Humana/imunologia , Adulto , Antirretrovirais/farmacologia , Antígenos CD4/imunologia , Linfócitos T CD4-Positivos/imunologia , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/imunologia , HIV/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Antígenos HLA/imunologia , Humanos , Evasão da Resposta Imune/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Latência Viral/efeitos dos fármacos , Latência Viral/imunologia , Adulto Jovem
11.
Pediatr Res ; 85(1): 36-42, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30337671

RESUMO

BACKGROUND: Social and environmental stressors may modify associations between environmental pollutants and asthma symptoms. We examined if neighborhood asthma prevalence (higher: HAPN vs. lower: LAPN), a surrogate for underlying risk factors for asthma, modified the relationship between pollutants and urgent asthma visits. METHODS: Through zip code, home addresses were linked to New York City Community Air Survey's land use regression model for street-level, annual average nitrogen dioxide (NO2), particulate matter (PM2.5), elemental carbon (EC), summer average ozone (O3), winter average sulfur dioxide (SO2) concentrations. Poisson regression models were fit to estimate the association (prevalence ratio, PR) between pollutant exposures and seeking urgent asthma care. RESULTS: All pollutants, except O3 were higher in HAPN than LAPN (P < 0.01). Neighborhood asthma prevalence modified the relationship between pollutants and urgent asthma (P-interaction < 0.01, for NO2 and SO3). Associations between pollutants and urgent asthma were observed only in LAPN (NO2: PR = 1.38, P = 0.01; SO3: PR = 1.85, P = 0.04). No association was observed between pollutants and urgent asthma among children in HAPN (P > 0.05). CONCLUSIONS: Relationships between modeled street-level pollutants and urgent asthma were stronger in LAPN compared to HAPN. Social stressors that may be more prevalent in HAPN than LAPN, could play a greater role in asthma exacerbations in HAPN vs. pollutant exposure alone.

12.
Nat Commun ; 9(1): 5023, 2018 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-30479346

RESUMO

Some closely related human leukocyte antigen (HLA) alleles are associated with variable clinical outcomes following HIV-1 infection despite presenting the same viral epitopes. Mechanisms underlying these differences remain unclear but may be due to intrinsic characteristics of the HLA alleles or responding T cell repertoires. Here we examine CD8+ T cell responses against the immunodominant HIV-1 Gag epitope TL9 (TPQDLNTML180-188) in the context of the protective allele B*81:01 and the less protective allele B*42:01. We observe a population of dual-reactive T cells that recognize TL9 presented by both B*81:01 and B*42:01 in individuals lacking one allele. The presence of dual-reactive T cells is associated with lower plasma viremia, suggesting a clinical benefit. In B*42:01 expressing individuals, the dual-reactive phenotype defines public T cell receptor (TCR) clones that recognize a wider range of TL9 escape variants, consistent with enhanced control of viral infection through containment of HIV-1 sequence adaptation.


Assuntos
HIV-1/metabolismo , Antígenos HLA-B/imunologia , Mutação/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Produtos do Gene gag do Vírus da Imunodeficiência Humana/genética , Adulto , Sequência de Aminoácidos , Linfócitos T CD8-Positivos/imunologia , Células Clonais , Feminino , Humanos , Masculino , Reprodutibilidade dos Testes , Carga Viral , Adulto Jovem , Produtos do Gene gag do Vírus da Imunodeficiência Humana/química
14.
Environ Res ; 166: 340-343, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29913435

RESUMO

Personal air pollution monitoring in research studies should not interfere with usual patterns of behavior and bias results. In an urban pediatric cohort study we tested whether wearing an air monitor impacted activity time based on continuous watch-based accelerometry. The majority (71%) reported that activity while wearing the monitor mimicked normal activity. Correspondingly, variation in activity while wearing versus not wearing the monitor did not differ greatly from baseline variation in activity (P = 0.84).


Assuntos
Poluição do Ar/análise , Exposição Ambiental/análise , Monitoramento Ambiental/instrumentação , Exercício Físico , Acelerometria , Adolescente , Criança , Estudos de Coortes , Feminino , Humanos , Masculino
15.
Blood Adv ; 2(9): 969-978, 2018 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-29712666

RESUMO

In sickle cell disease, respiratory infection and asthma may lead to respiratory complications that are a leading cause of morbidity and mortality. Vitamin D has anti-infective and immunomodulatory effects that may decrease the risk for respiratory infections, asthma, and acute chest syndrome. We conducted a randomized double-blind active-controlled clinical trial to determine whether monthly oral vitamin D3 can reduce the rate of respiratory events in children with sickle cell disease. Seventy sickle cell subjects, ages 3-20 years, with baseline records of respiratory events over 1 year before randomization, underwent screening. Sixty-two subjects with 25-hydroxyvitamin D levels of 5-60 ng/mL were randomly assigned to oral vitamin D3 (100 000 IU or 12 000 IU, n = 31 each) under observed administration once monthly for 2 years. The primary outcome was the annual rate of respiratory events (respiratory infection, asthma exacerbation, or acute chest syndrome) ascertained by the use of a validated questionnaire administered biweekly. Analysis included 62 children (mean age of 9.9 years, 52% female, and predominantly with homozygous HbS disease [87%]) with mean baseline 25-hydroxyvitamin D of 14.3 ng/mL. The annual rates of respiratory events at baseline and intervention years 1 and 2 were 4.34 ± 0.35, 4.28 ± 0.36, and 1.49 ± 0.37 (high dose) and 3.91 ± 0.35, 3.34 ± 0.37, and 1.54 ± 0.37 (standard dose), respectively. In pediatric patients with sickle cell disease, 2-year monthly oral vitamin D3 was associated with a >50% reduction in the rate of respiratory illness during the second year (P = .0005), with similar decreases associated with high- and standard-dose treatment. This trial was registered at www.clinicaltrials.gov as #NCT01443728.


