Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 146
Filtrar
1.
Clin Epigenetics ; 11(1): 122, 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31443688

RESUMO

BACKGROUND: Although epigenetic mechanisms are important risk factors for allergic disease, few studies have evaluated DNA methylation differences associated with atopic dermatitis (AD), and none has focused on AD with eczema herpeticum (ADEH+). We will determine how methylation varies in AD individuals with/without EH and associated traits. We modeled differences in genome-wide DNA methylation in whole blood cells from 90 ADEH+, 83 ADEH-, and 84 non-atopic, healthy control subjects, replicating in 36 ADEH+, 53 ADEH-, and 55 non-atopic healthy control subjects. We adjusted for cell-type composition in our models and used genome-wide and candidate-gene approaches. RESULTS: We replicated one CpG which was significantly differentially methylated by severity, with suggestive replication at four others showing differential methylation by phenotype or severity. Not adjusting for eosinophil content, we identified 490 significantly differentially methylated CpGs (ADEH+ vs healthy controls, genome-wide). Many of these associated with severity measures, especially eosinophil count (431/490 sites). CONCLUSIONS: We identified a CpG in IL4 associated with serum tIgE levels, supporting a role for Th2 immune mediating mechanisms in AD. Changes in eosinophil level, a measure of disease severity, are associated with methylation changes, providing a potential mechanism for phenotypic changes in immune response-related traits.

2.
Nature ; 570(7762): 514-518, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31217584

RESUMO

Genome-wide association studies (GWAS) have laid the foundation for investigations into the biology of complex traits, drug development and clinical guidelines. However, the majority of discovery efforts are based on data from populations of European ancestry1-3. In light of the differential genetic architecture that is known to exist between populations, bias in representation can exacerbate existing disease and healthcare disparities. Critical variants may be missed if they have a low frequency or are completely absent in European populations, especially as the field shifts its attention towards rare variants, which are more likely to be population-specific4-10. Additionally, effect sizes and their derived risk prediction scores derived in one population may not accurately extrapolate to other populations11,12. Here we demonstrate the value of diverse, multi-ethnic participants in large-scale genomic studies. The Population Architecture using Genomics and Epidemiology (PAGE) study conducted a GWAS of 26 clinical and behavioural phenotypes in 49,839 non-European individuals. Using strategies tailored for analysis of multi-ethnic and admixed populations, we describe a framework for analysing diverse populations, identify 27 novel loci and 38 secondary signals at known loci, as well as replicate 1,444 GWAS catalogue associations across these traits. Our data show evidence of effect-size heterogeneity across ancestries for published GWAS associations, substantial benefits for fine-mapping using diverse cohorts and insights into clinical implications. In the United States-where minority populations have a disproportionately higher burden of chronic conditions13-the lack of representation of diverse populations in genetic research will result in inequitable access to precision medicine for those with the highest burden of disease. We strongly advocate for continued, large genome-wide efforts in diverse populations to maximize genetic discovery and reduce health disparities.

3.
Acta Trop ; 195: 28-34, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30986379

RESUMO

The precise diagnosis of Schistosoma japonicum (S. japonicum) infection plays a critical role in achieving the ultimate goal of eliminating schistosomiasis in endemic regions. We evaluated the S. japonicum soluble worm antigen protein (SWAP) specific-IgG, IgG4 and IgE levels, and evaluated the association between S. japonicum infection and these antibodies in a sample of 837 residents from a S. japonicum-endemic area in Hubei province, China. The anticipants were divided into the Training Set (TS) and Validation Set (VS) based on the chronological order. Enzyme-linked immunosorbent assays were performed to detect the SWAP-specific antibodies. Three algorithms for identifying S. japonicum infection were generated in the TS and subsequently validated in the VS. The findings were further replicated in an independent cohort from an endemic area for Schistosoma mansoni (S. mansoni) in Brazil. Our results indicated for the first time that S. japonicum-infected individuals had higher levels of SWAP-specific IgG, IgG4 and IgE, and lower value of the IgE/IgG4 ratio than uninfected individuals in both the two sets (p < 0.01). Both the infected and uninfected individuals had a high prevalence of seropositivity for IgG. We further showed that the predictive model EGR (IgE/IgG4 ratio) score performed best in Chinese population (area under the receiver operating characteristic (AUROC) 0.905, sensitivity 82.7%, specificity 84.0% in the TS; AUROC 0.933, sensitivity 87.7%, specificity 89.1% in the VS). Nevertheless, the predictive model IgG4 score performed best in Brazilian cohort (AUROC 0.788, sensitivity 73.2%, specificity 73.3%). In summary, SWAP-specific IgG could be used as a biomarker for identifying individuals who have been previously exposed to S. japonicum, and furthermore the SWAP-specific IgE/IgG4 could be used as an immune biomarker for S. japonicum infection in particular in the endemic areas with low prevalence and intensity.


