The role of epigenetics in the development of childhood asthma

Figures & data

Figure 1. Types of epigenetic regulation, including histone modification, DNA methylation, and regulation of noncoding RNA.

Figure 2. Potential sources that could change DNA methylation in relation to asthma.

Table 1. Characteristics of asthma DNA methylation studies mentioned in this review.

Study	Study design	Age	Ancestry	Sample size (discovery and replication)	Methylation platform	Tissue	Asthma definition	Number of significant CpGs (or DMRs)	Significance threshold	Examples of candidate genes
Xu (2018) [29]	Cross-sectional	4–5 years old, and 8 years old	European	Discovery: (1) 4–5 years: 207 cases and 610 controls; (2) 8 year: 185 cases and 546 controls. Replication: 247 cases and 2949 controls	Illumina 450 K and Agena iPlex	Whole blood	Two of three criteria present: doctor diagnosis of asthma ever; use of asthma medication in the past 12 months; or wheezing or breathing difficulties in the past 12 months.	27 CpGs were identified, 14 were replicated.	P < 1.14 × 10^−7 (Bonferroni correction)	LMAN2; STX3; LPIN1; DICER1
Reese (2019) [30]	Prospective (newborn DNA methylation and childhood asthma) and cross-sectional (childhood methylation and childhood asthma)	7–17 years old	European (13 cohorts); mixed ancestry (3 cohorts), African American (1 cohort)	Discovery: (1) Prospective: 668 cases and 2,904 controls; (2) Cross sectional: 631 cases and 2231 controls	Illumina 450 K	Whole blood	A doctor’s diagnosis of asthma and the report of at least 1 of the following: (1) current asthma, (2) asthma in the last year, or (3) asthma medication use in the last year.	(1) Prospective part: 9 CpGs and 35 regions; (2) Cross-sectional part: 179 CpGs and 36 regions.	FDR<0.05	1) Prospective part: CLNS1A, Mir_548; GPATCH2; LOC100129858; AK091866; SUB1; WDR20 2) Cross-sectional part: ACOT7; IL5RA; KCNH2; RUNX1; ZFPM1
Arathimos (2017) [32]	Cross-sectional (7.5 years) and longitudinal (7.5 and 16.5 years)	7.5 years and 16.5 years	European	Discovery: (1) 7.5 years: 149 cases and 632 controls; (2) 16.5 years:194 cases and 554 controls (asthma ever) and 184 cases and 427 controls (current asthma)	Illumina 450 K	Peripheral blood	Current asthma (7.5 and 16.5 years): doctor’s diagnosis of asthma ever and at least one of following present (1) asthma in past 12 months; (2) asthma medication the last 12 months or (3) wheezing or whistling on the chest in the past 12 months	(1) Current asthma at 7.5 years: 302 CpGs; (2) Current asthma at 16.5 years: 2 CpGs. (3) DNA methylation at 7.5 years ~ asthma at 16.5 years: 4 CpGs; (4) DNA methylation at 16.5 years ~ asthma at 7.5 years: 28 CpGs	FDR<0.05	ZFPM1; AP2A2; IL5RA
Murphy (2015) [34]	Longitudinal	5 years, 10 years and 18 years	European	Discovery: 37 monozygotic twin pairs	Illumina 450 K	Buccal cells	(1) woken by an attack of shortness of breath at any time in the last 12 months; (2) an attack of asthma in the last 12 months; (3) currently asthma medicine (inhalers, aerosols or tablets)	No significant sites after Bonferroni correction, top-ranked nominal significant sites were provided	–	HGSNAT, HLX
Yang (2017) [36]	Cross-sectional	10–12 years	African American	Discovery: 36 cases and 36 controls. Replication: n = 30	Illumina 450 K	Nasal brushes cells	(1) a physician diagnosis of asthma; (2) persistent or uncontrolled asthma; (3) physiologic evidence of asthma (FEV1 <85% or FEV1/FVC <85%; and bronchodilator responsiveness (≥12%) or PC20 < 8 mg/ml of methacholine); and (4) positive skin prick test to at least one of a panel of indoor aeroallergens (dust mite, cockroach, mold, cat, dog, rat, mouse).	119 DMRs and 118 CpGs	FDR<0.05	ALOX15; HLA- DPA1; GJA4; POSTN; LDLRAD3; ATXN7L1; METTL1; CXCR6; CCL5; CTSC
Forno (2018) [37]	Cross-sectional	9–20 years	Hispanic or Latino ancestry	Discovery: (1) atopy: 312 cases and 171 controls; (2) atopic asthma: 169 cases and 104 controls. Replication: 72 African American children; 432 Dutch children	Illumina 450 K	Nasal brushes cells	Atopy was defined as: at least one positive IgE (≥0.35IU/mL) to five aeroallergens (house dust mite, cockroach, cat dander, dog dander and mouse urinary protein); asthma was defined as a physician’s diagnosis and at least one episode of wheeze in the past year.	(1) Atopy: 8664 CpGs were identified, 28 of top 30 CpGs were replicated; (2) atopic asthma: top 30 CpGs shown, and 28 of top 30 CpGs were replicated.	FDR<0.01	CDHR3; CDH26; FBXL7; NTRK1; SLC9A3
Cardenas (2019) [38]	Cross-sectional	12.9 ± 0.65 years	Mixed ancestry	Discovery: 65 cases and 463 controls; Replication: in two cohorts, n1 = 72, n2 = 483	Illumina EPIC	Nasal swab cells	Current asthma was defined as mother’s report of a doctor’s diagnosis of asthma since birth reported on the early teen questionnaire plus report of wheeze or asthma medication in the past year at early teen follow-up (comparison group had no asthma diagnosis, no wheeze, or no asthma medication use).	(1) current asthma: 285 CpGs were identified, 58 were replicated (2) allergic asthma: 1235 CpGs and 7 DMRs, 185 CpGs were replicated	FDR<0.05	ACOT7; EPX; EVL; NTRK1
DeVries (2017) [60]	Nested case-control	9 years	Mixed	Discovery: 18 cases and 18 control Replication: in 2 studies, n1 = 30, n2 = 28	Methylated CpG Island Recovery Assay (MIRA)-chip	Cord blood mononuclear cells	Physician-diagnosed, with symptoms or medication use for asthma in the past year reported at least once on the age 2-, 3-, 5-, or 9-year questionnaires	589 DMRs	FDR<0.01	SMAD3
Lund (2018) [85]	Longitudinal	13 months to 5-year	European	Discovery: (1) rhinovirus + asthma + (n = 16), (2) rhinovirus + asthma – (n = 16), (3) rhinovirus – asthma – (n = 16).	Reduced representation bisulfite sequencing (RRBS)	Whole blood	Current asthma at 4-years visit: present one or more criteria in the past 12 months: doctor-diagnosed asthma, regular use of doctor prescribed corticosteroid asthma therapy, use of oral corticosteroids for asthma exacerbations, acute asthma attack relieved by repeated use of bronchodilator	(1) 17 regions (rhinovirus + atopic asthma + (n = 11) vs rhinovirus + asthma – (n = 16)); (2) 13 regions (rhinovirus + nonatopic asthma + (n = 5) vs rhinovirus + asthma – (n = 10))	FDR≤0.05	SMAD3; DDO/METTL24
Nicodemus-Johnson (2016) [109]	Cross-sectional	39 ± 13years	African American and European American	Discovery: 74 cases and 41 controls	Illumina 450 K	Endobronchial airway epithelial cells	Doctor’s diagnosed asthma and current asthma medication use	40,892 CpGs	FDR<0.05	ORMDL3; CCL26

