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2.
Eur J Hum Genet ; 2018 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-30206357

RESUMO

The Saguenay-Lac-Saint-Jean (SLSJ) region is located in northeastern Quebec and is known for its unique demographic history and founder effect. As founder populations are enriched with population-specific variants, we characterized the variants distribution in SLSJ and compared it with four European populations (Finnish, Sweden, United Kingdom and France), of which the Finnish population is another founder population. Targeted sequencing of the coding and non-coding immune regulatory regions of the SLSJ asthma familial cohort and the four European populations were performed. Rare and low-frequency coding and non-coding regulatory variants identified in the SLSJ population were then investigated for variant- and gene-level associations with asthma and allergy-related traits (eosinophil percentage, immunoglobulin (Ig) E levels and lung function). Our data showed that (1) rare or deleterious variants were not enriched in the two founder populations as compared with the three non-founder European populations; (2) a larger proportion of founder population-specific variants occurred with higher frequencies; and (3) low-frequency variants appeared to be more deleterious. Furthermore, a rare variant, rs1386931, located in the 3'-UTR of CXCR6 and intron of FYCO1 was found to be associated with eosinophil percentage. Gene-based analyses identified NRP2, MRPL44 and SERPINE2 to be associated with various asthma and allergy-related traits. Our study demonstrated the usefulness of using a founder population to identify new genes associated with asthma and allergy-related traits; thus better understand the genes and pathways implicated in pathophysiology.

3.
Lancet Respir Med ; 6(5): 379-388, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29496485

RESUMO

BACKGROUND: DNA methylation profiles associated with childhood asthma might provide novel insights into disease pathogenesis. We did an epigenome-wide association study to assess methylation profiles associated with childhood asthma. METHODS: We did a large-scale epigenome-wide association study (EWAS) within the Mechanisms of the Development of ALLergy (MeDALL) project. We examined epigenome-wide methylation using Illumina Infinium Human Methylation450 BeadChips (450K) in whole blood in 207 children with asthma and 610 controls at age 4-5 years, and 185 children with asthma and 546 controls at age 8 years using a cross-sectional case-control design. After identification of differentially methylated CpG sites in the discovery analysis, we did a validation study in children (4-16 years; 247 cases and 2949 controls) from six additional European cohorts and meta-analysed the results. We next investigated whether replicated CpG sites in cord blood predict later asthma in 1316 children. We subsequently investigated cell-type-specific methylation of the identified CpG sites in eosinophils and respiratory epithelial cells and their related gene-expression signatures. We studied cell-type specificity of the asthma association of the replicated CpG sites in 455 respiratory epithelial cell samples, collected by nasal brushing of 16-year-old children as well as in DNA isolated from blood eosinophils (16 with asthma, eight controls [age 2-56 years]) and compared this with whole-blood DNA samples of 74 individuals with asthma and 93 controls (age 1-79 years). Whole-blood transcriptional profiles associated with replicated CpG sites were annotated using RNA-seq data of subsets of peripheral blood mononuclear cells sorted by fluorescence-activated cell sorting. FINDINGS: 27 methylated CpG sites were identified in the discovery analysis. 14 of these CpG sites were replicated and passed genome-wide significance (p<1·14 × 10-7) after meta-analysis. Consistently lower methylation levels were observed at all associated loci across childhood from age 4 to 16 years in participants with asthma, but not in cord blood at birth. All 14 CpG sites were significantly associated with asthma in the second replication study using whole-blood DNA, and were strongly associated with asthma in purified eosinophils. Whole-blood transcriptional signatures associated with these CpG sites indicated increased activation of eosinophils, effector and memory CD8 T cells and natural killer cells, and reduced number of naive T cells. Five of the 14 CpG sites were associated with asthma in respiratory epithelial cells, indicating cross-tissue epigenetic effects. INTERPRETATION: Reduced whole-blood DNA methylation at 14 CpG sites acquired after birth was strongly associated with childhood asthma. These CpG sites and their associated transcriptional profiles indicate activation of eosinophils and cytotoxic T cells in childhood asthma. Our findings merit further investigations of the role of epigenetics in a clinical context. FUNDING: EU and the Seventh Framework Programme (the MeDALL project).