Assuntos
Anticorpos Anti-Helmínticos/sangue , Antígenos de Helmintos/imunologia , Schistosoma japonicum/imunologia , Esquistossomose Japônica/epidemiologia , Adulto , Idoso , Animais , Biomarcadores , China/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Coelhos
5.
Ann Allergy Asthma Immunol ; 122(5): 456-462, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30772392

RESUMO

OBJECTIVE: Asthma and atopic dermatitis (AD) are complex diseases with striking disparities across racial and ethnic groups, which may be partly attributable to genetic factors. Here we summarize current knowledge from asthma and AD genome-wide association studies (GWAS) and pharmacogenetic studies in African ancestry populations. DATA SOURCES: GWAS catalog; PUBMed. STUDY SELECTIONS: GWAS catalog studies with trait annotations "asthma" and "atopic eczema" and African ancestry individuals in the discovery dataset; the recent CAAPA asthma GWAS; reports on pharmacogenetic studies in asthma and AD. RESULTS: Although GWASs have revolutionized gene discovery for multiple complex traits, African Americans continue to be severely underrepresented in sufficiently powered genetics studies. Indeed, of the 16 asthma and 21 AD loci that reached genomewide significance in Europeans, very few have replicated in African ancestry populations. Challenges in comparing results from European vs African ancestry cohorts include modest sample size, differences in risk allele frequency, effect size, correlation between genetic variants, and environmental exposure in evolutionary history. African Americans also constitute a small percentage of dermatological and respiratory-focused clinical trials. Pharmacogenetic studies have similarly been focused largely on non-Hispanic whites, despite compelling evidence that genetic variation from different ancestral backgrounds may alter therapeutic efficacy of asthma and AD drugs. CONCLUSION: Large-scale genetic studies of asthma and AD in African Americans are essential to reduce research and health disparities and empower scientific discoveries.

9.
Nat Genet ; 2018 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-30455414

RESUMO

We used a deeply sequenced dataset of 910 individuals, all of African descent, to construct a set of DNA sequences that is present in these individuals but missing from the reference human genome. We aligned 1.19 trillion reads from the 910 individuals to the reference genome (GRCh38), collected all reads that failed to align, and assembled these reads into contiguous sequences (contigs). We then compared all contigs to one another to identify a set of unique sequences representing regions of the African pan-genome missing from the reference genome. Our analysis revealed 296,485,284 bp in 125,715 distinct contigs present in the populations of African descent, demonstrating that the African pan-genome contains ~10% more DNA than the current human reference genome. Although the functional significance of nearly all of this sequence is unknown, 387 of the novel contigs fall within 315 distinct protein-coding genes, and the rest appear to be intergenic.

10.
Obesity (Silver Spring) ; 26(12): 1938-1948, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30358166

RESUMO

OBJECTIVE: Asthmatic children who develop obesity through adolescence have poorer disease outcomes compared with those who do not. This study aimed to characterize the biology of childhood asthma complicated by adult obesity. METHODS: Gene expression networks are powerful statistical tools for characterizing human disease that leverage the putative coregulatory relationships of genes to infer relevant biological pathways. Weighted gene coexpression network analysis of gene expression data was performed in whole blood from 514 adult asthmatic subjects. Then, module preservation and association replication analyses were performed in 418 subjects from two independent asthma cohorts (one pediatric and one adult). RESULTS: A multivariate model was identified in which three gene coexpression network modules were associated with incident obesity in the discovery cohort (each P < 0.05). Two module memberships were enriched for genes in pathways related to platelets, integrins, extracellular matrix, smooth muscle, NF-κB signaling, and Hedgehog signaling. The network structures of each of the obesity modules were significantly preserved in both replication cohorts (permutation P = 9.999E-05). The corresponding module gene sets were significantly enriched for differential expression in subjects with obesity in both replication cohorts (each P < 0.05). CONCLUSIONS: The gene coexpression network profiles thus implicate multiple interrelated pathways in the biology of an important endotype of asthma with obesity.

