RESUMO
The in vivo mechanisms underlying dominant syndromes caused by mutations in SRY-Box Transcription Factor 9 (SOX9) and SOX10 (SOXE) transcription factors, when they either are expressed alone or are coexpressed, are ill-defined. We created a mouse model for the campomelic dysplasia SOX9Y440X mutation, which truncates the transactivation domain but leaves DNA binding and dimerization intact. Here, we find that SOX9Y440X causes deafness via distinct mechanisms in the endolymphatic sac (ES)/duct and cochlea. By contrast, conditional heterozygous Sox9-null mice are normal. During the ES development of Sox9Y440X/+ heterozygotes, Sox10 and genes important for ionic homeostasis are down-regulated, and there is developmental persistence of progenitors, resulting in fewer mature cells. Sox10 heterozygous null mutants also display persistence of ES/duct progenitors. By contrast, SOX10 retains its expression in the early Sox9Y440X/+ mutant cochlea. Later, in the postnatal stria vascularis, dominant interference by SOX9Y440X is implicated in impairing the normal cooperation of SOX9 and SOX10 in repressing the expression of the water channel Aquaporin 3, thereby contributing to endolymphatic hydrops. Our study shows that for a functioning endolymphatic system in the inner ear, SOX9 regulates Sox10, and depending on the cell type and target gene, it works either independently of or cooperatively with SOX10. SOX9Y440X can interfere with the activity of both SOXE factors, exerting effects that can be classified as haploinsufficient/hypomorphic or dominant negative depending on the cell/gene context. This model of disruption of transcription factor partnerships may be applicable to congenital deafness, which affects â¼0.3% of newborns, and other syndromic disorders.
Assuntos
Surdez , Orelha Interna , Fatores de Transcrição SOX9 , Fatores de Transcrição SOXE , Animais , Camundongos , Surdez/metabolismo , Orelha Interna/metabolismo , Audição/genética , Homeostase , Camundongos Knockout , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Fatores de Transcrição SOXE/genética , Fatores de Transcrição SOXE/metabolismoRESUMO
BACKGROUND: Albuterol is the drug most widely used as asthma treatment among African Americans despite having a lower bronchodilator drug response (BDR) than other populations. Although BDR is affected by gene and environmental factors, the influence of DNA methylation is unknown. OBJECTIVE: This study aimed to identify epigenetic markers in whole blood associated with BDR, study their functional consequences by multi-omic integration, and assess their clinical applicability in admixed populations with a high asthma burden. METHODS: We studied 414 children and young adults (8-21 years old) with asthma in a discovery and replication design. We performed an epigenome-wide association study on 221 African Americans and replicated the results on 193 Latinos. Functional consequences were assessed by integrating epigenomics with genomics, transcriptomics, and environmental exposure data. Machine learning was used to develop a panel of epigenetic markers to classify treatment response. RESULTS: We identified 5 differentially methylated regions and 2 CpGs genome-wide significantly associated with BDR in African Americans located in FGL2 (cg08241295, P = 6.8 × 10-9) and DNASE2 (cg15341340, P = 7.8 × 10-8), which were regulated by genetic variation and/or associated with gene expression of nearby genes (false discovery rate < 0.05). The CpG cg15341340 was replicated in Latinos (P = 3.5 × 10-3). Moreover, a panel of 70 CpGs showed good classification for those with response and nonresponse to albuterol therapy in African American and Latino children (area under the receiver operating characteristic curve for training, 0.99; for validation, 0.70-0.71). The DNA methylation model showed similar discrimination as clinical predictors (P > .05). CONCLUSIONS: We report novel associations of epigenetic markers with BDR in pediatric asthma and demonstrate for the first time the applicability of pharmacoepigenetics in precision medicine of respiratory diseases.