Assuntos
Asma/genética , Ilhas de CpG , Metilação de DNA , Eosinófilos/imunologia , Epigênese Genética , Asma/sangue , Criança , Pré-Escolar , DNA/sangue , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Linfócitos T Citotóxicos
4.
J Allergy Clin Immunol ; 142(3): 749-764.e3, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29307657

RESUMO

Chromosome 17q12-21 remains the most highly replicated and significant asthma locus. Genotypes in the core region defined by the first genome-wide association study correlate with expression of 2 genes, ORM1-like 3 (ORMDL3) and gasdermin B (GSDMB), making these prime candidate asthma genes, although recent studies have implicated gasdermin A (GSDMA) distal to and post-GPI attachment to proteins 3 (PGAP3) proximal to the core region as independent loci. We review 10 years of studies on the 17q12-21 locus and suggest that genotype-specific risks for asthma at the proximal and distal loci are not specific to early-onset asthma and mediated by PGAP3, ORMDL3, and/or GSDMA expression. We propose that the weak and inconsistent associations of 17q single nucleotide polymorphisms with asthma in African Americans is due to the high frequency of some 17q alleles, the breakdown of linkage disequilibrium on African-derived chromosomes, and possibly different early-life asthma endotypes in these children. Finally, the inconsistent association between asthma and gene expression levels in blood or lung cells from older children and adults suggests that genotype effects may mediate asthma risk or protection during critical developmental windows and/or in response to relevant exposures in early life. Thus studies of young children and ethnically diverse populations are required to fully understand the relationship between genotype and asthma phenotype and the gene regulatory architecture at this locus.

5.
J Allergy Clin Immunol ; 141(5): 1659-1667.e11, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-28927820

RESUMO

BACKGROUND: Atopy, an endotype underlying allergic diseases, has a substantial genetic component. OBJECTIVE: Our goal was to identify novel genes associated with atopy in asthma-ascertained families. METHODS: We implemented a 3-step analysis strategy in 3 data sets: the Epidemiological Study on the Genetics and Environment of Asthma (EGEA) data set (1660 subjects), the Saguenay-Lac-Saint-Jean study data set (1138 subjects), and the Medical Research Council (MRC) data set (446 subjects). This strategy included a single nucleotide polymorphism (SNP) genome-wide association study (GWAS), the selection of related gene pairs based on statistical filtering of GWAS results, and text-mining filtering using Gene Relationships Across Implicated Loci and SNP-SNP interaction analysis of selected gene pairs. RESULTS: We identified the 5q14 locus, harboring the adhesion G protein-coupled receptor V1 (ADGRV1) gene, which showed genome-wide significant association with atopy (rs4916831, meta-analysis P value = 6.8 × 10-9). Statistical filtering of GWAS results followed by text-mining filtering revealed relationships between ADGRV1 and 3 genes showing suggestive association with atopy (P ≤ 10-4). SNP-SNP interaction analysis between ADGRV1 and these 3 genes showed significant interaction between ADGRV1 rs17554723 and 2 correlated SNPs (rs2134256 and rs1354187) within the dynein axonemal heavy chain 5 (DNAH5) gene (Pmeta-int = 3.6 × 10-5 and 6.1 × 10-5, which met the multiple-testing corrected threshold of 7.3 × 10-5). Further conditional analysis indicated that rs2134256 alone accounted for the interaction signal with rs17554723. CONCLUSION: Because both DNAH5 and ADGRV1 contribute to ciliary function, this study suggests that ciliary dysfunction might represent a novel mechanism underlying atopy. Combining GWAS and epistasis analysis driven by statistical and knowledge-based evidence represents a promising approach for identifying new genes involved in complex traits.

6.
Genome Biol ; 18(1): 50, 2017 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-28283040

RESUMO

BACKGROUND: The functional impact of genetic variation has been extensively surveyed, revealing that genetic changes correlated to phenotypes lie mostly in non-coding genomic regions. Studies have linked allele-specific genetic changes to gene expression, DNA methylation, and histone marks but these investigations have only been carried out in a limited set of samples. RESULTS: We describe a large-scale coordinated study of allelic and non-allelic effects on DNA methylation, histone mark deposition, and gene expression, detecting the interrelations between epigenetic and functional features at unprecedented resolution. We use information from whole genome and targeted bisulfite sequencing from 910 samples to perform genotype-dependent analyses of allele-specific methylation (ASM) and non-allelic methylation (mQTL). In addition, we introduce a novel genotype-independent test to detect methylation imbalance between chromosomes. Of the ~2.2 million CpGs tested for ASM, mQTL, and genotype-independent effects, we identify ~32% as being genetically regulated (ASM or mQTL) and ~14% as being putatively epigenetically regulated. We also show that epigenetically driven effects are strongly enriched in repressed regions and near transcription start sites, whereas the genetically regulated CpGs are enriched in enhancers. Known imprinted regions are enriched among epigenetically regulated loci, but we also observe several novel genomic regions (e.g., HOX genes) as being epigenetically regulated. Finally, we use our ASM datasets for functional interpretation of disease-associated loci and show the advantage of utilizing naïve T cells for understanding autoimmune diseases. CONCLUSIONS: Our rich catalogue of haploid methylomes across multiple tissues will allow validation of epigenome association studies and exploration of new biological models for allelic exclusion in the human genome.