11.
Acad Emerg Med ; 2018 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-30239069

RESUMO

The Emergency Medicine Specimen Bank (EMSB) was developed to facilitate precision medicine in acute care. The EMSB is a biorepository of clinical health data and biospecimens collected from all adult English- or Spanish-speaking individuals who are able and willing to provide consent and are treated at the UCHealth-University of Colorado Hospital Emergency Department. The EMSB is the first acute care biobank that seeks to enroll all patients, with all conditions who present to the ED. Acute care biobanking presents many challenges that are unique to acute care settings such as providing informed consent in a uniquely stressful and fast-paced environment and collecting, processing, and storing samples for tens of thousands of patients per year. Here, we describe the process by which the EMSB overcame these challenges and was integrated into clinical workflow allowing for operation 24 hours a day, 7 days a week at a reasonable cost. Other institutions can implement this template, further increasing the power of biobanking research to inform treatment strategies and interventions for common and uncommon phenotypes in acute care settings.

12.
Hum Mol Genet ; 27(21): 3801-3812, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30060175

RESUMO

Chronic obstructive pulmonary disease (COPD), one of the leading causes of death worldwide, is substantially influenced by genetic factors. Alpha-1 antitrypsin deficiency demonstrates that rare coding variants of large effect can influence COPD susceptibility. To identify additional rare coding variants in patients with severe COPD, we conducted whole exome sequencing analysis in 2543 subjects from two family-based studies (Boston Early-Onset COPD Study and International COPD Genetics Network) and one case-control study (COPDGene). Applying a gene-based segregation test in the family-based data, we identified significant segregation of rare loss of function variants in TBC1D10A and RFPL1 (P-value < 2x10-6), but were unable to find similar variants in the case-control study. In single-variant, gene-based and pathway association analyses, we were unable to find significant findings that replicated or were significant in meta-analysis. However, we found that the top results in the two datasets were in proximity to each other in the protein-protein interaction network (P-value = 0.014), suggesting enrichment of these results for similar biological processes. A network of these association results and their neighbors was significantly enriched in the transforming growth factor beta-receptor binding and cilia-related pathways. Finally, in a more detailed examination of candidate genes, we identified individuals with putative high-risk variants, including patients harboring homozygous mutations in genes associated with cutis laxa and Niemann-Pick Disease Type C. Our results likely reflect heterogeneity of genetic risk for COPD along with limitations of statistical power and functional annotation, and highlight the potential of network analysis to gain insight into genetic association studies.

13.
J Invest Dermatol ; 138(10): 2224-2233, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29604251

RESUMO

Patients with atopic dermatitis (AD) are commonly colonized with Staphylococcus aureus (AD S. aureus+), but what differentiates this group from noncolonized AD patients (AD S. aureus-) has not been well studied. To evaluate whether these two groups have unique phenotypic or endotypic features, we performed a multicenter, cross-sectional study enrolling AD S. aureus+ (n = 51) and AD S. aureus- (n = 45) participants defined by the presence or absence of S. aureus by routine culture techniques and nonatopic, noncolonized control individuals (NA S. aureus-) (n = 46). Filaggrin (FLG) genotypes were determined, and disease severity (Eczema Area and Severity Index, Rajka-Langeland Severity Score, Investigator's Global Assessment score, Numerical Rating Scale, and Dermatology Life Quality Index) was captured. Skin physiology was assessed (transepidermal water loss [TEWL], stratum corneum integrity, hydration, and pH), and serum biomarkers were also measured. We found that AD S. aureus+ patients had more severe disease based on all scoring systems except itch (Numerical Rating Scale), and they had higher levels of type 2 biomarkers (eosinophil count, tIgE, CCL17, and periostin). Additionally, AD S. aureus+ patients had significantly greater allergen sensitization (Phadiatop and tIgE), barrier dysfunction (TEWL and stratum corneum integrity), and serum lactate dehydrogenase (LDH) than both the AD S. aureus- and NA S. aureus- groups. FLG mutations did not associate with S. aureus+ colonization. In conclusion, adult patients with AD who are colonized on their skin with S. aureus have more severe disease, greater type 2 immune deviation, allergen sensitization, barrier disruption, and LDH level elevation than noncolonized patients with AD.