Assuntos
Asma , Broncodilatadores , Criança , Adulto Jovem , Humanos , Adolescente , Adulto , Broncodilatadores/uso terapêutico , Epigenoma , Multiômica , Asma/tratamento farmacológico , Asma/genética , Asma/metabolismo , Albuterol/uso terapêutico , Metilação de DNA , Estudo de Associação Genômica Ampla , Fibrinogênio/metabolismoRESUMO
BACKGROUND: In the USA, genetically admixed populations have the highest asthma prevalence and severe asthma exacerbations rates. This could be explained not only by environmental factors but also by genetic variants that exert ethnic-specific effects. However, no admixture mapping has been performed for severe asthma exacerbations. OBJECTIVE: We sought to identify genetic variants associated with severe asthma exacerbations in Hispanic/Latino subgroups by means of admixture mapping analyses and fine mapping, and to assess their transferability to other populations and potential functional roles. METHODS: We performed an admixture mapping in 1124 Puerto Rican and 625 Mexican American children with asthma. Fine-mapping of the significant peaks was performed via allelic testing of common and rare variants. We performed replication across Hispanic/Latino subgroups, and the transferability to non-Hispanic/Latino populations was assessed in 1001 African Americans, 1250 Singaporeans and 941 Europeans with asthma. The effects of the variants on gene expression and DNA methylation from whole blood were also evaluated in participants with asthma and in silico with data obtained through public databases. RESULTS: Genomewide significant associations of Indigenous American ancestry with severe asthma exacerbations were found at 5q32 in Mexican Americans as well as at 13q13-q13.2 and 3p13 in Puerto Ricans. The single nucleotide polymorphism (SNP) rs1144986 (C5orf46) showed consistent effects for severe asthma exacerbations across Hispanic/Latino subgroups, but it was not validated in non-Hispanics/Latinos. This SNP was associated with DPYSL3 DNA methylation and SCGB3A2 gene expression levels. CONCLUSIONS: Admixture mapping study of asthma exacerbations revealed a novel locus that exhibited Hispanic/Latino-specific effects and regulated DPYSL3 and SCGB3A2.
Assuntos
Asma , Hispânico ou Latino , Adolescente , Humanos , Asma/genética , Estudo de Associação Genômica Ampla , Hispânico ou Latino/genética , Polimorfismo de Nucleotídeo Único , Estados Unidos/epidemiologia , Criança , Americanos MexicanosRESUMO
BACKGROUND: Sex differences in Parkinson's disease (PD) risk are well-known. However, the role of sex chromosomes in the development and progression of PD is still unclear. OBJECTIVE: The objective of this study was to perform the first X-chromosome-wide association study for PD risk in a Latin American cohort. METHODS: We used data from three admixed cohorts: (1) Latin American Research consortium on the Genetics of Parkinson's Disease (n = 1504) as discover cohort, and (2) Latino cohort from International Parkinson Disease Genomics Consortium (n = 155) and (3) Bambui Aging cohort (n = 1442) as replication cohorts. We also developed an X-chromosome framework specifically designed for admixed populations. RESULTS: We identified eight linkage disequilibrium regions associated with PD. We replicated one of these regions (top variant rs525496; discovery odds ratio [95% confidence interval]: 0.60 [0.478-0.77], P = 3.13 × 10-5 replication odds ratio: 0.60 [0.37-0.98], P = 0.04). rs5525496 is associated with multiple expression quantitative trait loci in brain and non-brain tissues, including RAB9B, H2BFM, TSMB15B, and GLRA4, but colocalization analysis suggests that rs5525496 may not mediate risk by expression of these genes. We also replicated a previous X-chromosome-wide association study finding (rs28602900), showing that this variant is associated with PD in non-European populations. CONCLUSIONS: Our results reinforce the importance of including X-chromosome and diverse populations in genetic studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Assuntos
Cromossomos Humanos X , Doença de Parkinson , Feminino , Humanos , Masculino , Estudo de Associação Genômica Ampla , Hispânico ou Latino , América Latina , Doença de Parkinson/genética , Fatores Sexuais , Cromossomos Humanos X/genética , Desequilíbrio de Ligação/genéticaRESUMO
The genetic control of gene expression is a core component of human physiology. For the past several years, transcriptome-wide association studies have leveraged large datasets of linked genotype and RNA sequencing information to create a powerful gene-based test of association that has been used in dozens of studies. While numerous discoveries have been made, the populations in the training data are overwhelmingly of European descent, and little is known about the generalizability of these models to other populations. Here, we test for cross-population generalizability of gene expression prediction models using a dataset of African American individuals with RNA-Seq data in whole blood. We find that the default models trained in large datasets such as GTEx and DGN fare poorly in African Americans, with a notable reduction in prediction accuracy when compared to European Americans. We replicate these limitations in cross-population generalizability using the five populations in the GEUVADIS dataset. Via realistic simulations of both populations and gene expression, we show that accurate cross-population generalizability of transcriptome prediction only arises when eQTL architecture is substantially shared across populations. In contrast, models with non-identical eQTLs showed patterns similar to real-world data. Therefore, generating RNA-Seq data in diverse populations is a critical step towards multi-ethnic utility of gene expression prediction.
