The Clinical and Environmental Determinants of Airway Transcriptional Profiles in Allergic Asthma

Yang, Ivana V.; Tomfohr, John K.; Singh, Jaspal; Foss, Catherine M; Marshall, Hiram W.; Que, Loretta G.; McElvania-Tekippe, Erin; Florence, Sarita; Sundy, John S.; Schwartz, David A.

doi:10.1164/rccm.201108-1503oc

Cited by 27 publications

(33 citation statements)

References 30 publications

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“…Moreover, the magnitude of these allergic asthma-associated epigenetic signals is substantial when compared with other diseases(38, 39). These findings suggest that genes that have been previously reported to be differentially expressed in the airway epithelium of allergic asthmatics(14–16) may be regulated by epigenetic mechanisms.…”

Section: Discussionsupporting

confidence: 54%

“…Gene expression profiles of the allergic asthmatic airway(14–16) and nasal(17) epithelia demonstrate that these cells are involved in an active biological process. Our findings demonstrate a clear relationship between DNA methylation and gene expression in the nasal epithelia of young allergic asthmatics using a stringent analytical pipeline to ensure that methylation changes we identified are not false positives due to influence of demographic factors or technical variables.…”

Section: Discussionmentioning

confidence: 99%

“…However, the airway epithelium is the primary interface with the environment, interacts with allergens(12) and other environmental stimuli(13), and represents a potentially important mediator of allergic airway disease. Gene expression profiles of the asthmatic airway epithelium have identified genes associated with exposure to endotoxin and house dust mite allergen(14) as well as cigarette smoke(15), asthma(15), and Th 2 -high vs –low subphenotypes of disease(16). More recently, it has been demonstrated that gene expression in nasal epithelia is a proxy measure for gene expression of the lower airway epithelium(17).…”

Section: Introductionmentioning

confidence: 99%

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The nasal methylome and childhood atopic asthma

Yang

Pedersen

Liu

et al. 2017

Journal of Allergy and Clinical Immunology

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145

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Background Given strong environmental influence on both epigenetic marks and allergic asthma in children, the epigenetic alterations in respiratory epithelia may provide insight into allergic asthma. Objective To identify DNA methylation and gene expression changes associated with childhood allergic persistent asthma. Methods We compared genomic DNA methylation patterns and gene expression in African American children with persistent atopic asthma[N=36] versus healthy controls[N=36]. Results were validated in an independent population of asthmatic children[N=30] using a shared healthy control population[N=36] and in independent population of Caucasian adult atopic asthmatics[N=12] and controls[N=12]. Results We identified 186 genes with significant methylation changes, differentially methylated regions(DMRs) or differentially methylated probes(DMPs), after adjustment for age, gender, race/ethnicity, batch effects, inflation, and multiple comparisons. Genes differentially methylated included those with established roles in asthma and atopy, genes related to extracellular matrix, immunity, cell adhesion, epigenetic regulation, and airflow obstruction. The methylation changes were substantial (median 9.5%, range:2.6–29.5%). Hypo- and hyper-methylated genes were associated with increased and decreased gene expression respectively (P<2.8x10−6 for DMRs and P<7.8x10−10 for DMPs). Quantitative analysis in 53 differentially expressed genes demonstrated that 32(60%) have significant methylation-expression relationships within 5kb of the gene. 10 loci selected based on the relevance to asthma, magnitude of methylation change, and methylation-expression relationships were validated in an independent cohort of children with atopic asthma. 67/186 genes also have significant asthma-associated methylation changes in nasal epithelia of adult Caucasian asthmatics. Conclusions Epigenetic marks in respiratory epithelia are associated with allergic asthma and gene expression changes in inner-city children.