Assuntos
Síndrome Torácica Aguda/prevenção & controle , Asma/prevenção & controle , Colecalciferol/administração & dosagem , Infecções Respiratórias/prevenção & controle , Síndrome Torácica Aguda/epidemiologia , Adolescente , Asma/epidemiologia , Criança , Método Duplo-Cego , Feminino , Humanos , Masculino , Infecções Respiratórias/epidemiologia , Fatores de Tempo
16.
Ann Am Thorac Soc ; 15(Suppl 2): S103-S108, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29676631

RESUMO

A common explanation for the origins and rising prevalence of asthma is that they involve complex interactions between hereditary predispositions and environmental exposures that are incompletely understood. Yet, emerging evidence substantiates the paradigm that environmental exposures prenatally and during very early childhood induce epigenetic alterations that affect the expression of asthma genes and, thereby, asthma itself. Here, we review much of the key evidence supporting this paradigm. First, we describe evidence that the prenatal and early postnatal periods are key time windows of susceptibility to environmental exposures that may trigger asthma. Second, we explain how environmental epigenetic regulation may explain the immunopathology underlying asthma. Third, we outline specific evidence that environmental exposures induce epigenetic regulation, both from animal models and robust human epidemiological research. Finally, we review some emerging topics, including the importance of coexposures, population divergence, and how epigenetic regulation may change over time. Despite all the inherent complexity, great progress has been made toward understanding what we still consider reversible asthma risk factors. These, in time, may impact patient care.


Assuntos
Asma/etiologia , Asma/genética , Exposição Ambiental/efeitos adversos , Epigênese Genética , Predisposição Genética para Doença , Animais , Feminino , Humanos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/imunologia , Fatores de Risco
17.
Environ Res ; 165: 118-124, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29689456

RESUMO

The dramatic rise in the prevalence of food allergy and food allergy-associated anaphylaxis in the past few decades has fueled investigative interest into understanding this puzzling trend. Here, we review the question as to whether important external environmental determinants beyond dietary habits and exposure to food allergens are involved. This review will summarize our current understanding of these environment determinants, derived from the latest experimental and epidemiological research. Specifically, we will review the role of exposures that affect skin barrier function, development of a diverse microbiome, and food processing. Additional exposures of concern are insufficient sunlight, endocrine disrupting chemicals and pesticides, and use of specific pharmaceutical agents that may drive or modify the risk for food allergy. Despite limitations in the quantity and quality of research to date, many new epidemiological associations and experimental data in support of this paradigm have emerged.


Assuntos
Meio Ambiente , Hipersensibilidade Alimentar , Alérgenos/imunologia , Dieta , Hipersensibilidade Alimentar/epidemiologia , Hipersensibilidade Alimentar/imunologia , Humanos , Microbiota
18.
Ann Allergy Asthma Immunol ; 120(3): 278-284.e2, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29508714

RESUMO

BACKGROUND: Rhinitis and conjunctivitis are often linked to asthma development through an allergic pathway. However, runny nose and watery eyes can result from nonallergic mechanisms. These mechanisms can also underlie exercise-induced wheeze (EIW), which has been associated with urgent medical visits for asthma, independent of other indicators of asthma severity or control. OBJECTIVE: To test the hypothesis that rhinitis or watery eyes without cold symptoms (RWWC) in infancy predict development of EIW and urgent respiratory-related medical visits at school age, independent of seroatopy. METHODS: Within a prospective birth cohort of low-income, urban children (n = 332), RWWC was queried during the first year of life. Relative risks (RRs) for EIW, emergency department (ED) visits, and hospitalizations for asthma and other breathing difficulties at 5 to 7 years of age were estimated with multivariable models. Seroatopy was determined at 7 years of age. RESULTS: Infant RWWC was common (49% of children) and predicted school-age EIW (RR, 2.8; P < .001), ED visits (RR, 1.8; P = .001), and hospitalizations (RR, 9.8; P = .002). These associations were independent of infant wheeze. They were also independent of birth order, an indicator of increased risk of exposure to viruses in infancy, and infant ear infections, an indicator of sequelae of upper airway infections. The association between infant RWWC and ED visits at 5 to 7 years of age was attenuated (RR, 1.2; P = .23) when EIW at 5 to 7 years of age was included in the model, suggesting EIW mediates the association. Adjustment for seroatopy did not diminish the magnitudes of any of these associations. CONCLUSION: These findings suggest a nonallergic connection between infant nonwheeze symptoms and important consequences of urban respiratory health by school age through EIW.