Assuntos
Negro ou Afro-Americano/genética , Estudo de Associação Genômica Ampla/métodos , Modelos Genéticos , Transcriptoma , Perfilação da Expressão Gênica/métodos , Perfilação da Expressão Gênica/normas , Estudo de Associação Genômica Ampla/normas , Humanos , Locos de Características Quantitativas , RNA-Seq/métodos , RNA-Seq/normas , Padrões de ReferênciaRESUMO
Bronchodilator (BD) drugs are commonly prescribed for treatment and management of obstructive lung function present with diseases such as asthma. Administration of BD medication can partially or fully restore lung function as measured by pulmonary function tests. The genetics of baseline lung function measures taken before BD medication have been extensively studied, and the genetics of the BD response itself have received some attention. However, few studies have focused on the genetics of post-BD lung function. To address this gap, we analyzed lung function phenotypes in 1103 subjects from the Study of African Americans, Asthma, Genes, and Environment, a pediatric asthma case-control cohort, using an integrative genomic analysis approach that combined genotype, locus-specific genetic ancestry, and functional annotation information. We integrated genome-wide association study (GWAS) results with an admixture mapping scan of three pulmonary function tests (forced expiratory volume in 1 s [FEV1 ], forced vital capacity [FVC], and FEV1 /FVC) taken before and after albuterol BD administration on the same subjects, yielding six traits. We identified 18 GWAS loci, and five additional loci from admixture mapping, spanning several known and novel lung function candidate genes. Most loci identified via admixture mapping exhibited wide variation in minor allele frequency across genotyped global populations. Functional fine-mapping revealed an enrichment of epigenetic annotations from peripheral blood mononuclear cells, fetal lung tissue, and lung fibroblasts. Our results point to three novel potential genetic drivers of pre- and post-BD lung function: ADAMTS1, RAD54B, and EGLN3.
Assuntos
Asma , Estudo de Associação Genômica Ampla , Negro ou Afro-Americano/genética , Asma/tratamento farmacológico , Asma/genética , Criança , Volume Expiratório Forçado , Genômica , Humanos , Leucócitos Mononucleares , Pulmão , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Propionibacterium acnes, though generally considered part of the normal flora of human skin, is an opportunistic pathogen associated with acne vulgaris as well as other diseases, including endocarditis, endophthalmitis and prosthetic joint infections. Its virulence potential is also supported by knowledge gained from its sequenced genome. Indeed, a vaccine targeting a putative cell wall-anchored P. acnes sialidase has been shown to suppress cytotoxicity and pro-inflammatory cytokine release induced by the organism, and is proposed as an alternative treatment for P. acnes-associated diseases. Here, we report the crystal structures of the surface sialidase and its complex with the transition-state mimic Neu5Ac2en. Our structural and kinetic analyses, together with insight from a glycan array screen, which probes subtle specificities of the sialidase for α-2,3-sialosides, provide a basis for the structure-based design of novel small-molecule therapeutics against P. acnes infections.
Assuntos
Acne Vulgar , Propionibacterium acnes , Acne Vulgar/tratamento farmacológico , Acne Vulgar/microbiologia , Humanos , Neuraminidase , PeleRESUMO
Runs of homozygosity (ROH) are important genomic features that manifest when an individual inherits two haplotypes that are identical by descent. Their length distributions are informative about population history, and their genomic locations are useful for mapping recessive loci contributing to both Mendelian and complex disease risk. We have previously shown that ROH, and especially long ROH that are likely the result of recent parental relatedness, are enriched for homozygous deleterious coding variation in a worldwide sample of outbred individuals. However, the distribution of ROH in admixed populations and their relationship to deleterious homozygous genotypes is understudied. Here we analyze whole-genome sequencing data from 1,441 unrelated individuals from self-identified African American, Puerto Rican, and Mexican American populations. These populations are three-way admixed between European, African, and Native American ancestries and provide an opportunity to study the distribution of deleterious alleles partitioned by local ancestry and ROH. We re-capitulate previous findings that long ROH are enriched for deleterious variation genome-wide. We then partition by local ancestry and show that deleterious homozygotes arise at a higher rate when ROH overlap African ancestry segments than when they overlap European or Native American ancestry segments of the genome. These results suggest that, while ROH on any haplotype background are associated with an inflation of deleterious homozygous variation, African haplotype backgrounds may play a particularly important role in the genetic architecture of complex diseases for admixed individuals, highlighting the need for further study of these populations.