14.
Respir Res ; 19(1): 59, 2018 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-29631575

RESUMO

BACKGROUND: Smoking is the principal modifiable environmental risk factor for chronic obstructive pulmonary disease (COPD) which affects 300 million people and is the 3rd leading cause of death worldwide. Most of the genetic studies of smoking have relied on self-reported smoking status which is vulnerable to reporting and recall bias. Using data from the Lung Health Study (LHS), we sought to identify genetic variants associated with quantitative smoking and cessation in individuals with mild to moderate COPD. METHODS: The LHS is a longitudinal multicenter study of mild-to-moderate COPD subjects who were all smokers at recruitment. We performed genome-wide association studies (GWASs) for salivary cotinine (n = 4024), exhaled carbon monoxide (eCO) (n = 2854), cigarettes per day (CPD) (n = 2706) and smoking cessation at year 5 follow-up (n = 717 quitters and 2175 smokers). The GWAS analyses were adjusted for age, gender, and genetic principal components. RESULTS: For cotinine levels, SNPs near UGT2B10 gene achieved genome-wide significance (i.e. P < 5 × 10- 8) with top SNP rs10023464, P = 1.27 × 10- 11. For eCO levels, one significant SNP was identified which mapped to the CHRNA3 gene (rs12914385, P = 2.38 × 10- 8). A borderline region mapping to KCNMA1 gene was associated with smoking cessation (rs207675, P = 5.95 × 10- 8). Of the identified loci, only the CHRNA3/5 locus showed significant associations with lung function but only in heavy smokers. No regions met genome-wide significance for CPD. CONCLUSION: The study demonstrates that using objective measures of smoking such as eCO and/or salivary cotinine can more precisely capture the genetic contribution to multiple aspects of smoking behaviour. The KCNMA1 gene association with smoking cessation may represent a potential therapeutic target and warrants further studies. TRIAL REGISTRATION: The Lung Health Study ClinicalTrials.gov Identifier: NCT00000568 . Date of registration: October 28, 1999.


Assuntos
Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/genética , Fumar/epidemiologia , Fumar/genética , Adulto , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/genética , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Doença Pulmonar Obstrutiva Crônica/terapia , Fumar/terapia , Abandono do Hábito de Fumar/métodos
15.
Ann Am Thorac Soc ; 15(4): 440-448, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29323929

RESUMO

RATIONALE: Cystic fibrosis, like primary ciliary dyskinesia, is an autosomal recessive disorder characterized by abnormal mucociliary clearance and obstructive lung disease. We hypothesized that genes underlying the development or function of cilia may modify lung disease severity in persons with cystic fibrosis. OBJECTIVES: To test this hypothesis, we compared variants in 93 candidate genes in both upper and lower tertiles of lung function in a large cohort of children and adults with cystic fibrosis with those of a population control dataset. METHODS: Variants within candidate genes were tested for association using the SKAT-O test, comparing cystic fibrosis cases defined by poor (n = 127) or preserved (n = 127) lung function with population controls (n = 3,269 or 3,148, respectively). Associated variants were then tested for association with related phenotypes in independent datasets. RESULTS: Variants in DNAH14 and DNAAF3 were associated with poor lung function in cystic fibrosis, whereas variants in DNAH14 and DNAH6 were associated with preserved lung function in cystic fibrosis. Associations between DNAH14 and lung function were replicated in disease-related phenotypes characterized by obstructive lung disease in adults. CONCLUSIONS: Genetic variants within DNAH6, DNAH14, and DNAAF3 are associated with variation in lung function among persons with cystic fibrosis.

17.
Nat Genet ; 50(1): 42-53, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29273806

RESUMO

We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.

18.
Eur Respir J ; 50(5)2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29191953

RESUMO

Surfactant protein D (SP-D) is produced primarily in the lung and is involved in regulating pulmonary surfactants, lipid homeostasis and innate immunity. Circulating SP-D levels in blood are associated with chronic obstructive pulmonary disease (COPD), although causality remains elusive.In 4061 subjects with COPD, we identified genetic variants associated with serum SP-D levels. We then determined whether these variants affected lung tissue gene expression in 1037 individuals. A Mendelian randomisation framework was then applied, whereby serum SP-D-associated variants were tested for association with COPD risk in 11 157 cases and 36 699 controls and with 11 years decline of lung function in the 4061 individuals.Three regions on chromosomes 6 (human leukocyte antigen region), 10 (SFTPD gene) and 16 (ATP2C2 gene) were associated with serum SP-D levels at genome-wide significance. In Mendelian randomisation analyses, variants associated with increased serum SP-D levels decreased the risk of COPD (estimate -0.19, p=6.46×10-03) and slowed the lung function decline (estimate=0.0038, p=7.68×10-3).Leveraging genetic variation effect on protein, lung gene expression and disease phenotypes provided novel insights into SP-D biology and established a causal link between increased SP-D levels and protection against COPD risk and progression. SP-D represents a very promising biomarker and therapeutic target for COPD.