Assuntos
Alelos , Metilação de DNA , Epigênese Genética , Epigenômica , Variação Genética , Genoma Humano , Efeitos da Posição Cromossômica , Ilhas de CpG , Elementos Facilitadores Genéticos , Epigenômica/métodos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Especificidade de Órgãos/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
7.
Clin Epigenetics ; 9: 3, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28149331

RESUMO

Allergic rhinitis is a common chronic disorder characterized by immunoglobulin E-mediated inflammation. To identify new genes associated with this trait, we performed genome- and epigenome-wide association studies and linked marginally significant CpGs located in genes or its promoter and SNPs located 1 Mb from the CpGs, by identifying cis methylation quantitative trait loci (mQTL). This approach relies on functional cellular aspects rather than stringent statistical correction. We were able to identify one gene with significant cis-mQTL for allergic rhinitis, caudal-type homeobox 1 (CDX1). We also identified 11 genes with marginally significant cis-mQTLs (p < 0.05) including one with both allergic rhinitis with or without asthma (RNF39). Moreover, most SNPs identified were not located closest to the gene they were linked to through cis-mQTLs counting the one linked to CDX1 located in a gene previously associated with asthma and atopic dermatitis. By combining omics data, we were able to identify new genes associated with allergic rhinitis and better assess the genes linked to associated SNPs.


Assuntos
Proteínas de Homeodomínio/genética , Proteínas Imediatamente Precoces/genética , Rinite Alérgica/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Asma/genética , Criança , Pré-Escolar , Ilhas de CpG , Epigênese Genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Adulto Jovem
8.
Bioinformatics ; 33(4): 491-499, 2017 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-27797775

RESUMO

Motivation: Many peak detection algorithms have been proposed for ChIP-seq data analysis, but it is not obvious which algorithm and what parameters are optimal for any given dataset. In contrast, regions with and without obvious peaks can be easily labeled by visual inspection of aligned read counts in a genome browser. We propose a supervised machine learning approach for ChIP-seq data analysis, using labels that encode qualitative judgments about which genomic regions contain or do not contain peaks. The main idea is to manually label a small subset of the genome, and then learn a model that makes consistent peak predictions on the rest of the genome. Results: We created 7 new histone mark datasets with 12 826 visually determined labels, and analyzed 3 existing transcription factor datasets. We observed that default peak detection parameters yield high false positive rates, which can be reduced by learning parameters using a relatively small training set of labeled data from the same experiment type. We also observed that labels from different people are highly consistent. Overall, these data indicate that our supervised labeling method is useful for quantitatively training and testing peak detection algorithms. Availability and Implementation: Labeled histone mark data http://cbio.ensmp.fr/~thocking/chip-seq-chunk-db/ , R package to compute the label error of predicted peaks https://github.com/tdhock/PeakError. Contacts: toby.hocking@mail.mcgill.ca or guil.bourque@mcgill.ca. Supplementary information: Supplementary data are available at Bioinformatics online.


Assuntos
Imunoprecipitação da Cromatina/métodos , Análise de Sequência de DNA/métodos , Software , Aprendizado de Máquina Supervisionado , Animais , Genômica/métodos , Humanos
9.
BMC Med Genomics ; 9(1): 59, 2016 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-27624058

RESUMO

BACKGROUND: The observation that the genetic variants identified in genome-wide association studies (GWAS) frequently lie in non-coding regions of the genome that contain cis-regulatory elements suggests that altered gene expression underlies the development of many complex traits. In order to efficiently make a comprehensive assessment of the impact of non-coding genetic variation in immune related diseases we emulated the whole-exome sequencing paradigm and developed a custom capture panel for the known DNase I hypersensitive site (DHS) in immune cells - "Immunoseq". RESULTS: We performed Immunoseq in 30 healthy individuals where we had existing transcriptome data from T cells. We identified a large number of novel non-coding variants in these samples. Relying on allele specific expression measurements, we also showed that our selected capture regions are enriched for functional variants that have an impact on differential allelic gene expression. The results from a replication set with 180 samples confirmed our observations. CONCLUSIONS: We show that Immunoseq is a powerful approach to detect novel rare variants in regulatory regions. We also demonstrate that these novel variants have a potential functional role in immune cells.