Assuntos
Homozigoto , Alelos , Genótipo , Heterozigoto , Humanos , Sequenciamento Completo do GenomaRESUMO
OBJECTIVE: This work was undertaken in order to identify Parkinson's disease (PD) risk variants in a Latino cohort, to describe the overlap in the genetic architecture of PD in Latinos compared to European-ancestry subjects, and to increase the diversity in PD genome-wide association (GWAS) data. METHODS: We genotyped and imputed 1,497 PD cases and controls recruited from nine clinical sites across South America. We performed a GWAS using logistic mixed models; variants with a p-value <1 × 10-5 were tested in a replication cohort of 1,234 self-reported Latino PD cases and 439,522 Latino controls from 23andMe, Inc. We also performed an admixture mapping analysis where local ancestry blocks were tested for association with PD status. RESULTS: One locus, SNCA, achieved genome-wide significance (p-value <5 × 10-8 ); rs356182 achieved genome-wide significance in both the discovery and the replication cohorts (discovery, G allele: 1.58 OR, 95% CI 1.35-1.86, p-value 2.48 × 10-8 ; 23andMe, G allele: 1.26 OR, 95% CI 1.16-1.37, p-value 4.55 × 10-8 ). In our admixture mapping analysis, a locus on chromosome 14, containing the gene STXBP6, achieved significance in a joint test of ancestries and in the Native American single-ancestry test (p-value <5 × 10-5 ). A second locus on chromosome 6, containing the gene RPS6KA2, achieved significance in the African single-ancestry test (p-value <5 × 10-5 ). INTERPRETATION: This study demonstrated the importance of the SNCA locus for the etiology of PD in Latinos. By leveraging the demographic history of our cohort via admixture mapping, we identified two potential PD risk loci that merit further study. ANN NEUROL 2021;90:353-365.
Assuntos
Loci Gênicos/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Hispânico ou Latino/genética , Doença de Parkinson/etnologia , Doença de Parkinson/genética , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico , Polimorfismo de Nucleotídeo Único/genética , América do Sul/etnologiaRESUMO
Rationale: The 17q12-21.1 locus is one of the most highly replicated genetic associations with asthma. Individuals of African descent have lower linkage disequilibrium in this region, which could facilitate identifying causal variants.Objectives: To identify functional variants at 17q12-21.1 associated with early-onset asthma among African American individuals.Methods: We evaluated African American participants from SAPPHIRE (Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity) (n = 1,940), SAGE II (Study of African Americans, Asthma, Genes and Environment) (n = 885), and GCPD-A (Study of the Genetic Causes of Complex Pediatric Disorders-Asthma) (n = 2,805). Associations with asthma onset at ages under 5 years were meta-analyzed across cohorts. The lead signal was reevaluated considering haplotypes informed by genetic ancestry (i.e., African vs. European). Both an expression-quantitative trait locus analysis and a phenome-wide association study were performed on the lead variant.Measurements and Main Results: The meta-analyzed results from SAPPHIRE, SAGE II, and the GCPD-A identified rs11078928 as the top association for early-onset asthma. A haplotype analysis suggested that the asthma association partitioned most closely with the rs11078928 genotype. Genetic ancestry did not appear to influence the effect of this variant. In the expression-quantitative trait locus analysis, rs11078928 was related to alternative splicing of GSDMB (gasdermin-B) transcripts. The phenome-wide association study of rs11078928 suggested that this variant was predominantly associated with asthma and asthma-associated symptoms.Conclusions: A splice-acceptor polymorphism appears to be a causal variant for asthma at the 17q12-21.1 locus. This variant appears to have the same magnitude of effect in individuals of African and European descent.