Assuntos
Hipersensibilidade Respiratória/epidemiologia , Sons Respiratórios , Rinite/epidemiologia , Criança , Serviço Hospitalar de Emergência , Olho , Feminino , Hospitalização , Humanos , Imunoglobulina E/sangue , Lactente , Masculino , Cidade de Nova Iorque/epidemiologia , Hipersensibilidade Respiratória/sangue , População Urbana
19.
Epigenetics ; 13(3): 240-250, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29436922

RESUMO

Family history, a well-established risk factor for breast cancer, can have both genetic and environmental contributions. Shared environment in families as well as epigenetic changes that also may be influenced by shared genetics and environment may also explain familial clustering of cancers. Epigenetic regulation, such as DNA methylation, can change the activity of a DNA segment without a change in the sequence; environmental exposures experienced across the life course can induce such changes. However, genetic-epigenetic interactions, detected as methylation quantitative trait loci (mQTLs; a.k.a. meQTLs) and haplotype-dependent allele-specific methylation (hap-ASM), can also contribute to inter-individual differences in DNA methylation patterns. To identify differentially methylated regions (DMRs) associated with breast cancer susceptibility, we examined differences in white blood cell DNA methylation in 29 candidate genes in 426 girls (ages 6-13 years) from the LEGACY Girls Study, 239 with and 187 without a breast cancer family history (BCFH). We measured methylation by targeted massively parallel bisulfite sequencing (bis-seq) and observed BCFH DMRs in two genes: ESR1 (Δ4.9%, P = 0.003) and SEC16B (Δ3.6%, P = 0.026), each of which has been previously implicated in breast cancer susceptibility and pubertal development. These DMRs showed high inter-individual variability in methylation, suggesting the presence of mQTLs/hap-ASM. Using single nucleotide polymorphisms data in the bis-seq amplicon, we found strong hap-ASM in SEC16B (with allele specific-differences ranging from 42% to 74%). These findings suggest that differential methylation in genes relevant to breast cancer susceptibility may be present early in life, and that inherited genetic factors underlie some of these epigenetic differences.


Assuntos
Neoplasias da Mama/genética , Metilação de DNA/genética , Proteínas de Ligação a DNA/genética , Receptor alfa de Estrogênio/genética , Adolescente , Alelos , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Criança , Ilhas de CpG/genética , Epigênese Genética , Feminino , Estudo de Associação Genômica Ampla , Haplótipos , Humanos , Anamnese , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética
20.
Clin Epigenetics ; 10: 2, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29317916

RESUMO

Background: DNA methylation of CpG sites on genetic loci has been linked to increased risk of asthma in children exposed to elevated ambient air pollutants (AAPs). Further identification of specific CpG sites and the pollutants that are associated with methylation of these CpG sites in immune cells could impact our understanding of asthma pathophysiology. In this study, we sought to identify some CpG sites in specific genes that could be associated with asthma regulation (Foxp3 and IL10) and to identify the different AAPs for which exposure prior to the blood draw is linked to methylation levels at these sites. We recruited subjects from Fresno, California, an area known for high levels of AAPs. Blood samples and responses to questionnaires were obtained (n = 188), and in a subset of subjects (n = 33), repeat samples were collected 2 years later. Average measures of AAPs were obtained for 1, 15, 30, 90, 180, and 365 days prior to each blood draw to estimate the short-term vs. long-term effects of the AAP exposures. Results: Asthma was significantly associated with higher differentially methylated regions (DMRs) of the Foxp3 promoter region (p = 0.030) and the IL10 intronic region (p = 0.026). Additionally, at the 90-day time period (90 days prior to the blood draw), Foxp3 methylation was positively associated with NO2, CO, and PM2.5 exposures (p = 0.001, p = 0.001, and p = 0.012, respectively). In the subset of subjects retested 2 years later (n = 33), a positive association between AAP exposure and methylation was sustained. There was also a negative correlation between the average Foxp3 methylation of the promoter region and activated Treg levels (p = 0.039) and a positive correlation between the average IL10 methylation of region 3 of intron 4 and IL10 cytokine expression (p = 0.030). Conclusions: Short-term and long-term exposures to high levels of CO, NO2, and PM2.5 were associated with alterations in differentially methylated regions of Foxp3. IL10 methylation showed a similar trend. For any given individual, these changes tend to be sustained over time. In addition, asthma was associated with higher differentially methylated regions of Foxp3 and IL10.


Assuntos
Asma/genética , Monóxido de Carbono/análise , Metilação de DNA , Fatores de Transcrição Forkhead/genética , Interleucina-10/genética , Dióxido de Nitrogênio/análise , Material Particulado/análise , Adolescente , Asma/sangue , Asma/induzido quimicamente , California , Monóxido de Carbono/efeitos adversos , Ilhas de CpG/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica , Estudos de Associação Genética , Humanos , Íntrons , Masculino , Dióxido de Nitrogênio/efeitos adversos , Material Particulado/efeitos adversos , Regiões Promotoras Genéticas
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