DNA methylation loci associated with atopy and high serum IgE: a genome-wide application of recursive Random Forest feature selection

Everson, Todd M.; Lyons, Genevieve; Zhang, Hongmei; Soto‐Ramírez, Nelís; Lockett, Gabrielle A.; Patil, Veeresh; Merid, Simon Kebede; Söderhäll, Cilla; Melén, Erik; Holloway, John W.; Arshad, Syed Hasan; Karmaus, Wilfried

doi:10.1186/s13073-015-0213-8

Cited by 62 publications

(62 citation statements)

References 57 publications

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“…ZFPM1 suppresses expression of interleukin 4 (IL-4) and induces expression of IFN-γ in CD4+ T cells, thus reducing Th2 cell differentiation 29 . Moreover, WBC DNA methylation in both ZFPM1 and ACOT7 has been associated with asthma 30 , and WBC DNA methylation of ZFPM1 was consistently associated with atopy (defined as at least one positive IgE to allergens) or high total IgE (≥200 kU/L) across two Caucasian cohorts included in a prior study 31 . In that study, DNA methylation of acyl-CoA thioesterase 7 ( ACOT7 ) was significantly associated with atopy or high total IgE in the discovery cohort but not in a replication cohort.…”

Section: Discussionmentioning

confidence: 92%

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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Section: Discussionmentioning

confidence: 92%

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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“…The PBMC data show that cytosolic acyl coenzyme A thioester hydrolase 7 (ACOT7) gene might act in concert with another candidate gene, Zinc Finger Protein 366 (ZNF366) gene, to jointly influence the risk of asthma. The role of methylations of ACOT7 gene in asthma has been reported by several genome-wide epigenomic studies on serum immunoglobin E (IgE) levels [42][43][44] . One of the top five loci based on the NEC data, cg00625963, is located in the LCK Proto-Oncogene, Src Family Tyrosine Kinase (LCK) gene, which can mediate the allergic airway inflammation in asthma [45][46][47] .…”

Section: Discussionmentioning

confidence: 97%

Comparing DNA methylation profiles across different tissues associated with the diagnosis of pediatric asthma

Lin

Shu

Mersha

2020

Sci Rep

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DNA methylation (DNAm) profiles in central airway epithelial cells (AECs) may play a key role in pathological processes in asthma. The goal of the current study is to compare the diagnostic performance of DNAm markers across three tissues: AECs, nasal epithelial cells (NECs), and peripheral blood mononuclear cells (PBMCs). Additionally, we focused on the results using the machine learning algorithm in the context of multi-locus effects to evaluate the diagnostic performance of the optimal subset of CpG sites. We obtained 74 subjects with asthma and 41 controls from AECs, 15 subjects with asthma and 14 controls from NECs, 697 subjects with asthma and 97 controls from PBMCs. Epigenomewide DNA methylation levels in AECs, NECs and PBMCs were measured using the Infinium Human Methylation 450 K BeadChip. Overlap analysis across the three different sample sources at the locus and pathway levels were studied to investigate shared or unique pathophysiological processes of asthma across tissues. Using the top 100 asthma-associated methylation markers as classifiers from each dataset, we found that both AEC-and NEC-based DNAm signatures exerted a lower classification error than the PBMC-based DNAm markers (p-value = 0.0002). The area-under-the-curve (AUC) analysis based on out-of-bag errors using the random forest classification algorithm revealed that PBMC-, NEC-, and AEC-based methylation data yielded 31 loci (AUC: 0.87), 8 loci (AUC: 0.99), and 4 loci (AUC: 0.97) from each optimal subset of tissue-specific markers, respectively. We also discovered the locus-locus interaction of DNAm levels of the CDH6 gene and RAPGEF3 gene might interact with each other to jointly predict the risk of asthma -which suggests the pivotal role of cell-cell junction in the pathological changes of asthma. Both AECs and NECs might provide better diagnostic accuracy and efficacy levels than PBMCs. Further research is warranted to evaluate how these tissue-specific DNAm markers classify and predict asthma risk.Asthma affects 11 million children in the U.S., and has been on the rise over the past two decades 1 . Although the heritability estimate may reach 80% 2 , the rapid increment in its incidence cannot be simply explained by genetic factors alone. Epigenetics may account for the mechanisms underlying environmental effects on genetic functions 3 , and hence may play a role in the environment-related pathogenesis of asthma 4 . DNA methylation (DNAm) is the first identified epigenetic mechanism that been extensively studied in allergic disease [5][6][7][8] . Emerging evidence has suggested that DNAm can be considered as a robust epigenetic marker that could aid clinical applications, such as diagnostics 9 .One of the major challenges of DNAm research on asthma is the selection of the target tissue for DNA samples. The direct access to the lung tissue DNA which is primarily involved in asthma pathophysiology is limited 10 . Surrogate markers from easily accessible tissues are the markers of choice for studies involving large-scale screening and c...

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“…The studies described above have focused on candidate genes. In one cross‐sectional study, the association of DNAm with allergic sensitization was examined at a genome scale and 13 CpGs were identified . Participants in this study were young females aged 18 years, while participants in the aforementioned studies were either in early childhood (6 years or younger), adults, or older men.…”

Section: Introductionmentioning

confidence: 99%

DNA methylation and allergic sensitizations: A genome‐scale longitudinal study during adolescence

Zhang

Kaushal

Merid

et al. 2019

Allergy

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Background: The presence of allergic sensitization has a major influence on the development and course of common childhood conditions such as asthma and rhinitis. The etiology of allergic sensitization is poorly understood, and its underlying biological mechanisms are not well established. Several studies showed that DNA methylation (DNAm) at some CpGs is associated with allergic sensitization. However, no studies have focused on the critical adolescence period. Methods: We assessed the association of pre- and postadolescence genome-wide DNAm with allergic sensitization against indoor, outdoor and food allergens, using linear mixed models. We hypothesized that DNAm is associated with sensitization in general, and with poly-sensitization status, and these associations are age- and gender-specific. We tested these hypotheses in the IoW cohort (n = 376) and examined the findings in the BAMSE cohort (n = 267). Results: Via linear mixed models, we identified 35 CpGs in IoW associated with allergic sensitization (at false discovery rate of 0.05), of which 33 were available in BAMSE and replicated with respect to the direction of associations with allergic sensitization. At the 35 CpGs except for cg19210306 on C13orf27, a reduction in methylation among atopic subjects was observed, most notably for cg21220721 and cg11699125 (ACOT7). DNAm at cg10159529 was strongly correlated with expression of IL5RA in peripheral blood (P-value = 6.76 × 10−20). Three CpGs (cg14121142, cg23842695, and cg26496795) were identified in IoW with age-specific association between DNAm and allergic sensitization. Conclusion: In adolescence, the status of allergic sensitization was associated with DNAm differentiation and at some CpGs the association is likely to be age-specific.

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DNA methylation loci associated with atopy and high serum IgE: a genome-wide application of recursive Random Forest feature selection

Cited by 62 publications

References 57 publications

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

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

Comparing DNA methylation profiles across different tissues associated with the diagnosis of pediatric asthma

DNA methylation and allergic sensitizations: A genome‐scale longitudinal study during adolescence

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