Table 2. Epigenetic studies of environmental factors for asthma mentioned in this review.

Environmental factor		Risk/Protective	Epigenetic studies	Examples of candidate genes
Cigarette smoking	Maternal smoking	Risk	DNAm: [61; 64]	ESR1; IL-32
	Second hand smoking	Risk	–	–
	Active smoking	Risk	DNAm: [66] miRNA: [68]	CYP26A1; AHRR; miR-21
Air pollution		Risk	DNAm: [71,72,73,74; 76]	FAM13A; NOTCH4; TET1
Microbiome		Protective	–	–
Respiratory viral infection		Risk	DNAm: [85] Hism: [86; 87] miRNA: [88]	SMAD3; H3K4 Demethylase KDM5B; miR-29c; let-7b
In utero exposures	Maternal asthma	Risk	DNAm: [60; 90; 91]	SMAD3; PM20D1
	Maternal obesity	Risk	–	–
	Maternal nutrition intake	Protective (some nutrients)	–	–
Environmental allergens	House dust mite	Risk	DNAm: [94]	CMTM1; DNAH10
	Furred pets	Risk/Protective	–	–
	Pests (mice, cockroaches)	Risk	DNAm: [95] miRNA: [96]	FOXP3; miR-155
Breast feeding		Protective	–	–

DNAm: DNA methylation; miRNA: micro RNA; Hism: histone modification

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