TABLE 2

Associations of the top 10 significant identified differentially methylated regions (DMRs) with gene expression and related respiratory outcomes

Molecular location of the DMR (chromosome: start – end)	Lung function	Annotated gene^#	Expressed gene^¶	Gene expression in children	Gene expression in adults	Previously associated with lung development or respiratory morbidity⁺
chr1: 7 887 199–7 887 561	FEV₁	PER3	PER3, RP3-467l1.4, RNA5SP23, RP4-726F1.1	↓	−
			RP11-431K24.1	−	↑
chr1: 86 968 087–86 968 544	FEV₁/FVC	CLCA1	No expression	−	−	Lung development, asthma, COPD
chr5: 102 898 223–102 898 734	FEV₁/FVC	NUDT12	NUDT12	↓	−	Smoking behaviour in COPD
			CMBL	↓	−
chr6: 166 418 799–166 419 139	FEV₁	LINC00602	No expression	−	−
chr7: 27 183 133–27 184 854	FEV₁	HOXA5	HOXA1, HOTTIP	↓	↓	Lung development, FEV₁, FEV₁/FVC
			EVX1, HOXA4, HOXA7	↓	−	Lung development, asthma, COPD
chr7: 158 045 980–158 046 359	FEF_75%	PTPRN2	No expression	−	−
chr10: 135 202 522–135 203 201	FEV₁	PAOX	No expression	−	−
chr10: 135 051 149–135 051 582	FEV₁/FVC	VENTX	TUBGCP2, RP11-122K13.12	↓	−
			VENTX, ECHS1	↑	−
			SPRN	↑	↓
			ZNF511	−	↑
chr14: 96 180 406–96 181 045	FEF_75%	TCL1A	TCL1A, CCDC85C	↓	−	Asthma
chr19: 1 063 624–1 064 219	FEV₁	ABCA7	No expression	−	−

Results present identified DMRs from association-analyses of DNA-methylation at birth with childhood forced expiratory volume in 1 s (FEV₁), FEV₁/forced vital capacity (FVC) ratio and forced expiratory flow at 75% of FVC (FEF_75%). COPD: chronic obstructive pulmonary disease; ↓: a higher methylation of the DMR was associated with a decreased expression of the specific gene; ↑: a higher methylation of the DMR was associated with an increased expression of the specific gene; −: no direction of association observed. ^#: DMRs were annotated to their nearest gene; ^¶: identified DMRs at birth were associated with gene expression in childhood (INfancia y Medio Ambiente Study (INMA); mean age 4 years) and adulthood (the Rotterdam Study; mean age 66 years); gene expressions levels were assessed limited to 250 kb up- and downstream of the outer border of the DMR; ⁺: associations of expressed genes with lung development and respiratory morbidity were explored in previous published studies.