Assuntos
Alelos , Análise Mutacional de DNA , Perfilação da Expressão Gênica , Análise de Sequência de RNA , Linfócitos T/imunologia , Estudo de Associação Genômica Ampla , Humanos , Anotação de Sequência Molecular , Locos de Características Quantitativas/genética , Linfócitos T/metabolismo
10.
J Allergy Clin Immunol ; 138(3): 748-753, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27038909

RESUMO

BACKGROUND: Asthma and allergic rhinitis (AR) are common allergic comorbidities with a strong genetic component in which epigenetic mechanisms might be involved. OBJECTIVE: We aimed to identify novel risk loci for asthma and AR while accounting for parent-of-origin effect. METHODS: We performed a series of genetic analyses, taking into account the parent-of-origin effect in families ascertained through asthma: (1) genome-wide linkage scan of asthma and AR in 615 European families, (2) association analysis with 1233 single nucleotide polymorphisms (SNPs) covering the significant linkage region in 162 French Epidemiological Study on the Genetics and Environment of Asthma families with replication in 154 Canadian Saguenay-Lac-Saint-Jean asthma study families, and (3) association analysis of disease and significant SNPs with DNA methylation (DNAm) at CpG sites in 40 Saguenay-Lac-Saint-Jean asthma study families. RESULTS: We detected a significant paternal linkage of the 4q35 region to asthma and allergic rhinitis comorbidity (AAR; P = 7.2 × 10(-5)). Association analysis in this region showed strong evidence for the effect of the paternally inherited G allele of rs10009104 on AAR (P = 1.1 × 10(-5), reaching the multiple-testing corrected threshold). This paternally inherited allele was also significantly associated with DNAm levels at the cg02303933 site (P = 1.7 × 10(-4)). Differential DNAm at this site was found to mediate the identified SNP-AAR association. CONCLUSION: By integrating genetic and epigenetic data, we identified that a differentially methylated CpG site within the melatonin receptor 1A (MTNR1A) gene mediates the effect of a paternally transmitted genetic variant on the comorbidity of asthma and AR. This study provides a novel insight into the role of epigenetic mechanisms in patients with allergic respiratory diseases.


Assuntos
Asma/genética , Ilhas de CpG , Herança Paterna , Receptor MT1 de Melatonina/genética , Rinite Alérgica/genética , Alelos , Asma/epidemiologia , Comorbidade , Metilação de DNA , Variação Genética , Genótipo , Humanos , Rinite Alérgica/epidemiologia
11.
J Neuroimmunol ; 289: 139-42, 2015 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-26616883

RESUMO

Neuromyelitis optica (NMO) is rare in Finland. To identify rare genetic variants contributing to NMO risk we performed whole exome, HLA and regulatory region sequencing in all ascertained cases during 2005-2013 (n=5) in a Southern Finnish population of 1.6 million. There were no rare variant shared by all patients. Four missense variants were shared by two patients in C3ORF20, PDZD2, C5ORF47 and ZNF606. Another PDZD2 variant was found in a third patient. In the non-coding sequence two predictably functional rare variants were shared by two patients. Our results do not support a homogeneous genetic etiology of NMO in Finland.


Assuntos
Exoma/genética , Antígenos de Histocompatibilidade/genética , Mutação de Sentido Incorreto/genética , Neuromielite Óptica/genética , Adulto , Aquaporina 4/líquido cefalorraquidiano , Feminino , Finlândia , Humanos , Masculino , Pessoa de Meia-Idade , Neuromielite Óptica/líquido cefalorraquidiano
12.
Hum Genet ; 132(7): 811-22, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23546690

RESUMO

Chromosomal region 17q12-q21 is one of the best-replicated genome-wide association study (GWAS) hits and associated with childhood-onset asthma. However, the mechanism by which the genetic association is restricted to childhood-onset disease is unclear. During childhood, more boys than girls develop asthma. Therefore, we tested the hypothesis that the 17q12-q21 genetic association was sex-specific. Indeed, a TDT test showed that in the Saguenay-Lac-Saint-Jean familial collection, the 17q12-q21 association was significant among male, but not among female asthmatic subjects. We next hypothesized that the bias in the genetic association resulted from sex-specific and/or age-dependent DNA methylation at regulatory regions and determined the methylation profiles of five 17q12-q21 gene promoters using the bisulfite sequencing methylation assay. We identified a single regulatory region within the zona pellucida binding protein 2 (ZPBP2) gene, which showed statistically significant differences between males and females with respect to DNA methylation. DNA methylation also varied with age and was higher in adult males compared to boys. We have recently identified two functionally important polymorphisms, both within the ZPBP2 gene that influence expression levels of neighboring genes. Combined with the results of the present work, these data converge pointing to the same 5 kb region within the ZPBP2 gene as a critical region for both gene expression regulation and predisposition to asthma. Our data show that sex- and age-dependent DNA methylation may act as a modifier of genetic effects and influence the results of genetic association studies.