Assuntos
Negro ou Afro-Americano/genética , Cromossomos Humanos Par 17 , Estudos de Associação Genética , Predisposição Genética para Doença/genética , População Branca/genética , Adolescente , Adulto , Idade de Início , Asma/genética , Criança , Pré-Escolar , Mapeamento Cromossômico , Feminino , Variação Genética , Humanos , Lactente , Recém-Nascido , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Estados Unidos , Adulto JovemRESUMO
BACKGROUND: Asthma is a heterogeneous disease. Clinical blood parameters differ by race/ethnicity and are used to distinguish asthma subtypes and inform therapies. Differences in subtypes may explain population-specific trends in asthma outcomes. However, these differences in racial/ethnic minority pediatric populations are unclear. OBJECTIVE: We investigated the association of blood parameters and asthma subtypes with asthma outcomes and examined population-specific eligibility for biologic therapies in minority pediatric populations. METHODS: Using data from 2 asthma case-control studies of pediatric minority populations, we performed case-control (N = 3738) and case-only (N = 2743) logistic regressions to quantify the association of blood parameters and asthma subtypes with asthma outcomes. Heterogeneity of these associations was tested using an interaction term between race/ethnicity and each exposure. Differences in therapeutic eligibility were investigated using chi-square tests. RESULTS: Race/ethnicity modified the association between total IgE and asthma exacerbations. Elevated IgE level was associated with worse asthma outcomes in Puerto Ricans. Allergic asthma was associated with worse outcomes in Mexican Americans, whereas eosinophilic asthma was associated with worse outcomes in Puerto Ricans. A lower proportion of Puerto Ricans met dosing criteria for allergic asthma-directed biologic therapy than other groups. A higher proportion of Puerto Ricans qualified for eosinophilic asthma-directed biologic therapy than African Americans. CONCLUSIONS: We found population-specific associations between blood parameters and asthma subtypes with asthma outcomes. Our findings suggest that eligibility for asthma biologic therapies differs across pediatric racial/ethnic populations. These findings call for more studies in diverse populations for equitable treatment of minority patients with asthma.
Assuntos
Antiasmáticos/uso terapêutico , Asma/epidemiologia , Produtos Biológicos/uso terapêutico , Etnicidade , Grupos Minoritários , Grupos Raciais , Adolescente , Asma/terapia , Estudos de Casos e Controles , Criança , Definição da Elegibilidade , Feminino , Humanos , Imunoglobulina E/sangue , Masculino , Fenótipo , Estados Unidos/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Severe asthma exacerbations are a major cause of asthma morbidity and increased healthcare costs. Several studies have shown racial and ethnic differences in asthma exacerbation rates. We aimed to identify genetic variants associated with severe exacerbations in two high-risk populations for asthma. METHODS: A genome-wide association study of asthma in children and youth with severe exacerbations was performed in 1283 exacerbators and 2027 controls without asthma of Latino ancestry. Independent suggestive variants (P ≤ 5 × 10-6 ) were selected for replication in 448 African Americans exacerbators and 595 controls. Case-only analyses were performed comparing the exacerbators with additional 898 Latinos and 524 African Americans asthma patients without exacerbations, while adjusting by treatment category as a proxy of asthma severity. We analyzed the functionality of associated variants with in silico methods and by correlating genotypes with methylation levels in whole blood in a subset of 473 Latinos. RESULTS: We identified two genome-wide significant associations for susceptibility to asthma with severe exacerbations, including a novel locus located at chromosome 2p21 (rs4952375, odds ratio = 1.39, P = 3.8 × 10-8 ), which was also associated with asthma exacerbations in a case-only analysis (odds ratio = 1.25, P = 1.95 × 10-3 ). This polymorphism is an expression quantitative trait locus of the long intergenic non-protein coding RNA 1913 (LINC01913) in lung tissues (P = 1.3 × 10-7 ) and influences methylation levels of the protein kinase domain-containing cytoplasmic (PKDCC) gene in whole-blood cells (P = 9.8 × 10-5 ). CONCLUSION: We identified a novel susceptibility locus for severe asthma exacerbations in Hispanic/Latino and African American youths with functional effects in gene expression and methylation status of neighboring genes.