Assuntos
Análise da Randomização Mendeliana , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/genética , Proteína D Associada a Surfactante Pulmonar/sangue , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Progressão da Doença , Feminino , Humanos , Modelos Lineares , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Fatores de Risco
19.
Sci Rep ; 7: 46398, 2017 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-28429804

RESUMO

A primary goal of The Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) is to develop an 'African Diaspora Power Chip' (ADPC), a genotyping array consisting of tagging SNPs, useful in comprehensively identifying African specific genetic variation. This array is designed based on the novel variation identified in 642 CAAPA samples of African ancestry with high coverage whole genome sequence data (~30× depth). This novel variation extends the pattern of variation catalogued in the 1000 Genomes and Exome Sequencing Projects to a spectrum of populations representing the wide range of West African genomic diversity. These individuals from CAAPA also comprise a large swath of the African Diaspora population and incorporate historical genetic diversity covering nearly the entire Atlantic coast of the Americas. Here we show the results of designing and producing such a microchip array. This novel array covers African specific variation far better than other commercially available arrays, and will enable better GWAS analyses for researchers with individuals of African descent in their study populations. A recent study cataloging variation in continental African populations suggests this type of African-specific genotyping array is both necessary and valuable for facilitating large-scale GWAS in populations of African ancestry.

20.
Ann Allergy Asthma Immunol ; 118(4): 483-488.e1, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28284979

RESUMO

BACKGROUND: Allergic asthma is a complex disorder that results from a combination of genetic and environmental factors. Studies suggest that helminth infections can activate a regulatory network characterized by the production of regulatory cytokines, such as interleukin 10 and transforming growth factor ß1 (TGF-ß1) and subsequently protect against immune-mediated diseases, such as asthma. On the other hand, TGF-ß1 is increased in the lungs of individuals with asthma and may modulate airway inflammation. The role of TGF- ß 1 single-nucleotide polymorphisms (SNPs) in allergic disease remains inconclusive. OBJECTIVE: To evaluate the effects of genetic variations in the TGF-ß1 on allergy and helminths infections in children. METHODS: We tested for association among 4 TGF-ß1 SNPs and allergic asthma, specific IgE, skin prick test result, and IL-10 production in 1,335 Brazilians. In addition, we analyzed the association with markers of helminth infection (parasite burden, anti-Ascaris IgE, and worm specific IgG4). The polymorphisms were genotyped using Taq Man probes. RESULTS: We found an association between rs1800470 (C allele) and atopic wheezing (odds ratio [OR], 0.60; 95% confidence interval [CI], 0.37-0.95) and markers of allergy (OR, 0.41; 95% CI, 0.22-0.79). In contrast, a positive association was observed between the haplotype ACCA and Trichuris trichiura infection (OR, 1.85; P = .003) and Ascaris lumbricoides infection (OR, 2.01; P < .001). This haplotype was also associated with increased IL-10 production (ß = 50.7; P < .001). CONCLUSION: Individuals with TGF-ß1 polymorphisms have an increased susceptibility to helminth infections and a lower risk of developing allergy. These studies suggest that immune modulation of allergic disease results not only from environmental factors but also from genetic susceptibility and IL-10 production.


Assuntos
Asma/etiologia , Grupos Étnicos , Predisposição Genética para Doença , Helmintíase/etiologia , Polimorfismo Genético , Fator de Crescimento Transformador beta1/genética , Alelos , Asma/epidemiologia , Brasil/epidemiologia , Brasil/etnologia , Criança , Pré-Escolar , Feminino , Frequência do Gene , Genótipo , Haplótipos , Helmintíase/epidemiologia , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Interleucina-10/metabolismo , Masculino , Razão de Chances , Polimorfismo de Nucleotídeo Único , Testes Cutâneos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA