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2.
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.

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
4.
Nat Commun ; 10(1): 880, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30787307

RESUMO

Asthma is a complex disease with striking disparities across racial and ethnic groups. Despite its relatively high burden, representation of individuals of African ancestry in asthma genome-wide association studies (GWAS) has been inadequate, and true associations in these underrepresented minority groups have been inconclusive. We report the results of a genome-wide meta-analysis from the Consortium on Asthma among African Ancestry Populations (CAAPA; 7009 asthma cases, 7645 controls). We find strong evidence for association at four previously reported asthma loci whose discovery was driven largely by non-African populations, including the chromosome 17q12-q21 locus and the chr12q13 region, a novel (and not previously replicated) asthma locus recently identified by the Trans-National Asthma Genetic Consortium (TAGC). An additional seven loci reported by TAGC show marginal evidence for association in CAAPA. We also identify two novel loci (8p23 and 8q24) that may be specific to asthma risk in African ancestry populations.


Assuntos
Afro-Americanos/genética , Asma/genética , Predisposição Genética para Doença/genética , Asma/epidemiologia , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 8/genética , Loci Gênicos , Estudo de Associação Genômica Ampla , Hispano-Americanos/genética , Humanos , Polimorfismo de Nucleotídeo Único/genética , Estados Unidos/epidemiologia
6.
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.

7.
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
8.
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.

9.
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
10.
Thorax ; 72(11): 998-1006, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28637835

RESUMO

BACKGROUND: COPD is a heterogeneous disease, but there is little consensus on specific definitions for COPD subtypes. Unsupervised clustering offers the promise of 'unbiased' data-driven assessment of COPD heterogeneity. Multiple groups have identified COPD subtypes using cluster analysis, but there has been no systematic assessment of the reproducibility of these subtypes. OBJECTIVE: We performed clustering analyses across 10 cohorts in North America and Europe in order to assess the reproducibility of (1) correlation patterns of key COPD-related clinical characteristics and (2) clustering results. METHODS: We studied 17 146 individuals with COPD using identical methods and common COPD-related characteristics across cohorts (FEV1, FEV1/FVC, FVC, body mass index, Modified Medical Research Council score, asthma and cardiovascular comorbid disease). Correlation patterns between these clinical characteristics were assessed by principal components analysis (PCA). Cluster analysis was performed using k-medoids and hierarchical clustering, and concordance of clustering solutions was quantified with normalised mutual information (NMI), a metric that ranges from 0 to 1 with higher values indicating greater concordance. RESULTS: The reproducibility of COPD clustering subtypes across studies was modest (median NMI range 0.17-0.43). For methods that excluded individuals that did not clearly belong to any cluster, agreement was better but still suboptimal (median NMI range 0.32-0.60). Continuous representations of COPD clinical characteristics derived from PCA were much more consistent across studies. CONCLUSIONS: Identical clustering analyses across multiple COPD cohorts showed modest reproducibility. COPD heterogeneity is better characterised by continuous disease traits coexisting in varying degrees within the same individual, rather than by mutually exclusive COPD subtypes.


Assuntos
Análise por Conglomerados , Volume Expiratório Forçado , Doença Pulmonar Obstrutiva Crônica/classificação , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Índice de Massa Corporal , Europa (Continente)/epidemiologia , Humanos , Fenótipo , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Reprodutibilidade dos Testes , Estados Unidos/epidemiologia
11.
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
12.
Thorax ; 72(5): 400-408, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28174340

RESUMO

BACKGROUND: Genome-wide association studies have identified numerous genetic regions that influence cross-sectional lung function. Longitudinal decline in lung function also includes a heritable component but the genetic determinants have yet to be defined. OBJECTIVES: We aimed to determine whether regions associated with cross-sectional lung function were also associated with longitudinal decline and to seek novel variants which influence decline. METHODS: We analysed genome-wide data from 4167 individuals from the Busselton Health Study cohort, who had undergone spirometry (12 695 observations across eight time points). A mixed model was fitted and weighted risk scores were calculated for the joint effect of 26 known regions on baseline and longitudinal changes in FEV1 and FEV1/FVC. Potential additional regions of interest were identified and followed up in two independent cohorts. RESULTS: The 26 regions previously associated with cross-sectional lung function jointly showed a strong effect on baseline lung function (p=4.44×10-16 for FEV1/FVC) but no effect on longitudinal decline (p=0.160 for FEV1/FVC). This was replicated in an independent cohort. 39 additional regions of interest (48 variants) were identified; these associations were not replicated in two further cohorts. CONCLUSIONS: Previously identified genetic variants jointly have a strong effect on cross-sectional lung function in adults but little or no effect on the rate of decline of lung function. It is possible that they influence COPD risk through lung development. Although no genetic variants have yet been associated with lung function decline at stringent genome-wide significance, longitudinal change in lung function is heritable suggesting that there is scope for future discoveries.


Assuntos
Variação Genética , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Respiração/genética , Adulto , Estudos Transversais , Progressão da Doença , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Testes de Função Respiratória , Medição de Risco , Fatores de Risco , Espirometria , Fatores de Tempo , Austrália Ocidental
13.
J Allergy Clin Immunol ; 140(5): 1416-1422.e6, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28189770

RESUMO

BACKGROUND: Chronic schistosomiasis and its severe complication, periportal fibrosis, are characterized by a predominant Th2 response. To date, specific single nucleotide polymorphisms in ST2 have been some of the most consistently associated genetic variants for asthma. OBJECTIVE: We investigated the role of ST2 (a receptor for the Th2 cytokine IL-33) in chronic and late-stage schistosomiasis caused by Schistosoma japonicum and the potential effect of ST2 genetic variants on stage of disease and ST2 expression. METHODS: We recruited 947 adult participants (339 with end-stage schistosomiasis and liver cirrhosis, 307 with chronic infections without liver fibrosis, and 301 health controls) from a S japonicum-endemic area (Hubei, China). Six ST2 single nucleotide polymorphisms were genotyped. Serum soluble ST2 (sST2) was measured by ELISA, and ST2 expression in normal liver tissues, Hepatitis B virus-induced fibrotic liver tissues, and S japonicum-induced fibrotic liver tissues was measured by immunohistochemistry. RESULTS: We found sST2 levels were significantly higher in the end-stage group (36.04 [95% CI, 33.85-38.37]) compared with chronic cases and controls (22.7 [95% CI, 22.0-23.4], P < 1E-10). In addition, S japonicum-induced fibrotic liver tissues showed increased ST2 staining compared with normal liver tissues (P = .0001). Markers rs12712135, rs1420101, and rs6543119 were strongly associated with sST2 levels (P = 2E-10, 5E-05, and 6E-05, respectively), and these results were replicated in an independent cohort from Brazil living in a S mansoni endemic region. CONCLUSIONS: We demonstrate for the first time that end-stage schistosomiasis is associated with elevated sST2 levels and show that ST2 genetic variants are associated with sST2 levels in patients with schistosomiasis.


Assuntos
Doenças Endêmicas , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Cirrose Hepática/genética , Fígado/patologia , Schistosoma japonicum/imunologia , Schistosoma mansoni/imunologia , Esquistossomose/genética , Adulto , Animais , Brasil/epidemiologia , China/epidemiologia , Doença Crônica , Estudos de Coortes , Progressão da Doença , Feminino , Fibrose , Genótipo , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1/sangue , Interleucina-33/metabolismo , Fígado/parasitologia , Cirrose Hepática/complicações , Cirrose Hepática/epidemiologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Esquistossomose/complicações , Esquistossomose/epidemiologia
14.
Nat Commun ; 7: 12522, 2016 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-27725671

RESUMO

The African Diaspora in the Western Hemisphere represents one of the largest forced migrations in history and had a profound impact on genetic diversity in modern populations. To date, the fine-scale population structure of descendants of the African Diaspora remains largely uncharacterized. Here we present genetic variation from deeply sequenced genomes of 642 individuals from North and South American, Caribbean and West African populations, substantially increasing the lexicon of human genomic variation and suggesting much variation remains to be discovered in African-admixed populations in the Americas. We summarize genetic variation in these populations, quantifying the postcolonial sex-biased European gene flow across multiple regions. Moreover, we refine estimates on the burden of deleterious variants carried across populations and how this varies with African ancestry. Our data are an important resource for empowering disease mapping studies in African-admixed individuals and will facilitate gene discovery for diseases disproportionately affecting individuals of African ancestry.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Fluxo Gênico , Genoma Humano , Migração Humana , Sequência de Bases , DNA Intergênico/genética , Feminino , Heterogeneidade Genética , Geografia , Humanos , Masculino , Filogenia , Polimorfismo de Nucleotídeo Único/genética , Sexismo
15.
Int Forum Allergy Rhinol ; 6(9): 926-34, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27173434

RESUMO

BACKGROUND: Eosinophils are thought to play a significant role in nasal polyposis, but the exact mechanism by which they contribute to polyposis remains unclear. Therefore, we proposed to test the hypothesis that peripheral blood eosinophilia (PBE) is a surrogate and biomarker for polyp load. To do this, we examined whether PBE levels correlate with nasal polyp load in a longitudinal manner. METHODS: We retrospectively analyzed the fluctuation of PBE and nasal polyp load in each patient (n = 61) assessed preoperatively, 1-2 months postoperatively, and 3-12 months postoperatively. Nasal polyp load was assessed using computed tomography (CT) scan preoperatively and nasal endoscopy postoperatively. Correlation coefficients were analyzed using parametric statistics. RESULTS: There was a positive correlation between initial preoperative baseline PBE and CT scan staging of polyp load (r = 0.35, p < 0.01). When patients were analyzed longitudinally, we found that the change in PBE correlated with the change in nasal endoscopy scores obtained at or near the same timepoint (r = 0.82, p < 2.0 × 10(-10) ). When nasal polyp load increased with time, we observed a stepwise increase in eosinophil counts (r = 0.37, p < 0.02). CONCLUSIONS: PBE correlates with nasal polyp load. PBE levels may be used along with nasal endoscopy to prospectively follow nasal polyp load postoperatively in chronic rhinosinusitis patients with hyperplastic nasal polyposis who have eosinophilia, asthma, and/or aspirin-exacerbated respiratory disease.


Assuntos
Eosinofilia , Pólipos Nasais , Adolescente , Adulto , Idoso , Doença Crônica , Endoscopia , Eosinofilia/sangue , Eosinofilia/diagnóstico por imagem , Eosinofilia/patologia , Feminino , Humanos , Hiperplasia , Masculino , Pessoa de Meia-Idade , Cavidade Nasal/diagnóstico por imagem , Cavidade Nasal/patologia , Cavidade Nasal/cirurgia , Pólipos Nasais/sangue , Pólipos Nasais/diagnóstico por imagem , Pólipos Nasais/patologia , Pólipos Nasais/cirurgia , Seios Paranasais/diagnóstico por imagem , Seios Paranasais/patologia , Seios Paranasais/cirurgia , Estudos Retrospectivos , Rinite/sangue , Rinite/diagnóstico por imagem , Rinite/cirurgia , Sinusite/sangue , Sinusite/diagnóstico por imagem , Sinusite/cirurgia , Tomografia Computadorizada por Raios X , Adulto Jovem
16.
Arthritis Rheumatol ; 68(1): 191-200, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26473621

RESUMO

OBJECTIVE: To determine the contribution of rare variants as genetic modifiers of the expressivity, penetrance, and severity of systemic sclerosis (SSc). METHODS: We performed whole-exome sequencing of 78 European American patients with SSc, including 35 patients without pulmonary arterial hypertension (PAH) and 43 patients with PAH. Association testing of case-control probability for rare variants was performed using the unified sequence kernel association test with optimal kernel weighting and small sample adjustment by comparing all SSc patients with a reference population of 3,179 controls from the Exome Sequencing Project 5,500 exome data set. Replication genotyping was performed in an independent sample of 3,263 patients (415 patients with SSc and 2,848 controls). We conducted expression profiling of messenger RNA from 61 SSc patients (19 without PAH and 42 with PAH) and 41 corresponding controls. RESULTS: The ATP8B4 gene was associated with a significant increase in the risk of SSc (P = 2.77 × 10(-7)). Among the 64 ATP8B4 variants tested, a single missense variant, c.1308C>G (F436L, rs55687265), provided the most compelling evidence of association (P = 9.35 × 10(-10), odds ratio [OR] 6.11), which was confirmed in the replication cohort (P = 0.012, OR 1.86) and meta-analysis (P = 1.92 × 10(-7), OR 2.5). Genes involved in E3 ubiquitin-protein ligase complex (ASB10) and cyclic nucleotide gated channelopathies (CNGB3) as well as HLA-DRB5 and HSPB2 (heat-shock protein 27) provided additional evidence of association (P < 10(-5)). Differential ATP8B4 expression was observed among the SSc patients compared to the controls (P = 0.0005). CONCLUSION: ATP8B4 may represent a putative genetic risk factor for SSc and pulmonary vascular complications.


Assuntos
Adenosina Trifosfatases/genética , Hipertensão Pulmonar/genética , Escleroderma Sistêmico/genética , Adulto , Idoso , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Variação Genética , Humanos , Hipertensão Pulmonar/etiologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Escleroderma Sistêmico/complicações , Análise de Sequência de DNA
17.
J Allergy Clin Immunol ; 136(6): 1591-1600, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26343451

RESUMO

BACKGROUND: A subset of atopic dermatitis is associated with increased susceptibility to eczema herpeticum (ADEH+). We previously reported that common single nucleotide polymorphisms (SNPs) in the IFN-γ (IFNG) and IFN-γ receptor 1 (IFNGR1) genes were associated with the ADEH+ phenotype. OBJECTIVE: We sought to interrogate the role of rare variants in interferon pathway genes for the risk of ADEH+. METHODS: We performed targeted sequencing of interferon pathway genes (IFNG, IFNGR1, IFNAR1, and IL12RB1) in 228 European American patients with AD selected according to their eczema herpeticum status, and severity was measured by using the Eczema Area and Severity Index. Replication genotyping was performed in independent samples of 219 European American and 333 African American subjects. Functional investigation of loss-of-function variants was conducted by using site-directed mutagenesis. RESULTS: We identified 494 single nucleotide variants encompassing 105 kb of sequence, including 145 common, 349 (70.6%) rare (minor allele frequency <5%), and 86 (17.4%) novel variants, of which 2.8% were coding synonymous, 93.3% were noncoding (64.6% intronic), and 3.8% were missense. We identified 6 rare IFNGR1 missense variants, including 3 damaging variants (Val14Met [V14M], Val61Ile, and Tyr397Cys [Y397C]) conferring a higher risk for ADEH+ (P = .031). Variants V14M and Y397C were confirmed to be deleterious, leading to partial IFNGR1 deficiency. Seven common IFNGR1 SNPs, along with common protective haplotypes (2-7 SNPs), conferred a reduced risk of ADEH+ (P = .015-.002 and P = .0015-.0004, respectively), and both SNP and haplotype associations were replicated in an independent African American sample (P = .004-.0001 and P = .001-.0001, respectively). CONCLUSION: Our results provide evidence that both genetic variants in the gene encoding IFNGR1 are implicated in susceptibility to the ADEH+ phenotype.


Assuntos
Dermatite Atópica/genética , Erupção Variceliforme de Kaposi/genética , Receptores de Interferon/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular , Criança , Pré-Escolar , Feminino , Genes Reporter , Predisposição Genética para Doença , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Interferon gama/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Risco , Fator de Transcrição STAT1/metabolismo , Adulto Jovem
18.
PLoS One ; 10(8): e0135360, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26258681

RESUMO

The aim of this study was to determine whether two polymorphisms in the gene encoding IL13 previously associated with Schistosoma hematobium (S. hematobium) and S. mansoni infection are associated with S. japonicum infection. Single nucleotide polymorphisms (SNPs) rs1800925 (IL13/-1112C>T) and rs20541 (IL13R130Q) were genotyped in 947 unrelated individuals (307 chronically infected, 339 late-stage with liver fibrosis, 301 uninfected controls) from a schistosomiasis-endemic area of Hubei province in China. Regression models were used to evaluate allelic and haplotypic associations with chronic and late-stage schistosomiasis adjusted for non-genetic covariates. Expression of IL-13 was measured in S. japonicun-infected liver fibrosis tissue and normal liver tissue from uninfected controls by immunohistochemistry (IHC). The role of rs1800925 in IL-13 transcription was further determined by Luciferase report assay using the recombinant PGL4.17-rs180092 plasmid. We found SNP rs1800925T was associated with late-stage schistosomiasis caused by S. japonicum but not chronic schistosomiasis (OR = 1.39, 95%CI = 1.02-1.91, p = 0.03) and uninfected controls (OR = 1.49, 95%CI = 1.03-2.13, p = 0.03). Moreover, the haplotype rs1800925T-rs20541C increased the risk of disease progression to late-stage schistosomiasis (OR = 1.46, p = 0.035), whereas haplotype rs1800925C-rs20541A showed a protective role against development of late-stage schistosomiasis (F = 0.188, OR = 0.61, p = 0.002). Furthermore, S. japonicum-induced fibrotic liver tissue had higher IL13 expression than normal liver tissue. Plasmid PGL4.17-rs1800925T showed a stronger relative luciferase activity than Plasmid PGL4.17-rs1800925C in 293FT, QSG-7701 and HL-7702 cell lines. In conclusion, the functional IL13 polymorphism, rs1800925T, previously associated with risk of schistosomiasis, also contributes to risk of late-stage schistosomiasis caused by S. japonicum.


Assuntos
Interleucina-13/genética , Cirrose Hepática/genética , Fígado/metabolismo , Polimorfismo de Nucleotídeo Único , Schistosoma japonicum/patogenicidade , Esquistossomose Japônica/genética , Adulto , Animais , Estudos de Casos e Controles , Progressão da Doença , Feminino , Expressão Gênica , Haplótipos , Interações Hospedeiro-Parasita , Humanos , Interleucina-13/metabolismo , Fígado/parasitologia , Fígado/patologia , Cirrose Hepática/complicações , Cirrose Hepática/parasitologia , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Regiões Promotoras Genéticas , Risco , Schistosoma japonicum/fisiologia , Esquistossomose Japônica/complicações , Esquistossomose Japônica/parasitologia , Esquistossomose Japônica/patologia , Índice de Gravidade de Doença
19.
Nat Commun ; 6: 5965, 2015 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-25591454

RESUMO

Common variants at many loci have been robustly associated with asthma but explain little of the overall genetic risk. Here we investigate the role of rare (<1%) and low-frequency (1-5%) variants using the Illumina HumanExome BeadChip array in 4,794 asthma cases, 4,707 non-asthmatic controls and 590 case-parent trios representing European Americans, African Americans/African Caribbeans and Latinos. Our study reveals one low-frequency missense mutation in the GRASP gene that is associated with asthma in the Latino sample (P=4.31 × 10(-6); OR=1.25; MAF=1.21%) and two genes harbouring functional variants that are associated with asthma in a gene-based analysis: GSDMB at the 17q12-21 asthma locus in the Latino and combined samples (P=7.81 × 10(-8) and 4.09 × 10(-8), respectively) and MTHFR in the African ancestry sample (P=1.72 × 10(-6)). Our results suggest that associations with rare and low-frequency variants are ethnic specific and not likely to explain a significant proportion of the 'missing heritability' of asthma.


Assuntos
Asma/genética , Estudo de Associação Genômica Ampla/métodos , Proteínas de Transporte/genética , Feminino , Predisposição Genética para Doença/genética , Humanos , Desequilíbrio de Ligação/genética , Masculino , Proteínas de Membrana/genética , Proteínas de Neoplasias/genética
20.
J Clin Invest ; 125(2): 563-70, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25562321

RESUMO

Mutations in the essential telomerase genes TERT and TR cause familial pulmonary fibrosis; however, in telomerase-null mice, short telomeres predispose to emphysema after chronic cigarette smoke exposure. Here, we tested whether telomerase mutations are a risk factor for human emphysema by examining their frequency in smokers with chronic obstructive pulmonary disease (COPD). Across two independent cohorts, we found 3 of 292 severe COPD cases carried deleterious mutations in TERT (1%). This prevalence is comparable to the frequency of alpha-1 antitrypsin deficiency documented in this population. The TERT mutations compromised telomerase catalytic activity, and mutation carriers had short telomeres. Telomerase mutation carriers with emphysema were predominantly female and had an increased incidence of pneumothorax. In families, emphysema showed an autosomal dominant inheritance pattern, along with pulmonary fibrosis and other telomere syndrome features, but manifested only in smokers. Our findings identify germline mutations in telomerase as a Mendelian risk factor for COPD susceptibility that clusters in autosomal dominant families with telomere-mediated disease including pulmonary fibrosis.


Assuntos
Transtornos Cromossômicos , Enfisema Pulmonar , Sistema de Registros , Caracteres Sexuais , Fumar , Telomerase , Adulto , Animais , Transtornos Cromossômicos/enzimologia , Transtornos Cromossômicos/epidemiologia , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/patologia , Feminino , Humanos , Incidência , Masculino , Camundongos , Pessoa de Meia-Idade , Mutação , Pneumotórax/enzimologia , Pneumotórax/epidemiologia , Pneumotórax/genética , Pneumotórax/patologia , Prevalência , Enfisema Pulmonar/enzimologia , Enfisema Pulmonar/epidemiologia , Enfisema Pulmonar/genética , Enfisema Pulmonar/patologia , Fibrose Pulmonar/enzimologia , Fibrose Pulmonar/epidemiologia , Fibrose Pulmonar/genética , Fibrose Pulmonar/patologia , Fatores Sexuais , Fumar/epidemiologia , Fumar/genética , Fumar/metabolismo , Fumar/patologia , Telomerase/genética , Telomerase/metabolismo , Telômero/enzimologia , Telômero/genética , Telômero/patologia , alfa 1-Antitripsina/genética , alfa 1-Antitripsina/metabolismo
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