Assuntos
Asma , Estudo de Associação Genômica Ampla , Adolescente , Negro ou Afro-Americano/genética , Asma/genética , Predisposição Genética para Doença , Hispânico ou Latino/genética , Humanos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
An influential paradigm in coral reef ecology is that fishing causes trophic cascades through reef fish assemblages, resulting in reduced herbivory and thus benthic phase shifts from coral to algal dominance. Few long-term field tests exist of how fishing affects the trophic structure of coral reef fish assemblages, and how such changes affect the benthos. Alternatively, benthic change itself may drive the trophic structure of reef fish assemblages. Reef fish trophic structure and benthic cover were quantified almost annually from 1983 to 2014 at two small Philippine islands (Apo, Sumilon). At each island a No-Take Marine Reserve (NTMR) site and a site open to subsistence reef fishing were monitored. Thirteen trophic groups were identified. Large planktivores often accounted for >50% of assemblage biomass. Significant NTMR effects were detected at each island for total fish biomass, but for only 2 of 13 trophic components: generalist large predators and large planktivores. Fishing-induced changes in biomass of these components had no effect on live hard coral (HC) cover. In contrast, HC cover affected biomass of 11 of 13 trophic components significantly. Positive associations with HC cover were detected for total fish biomass, generalist large predators, piscivores, obligate coral feeders, large planktivores, and small planktivores. Negative associations with HC cover were detected for large benthic foragers, detritivores, excavators, scrapers, and sand feeders. These associations of fish biomass to HC cover were most clear when environmental disturbances (e.g., coral bleaching, typhoons) reduced HC cover, often quickly (1-2 yr), and when HC recovered, often slowly (5-10 yr). As HC cover changed, the biomass of 11 trophic components of the fish assemblage changed. Benthic and fish assemblages were distinct at all sites from the outset, remaining so for 31 yr, despite differences in fishing pressure and disturbance history. HC cover alone explained ~30% of the variability in reef fish trophic structure, whereas fishing alone explained 24%. Furthermore, HC cover affected more trophic groups more strongly than fishing. Management of coral reefs must include measures to maintain coral reef habitats, not just measures to reduce fishing by NTMRs.
Assuntos
Antozoários , Animais , Biomassa , Conservação dos Recursos Naturais , Recifes de Corais , Ecossistema , PeixesRESUMO
Rationale: Puerto Ricans have the highest childhood asthma prevalence in the United States (23.6%); however, the etiology is uncertain.Objectives: In this study, we sought to uncover the genetic architecture of lung function in Puerto Rican youth with and without asthma who were recruited from the island (n = 836).Methods: We used admixture-mapping and whole-genome sequencing data to discover genomic regions associated with lung function. Functional roles of the prioritized candidate SNPs were examined with chromatin immunoprecipitation sequencing, RNA sequencing, and expression quantitative trait loci data.Measurements and Main Results: We discovered a genomic region at 1q32 that was significantly associated with a 0.12-L decrease in the lung volume of exhaled air (95% confidence interval, -0.17 to -0.07; P = 6.62 × 10-8) with each allele of African ancestry. Within this region, two SNPs were expression quantitative trait loci of TMEM9 in nasal airway epithelial cells and MROH3P in esophagus mucosa. The minor alleles of these SNPs were associated with significantly decreased lung function and decreased TMEM9 gene expression. Another admixture-mapping peak was observed on chromosome 5q35.1, indicating that each Native American ancestry allele was associated with a 0.15-L increase in lung function (95% confidence interval, 0.08-0.21; P = 5.03 × 10-6). The region-based association tests identified four suggestive windows that harbored candidate rare variants associated with lung function.Conclusions: We identified common and rare genetic variants that may play a critical role in lung function among Puerto Rican youth. We independently validated an inflammatory pathway that could potentially be used to develop more targeted treatments and interventions for patients with asthma.
Assuntos
Asma/genética , População Negra/genética , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 5/genética , Volume Expiratório Forçado/genética , Indígenas Norte-Americanos/genética , Pulmão/fisiopatologia , Adolescente , Asma/fisiopatologia , Brônquios/citologia , Estudos de Casos e Controles , Linhagem Celular , Criança , Imunoprecipitação da Cromatina , Mapeamento Cromossômico , Mucosa Esofágica/metabolismo , Feminino , Expressão Gênica , Humanos , Desequilíbrio de Ligação , Pulmão/fisiologia , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Miócitos de Músculo Liso , Mucosa Nasal/metabolismo , Polimorfismo de Nucleotídeo Único , Porto Rico , Locos de Características Quantitativas , Análise de Sequência de RNA , População Branca/genética , Sequenciamento Completo do Genoma , Adulto JovemRESUMO
This investigation profiled circulating serum concentrations of microRNAs (miRNAs) in premature cardiovascular disease (CVD) patients screened for the 677Câ¯>â¯T polymorphism in methylenetetrahydrofolate reductase (MTHFR), a risk factor for hypertension. Serum samples from 75 premature CVD patients of known MTHFR genotype were analysed for CVD-related miRNA expression, to identify those that were associated with blood pressure. Samples were collected at baseline and following intervention with riboflavin as part of a randomized controlled trial. In patients with the MTHFR 677TT genotype, expression of miR-199a-5p in serum was inversely correlated with hypertension at baseline, and with change in blood pressure in TT genotype patients who responded to riboflavin intervention. These correlations were not observed in MTHFR 677CC genotype patients. In vitro experiments and in silico data analysis provided evidence that miR-199a-5p targets SMAD4. This is the first study to link miR-199a-5p expression with hypertension in a genetically at-risk cohort of premature CVD patients.
Assuntos
Pressão Sanguínea/genética , Regulação da Expressão Gênica , Homozigoto , Hipertensão , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , MicroRNAs/sangue , Polimorfismo Genético , Feminino , Genótipo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Hipertensão/sangue , Hipertensão/genética , Hipertensão/patologia , Hipertensão/fisiopatologia , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , MicroRNAs/genética , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
BACKGROUND: Global gene expression levels are known to be highly dependent upon gross demographic features including age, yet identification of age-related genomic indicators has yet to be comprehensively undertaken in a disease and treatment-specific context. METHODS: We used gene expression data from CD4+ lymphocytes in the Asthma BioRepository for Integrative Genomic Exploration (Asthma BRIDGE), an open-access collection of subjects participating in genetic studies of asthma with available gene expression data. Replication population participants were Puerto Rico islanders recruited as part of the ongoing Genes environments & Admixture in Latino Americans (GALA II), who provided nasal brushings for transcript sequencing. The main outcome measure was chronic asthma control as derived by questionnaires. Genomic associations were performed using regression of chronic asthma control score on gene expression with age in years as a covariate, including a multiplicative interaction term for gene expression times age. RESULTS: The SMARCD1 gene (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1) interacted with age to influence chronic asthma control on inhaled corticosteroids, with a doubling of expression leading to an increase of 1.3 units of chronic asthma control per year (95% CI [0.86, 1.74], p = 6 × 10- 9), suggesting worsening asthma control with increasing age. This result replicated in GALA II (p = 3.8 × 10- 8). Cellular assays confirmed the role of SMARCD1 in glucocorticoid response in airway epithelial cells. CONCLUSION: Focusing on age-dependent factors may help identify novel indicators of asthma medication response. Age appears to modulate the effect of SMARCD1 on asthma control with inhaled corticosteroids.
Assuntos
Corticosteroides/administração & dosagem , Asma/tratamento farmacológico , Asma/genética , Proteínas Cromossômicas não Histona/biossíntese , Proteínas Cromossômicas não Histona/genética , Hispânico ou Latino/genética , Administração por Inalação , Adolescente , Adulto , Fatores Etários , Asma/metabolismo , Criança , Estudos de Coortes , Feminino , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
Embedded research is an innovative means to improve performance in the learning healthcare system (LHS). However, few descriptions of successful embedded research programs have been published. In this perspective, we describe the Care Improvement Research Team, a mature partnership between researchers and clinicians at Kaiser Permanente Southern California. The program supports a core team of researchers and staff with dedicated resources to partner with health system leaders and practicing clinicians, using diverse methods to identify and rectify gaps in clinical practice. For example, recent projects helped clinicians to provide better care by reducing prescribing of unnecessary antibiotics for acute sinusitis and by preventing readmissions among the elderly. Embedded in operational workgroups, the team helps formulate research questions and enhances the rigor and relevance of data collection and analysis. A recent business-case analysis cited savings to the organization of over $10 million. We conclude that embedded research programs can play a key role in fulfilling the promise of the LHS. Program success depends on dedicated funding, robust data systems, and strong relationships between researchers and clinical stakeholders. Embedded researchers must be responsive to health system priorities and timelines, while clinicians should embrace researchers as partners in problem solving.