Assuntos
Envelhecimento , Asma/genética , Cromossomos Humanos Par 17/genética , Metilação de DNA/genética , Loci Gênicos , Caracteres Sexuais , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Asma/metabolismo , Criança , Pré-Escolar , Cromossomos Humanos Par 17/metabolismo , Proteínas do Ovo/genética , Proteínas do Ovo/metabolismo , Feminino , Seguimentos , Regulação da Expressão Gênica/genética , Humanos , Recém-Nascido , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade
13.
Int J Environ Res Public Health ; 9(8): 2620-35, 2012 08.
Artigo em Inglês | MEDLINE | ID: mdl-23066387

RESUMO

Eight candidate genes selected in this study were previously associated with gene-environment interactions in asthma in an urban area. These genes were analyzed in a familial collection from a founder and remote population (Saguenay-Lac-Saint-Jean; SLSJ) located in an area with low air levels of ozone but with localized areas of relatively high air pollutant levels, such as sulphur dioxide, when compared to many urban areas. Polymorphisms (SNPs) were extracted from the genome-wide association study (GWAS) performed on the SLSJ familial collection. A transmission disequilibrium test (TDT) was performed using the entire family sample (1,428 individuals in 254 nuclear families). Stratification according to the proximity of aluminium, pulp and paper industries was also analyzed. Two genes were associated with asthma in the entire sample before correction (CAT and NQO1) and one was associated after correction for multiple analyses (CAT). Two genes were associated when subjects were stratified according to the proximity of aluminium industries (CAT and NQO1) and one according to the proximity of pulp and paper industries (GSTP1). However, none of them resisted correction for multiple analyses. Given that the spatial pattern of environmental exposures can be complex and inadequately represented by a few stationary monitors and that exposures can also come from sources other than the standard outdoor air pollution (e.g., indoor air, occupation, residential wood smoke), a new approach and new tools are required to measure specific and individual pollutant exposures in order to estimate the real impact of gene-environment interactions on respiratory health.


Assuntos
Poluição do Ar/efeitos adversos , Asma/genética , Catalase/genética , NAD(P)H Desidrogenase (Quinona)/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Estudo de Associação Genômica Ampla , Humanos , Indústrias , Lactente , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Quebeque , População Rural , Adulto Jovem
14.
Curr Opin Allergy Clin Immunol ; 12(5): 449-54, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22885890

RESUMO

PURPOSE OF REVIEW: Asthma and rhinitis are commonly associated and they influence their respective control. New observations have contributed to better understand how to assess those conditions and how they influence each other. RECENT FINDINGS: Recent studies found that not only the intensity, but also the duration of rhinitis could be correlated with the development of asthma and possibly its remission. The measure of exhaled nitric oxide (FeNO) has been used to show the presence of lower airway inflammation in rhinitic patients, with or without asthma. Furthermore, it has been shown that allergic rhinitis could affect asthma control in children as in adults, and consequently suggested that allergic rhinitis and asthma should be concomitantly approached in regard to their diagnosis and treatment. Additional observations showed improvements in various asthma outcomes with the treatment of rhinitis. SUMMARY: These new data confirm the strong link between asthma and rhinitis, the importance of their interactions, and the need to identify and treat rhinitis adequately in asthmatic patients.


Assuntos
Asma/complicações , Rinite Alérgica Perene/complicações , Rinite Alérgica Sazonal/complicações , Rinite/complicações , Adulto , Asma/epidemiologia , Asma/fisiopatologia , Asma/terapia , Testes Respiratórios , Criança , Pré-Escolar , Expiração , Humanos , Óxido Nítrico/análise , Rinite/epidemiologia , Rinite/fisiopatologia , Rinite/terapia , Rinite Alérgica Perene/epidemiologia , Rinite Alérgica Perene/fisiopatologia , Rinite Alérgica Perene/terapia , Rinite Alérgica Sazonal/epidemiologia , Rinite Alérgica Sazonal/fisiopatologia , Rinite Alérgica Sazonal/terapia
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