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Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The nasal methylome and childhood atopic asthma

Yang

Pedersen

Liu

et al. 2017

Journal of Allergy and Clinical Immunology

Self Cite

145

180

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“…SPRY2 differentially regulates lymphoid and myeloid cell functions relevant to allergic asthma 32 . HLA-DQB2 is biologically relevant to immune responses and has previously associated with asthma 33 . ETV6-ABL gene rearrangement can result in chronic myeloid leukemia associated with eosinophilia 34 .…”

Section: Discussionmentioning

confidence: 99%

An epigenome-wide association study of total serum IgE in Hispanic children

Chen

Wang

Pino-Yanes

et al. 2017

Journal of Allergy and Clinical Immunology

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Background Total immunoglobulin E (IgE) is a therapeutic target in allergic diseases. DNA methylation in white blood cells (WBCs) was associated with total IgE in an epigenome-wide association study (EWAS) of Caucasians. Whether DNA methylation of eosinophils explains those findings is insufficiently understood. Methods We tested for association between genome-wide DNA methylation in WBCs and total IgE in two studies of Hispanic children: the Puerto Rico Genetics of Asthma and Lifestyle Study (PR-GOAL, n = 306) and the Genes-environments and Admixture in Latino Americans (GALA II, n = 573). Whole-genome methylation of DNA from WBCs was measured using the Illumina Infinium HumanMethylation450 BeadChip. Total IgE was measured using the UniCAP 100 system. In PR-GOAL, WBC types (i.e. neutrophils, eosinophils, basophils, lymphocytes, and monocytes) in peripheral blood were measured using Coulter-Counter techniques. In GALA II, WBC types were imputed. Multivariable linear regression was used for the analysis of DNA methylation and total IgE, which was first conducted separately for each cohort, and then combining results from the two cohorts in a meta-analysis. Results CpG sites in multiple genes, including novel findings and results previously reported in Caucasians, were significantly associated with total IgE. However, adjustment for WBC types resulted in markedly fewer significant sites. Top findings from this adjusted meta-analysis were in genes ZFPM1 (P=1.5×10−12), ACOT7 (P=2.5×10−11), and MND1 (P=1.4×10−9). Conclusions In an EWAS adjusted for WBC types (including eosinophils), methylation changes in genes enriched in pathways relevant to asthma and immune responses were associated with total IgE among Hispanic children.

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“…Genome-wide association studies in humans have identified several loci associated with asthma in multiple study populations (9)(10)(11)(12)(13)(14), and a genome-wide association study of allergic rhinitis also identified multiple loci, some of which overlap with asthma loci (e.g., LRRC32, HLA-G, and TSLP) (15). Several studies have also identified gene expression profiles that differentiate normal versus AAD in affected tissue (16)(17)(18)(19)(20)(21).…”

Section: Clinical Relevancementioning

confidence: 99%

Integrative Genetic Analysis of Allergic Inflammation in the Murine Lung

Kelada

Carpenter

Aylor

et al. 2014

Am J Respir Cell Mol Biol

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Airway allergen exposure induces inflammation among individuals with atopy that is characterized by altered airway gene expression, elevated levels of T helper type 2 cytokines, mucus hypersecretion, and airflow obstruction. To identify the genetic determinants of the airway allergen response, we employed a systems genetics approach. We applied a house dust mite mouse model of allergic airway disease to 151 incipient lines of the Collaborative Cross, a new mouse genetic reference population, and measured serum IgE, airway eosinophilia, and gene expression in the lung. Allergen-induced serum IgE and airway eosinophilia were not correlated. We detected quantitative trait loci (QTL) for airway eosinophilia on chromosome (Chr) 11 (71.802-87.098 megabases [Mb]) and allergen-induced IgE on Chr 4 (13.950-31.660 Mb). More than 4,500 genes expressed in the lung had gene expression QTL (eQTL), the majority of which were located near the gene itself. However, we also detected approximately 1,700 trans-eQTL, and many of these trans-eQTL clustered into two regions on Chr 2. We show that one of these loci (at 147.6 Mb) is associated with the expression of more than 100 genes, and, using bioinformatics resources, fine-map this locus to a 53 kb-long interval. We also use the gene expression and eQTL data to identify a candidate gene, Tlcd2, for the eosinophil QTL. Our results demonstrate that hallmark allergic airway disease phenotypes are associated with distinct genetic loci on Chrs 4 and 11, and that gene expression in the allergically inflamed lung is controlled by both cis and trans regulatory factors.

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The Clinical and Environmental Determinants of Airway Transcriptional Profiles in Allergic Asthma

Cited by 27 publications

References 30 publications

The nasal methylome and childhood atopic asthma

The nasal methylome and childhood atopic asthma

An epigenome-wide association study of total serum IgE in Hispanic children

Integrative Genetic Analysis of Allergic Inflammation in the Murine Lung

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