Assuntos
Sistema de Aprendizagem em Saúde , Idoso , Programas Governamentais , Prioridades em Saúde , Humanos , Estudos Longitudinais , PesquisadoresRESUMO
In the US, African Americans have a higher prevalence of hypertension than Whites. Previous studies show that social support contributes to the racial differences in hypertension but are limited in accounting for the social and environmental effects of racial residential segregation. We examined whether the association between race and hypertension varies by the level of social support among African Americans and Whites living in similar social and environmental conditions, specifically an urban, low-income, racially integrated community. Using data from the Exploring Health Disparities in Integrated Communities-Southwest Baltimore (EHDIC-SWB) sample, we hypothesized that social support moderates the relationship between race and hypertension and the racial difference in hypertension is smaller as the level of social support increases. Hypertension was defined as having systolic blood pressure greater than 140 mmHg and/or diastolic blood pressure greater than 90 mmHg, or the participant reports of taking antihypertensive medication(s). The study only included participants that self-reported as "Black/African American" or "White." Social support was measured as functional social support and marital status. After adjusting for demographics and health-related characteristics, we found no interaction between social support and race (DUFSS score, prevalence ratio 1.00; 95% confidence interval 0.99, 1.01; marital status, prevalence ratio 1.02; 95% confidence interval 0.86, 1.21); thus the hypothesis was not supported. A plausible explanation is that the buffering factor of social support cannot overcome the social and environmental conditions which the participants live in. Further, these findings emphasize social and environmental conditions of participants in EHDIC-SWB may equally impact race and hypertension.
Assuntos
Negro ou Afro-Americano/psicologia , Disparidades nos Níveis de Saúde , Hipertensão/epidemiologia , Pobreza/psicologia , Pobreza/estatística & dados numéricos , População Urbana/estatística & dados numéricos , População Branca/psicologia , Adulto , Negro ou Afro-Americano/estatística & dados numéricos , Baltimore/epidemiologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Apoio Social , Fatores Socioeconômicos , População Branca/estatística & dados numéricosRESUMO
We examined the association between perceived racial discrimination and hypertension among African Americans and whites who live in a low-income, racially integrated, urban community. Hypertension was defined as having a systolic blood pressure 140 mm Hg or more, a diastolic blood pressure 90 mm Hg or more, or taking antihypertensive medication(s). Perceived racial discrimination was based on self-reported responses of experiencing racial discrimination in various settings. Using modified Poisson multivariable regression models, we found no association between perceived racial discrimination and hypertension (prevalence ratio: 0.96, 95% confidence interval: 0.90-1.04). Findings suggest that social context may play a role in the relationship between perceived racial discrimination and hypertension.
Assuntos
Hipertensão/etnologia , Racismo/estatística & dados numéricos , Adulto , Estudos Transversais , Feminino , Humanos , Masculino , Pobreza , População UrbanaRESUMO
BACKGROUND: Telomere length (TL) can serve as a potential biomarker for conditions associated with chronic oxidative stress and inflammation, such as asthma. Air pollution can induce oxidative stress. Understanding the relationship between TL, asthma, and air pollution is important for identifying risk factors contributing to unhealthy aging in children. OBJECTIVES: We sought to investigate associations between exposures to ambient air pollutants and TL in African American children and adolescents and to examine whether African ancestry, asthma status, and steroid medication use alter the association. METHODS: Linear regression was used to examine associations between absolute telomere length (aTL) and estimated annual average residential ozone (O3) and fine particulate matter with a diameter of 2.5 µm or less (PM2.5) exposures in a cross-sectional analysis of 1072 children in an existing asthma case-control study. African ancestry, asthma status, and use of steroid medications were examined as effect modifiers. RESULTS: Participants' aTLs were measured by using quantitative PCR. A 1-ppb and 1 µg/m3 increase in annual average exposure to O3 and PM2.5 were associated with a decrease in aTL of 37.1 kilo-base pair (kb; 95% CI, -66.7 to -7.4 kb) and 57.1 kb (95% CI, -118.1 to 3.9 kb), respectively. African ancestry and asthma were not effect modifiers; however, exposure to steroid medications modified the relationships between TL and pollutants. Past-year exposure to O3 and PM2.5 was associated with shorter TLs in patients without steroid use. CONCLUSION: Exposure to air pollution was associated with shorter TLs in nonasthmatic children and adolescents. This was not the case for asthmatic children as a group, but those receiving steroid medication had less shortening than those not using steroids. Reduced exposure to air pollution in childhood might help to preserve TL.