Table 3. Studies showing gene-environment interactions.

Definition of exacerbation	Gene	Associated variants	Environment	Reference Number
Hospitalization	ADAM33	rs512625	Tobacco smoke	31
# In this case-control study, 423 asthmatic children and 414 non-asthmatic controls (age 5-18 yr) were recruited in Croatia. Early-life environmental tobacco smoke exposure was assessed by questionnaire. For rs512625 in ADAM33, there was significant interaction with environmental tobacco smoke exposure in relation to hospitalizations (Pinteraction=0.02).
ER visit or hospitalization	CHIT1	rs2486953, rs4950936, rs1417149	Household levels of mold	32
# High mold exposure ( ≥ 25,000 units per gram of house dust) significantly modified the relation between three SNPs in CHIT1 (rs2486953 [Pinteraction=0.0010], rs4950936 [Pinteraction=0.0008], and rs1417149 [Pinteraction=0.0005]) and severe AEs. Household levels of mold (an index of fungal exposure) were determined on house dust samples. A total of 395 subjects and their parents as part of the CAMP trial were enrolled.
Hospitalization	CD14, LY96	rs2915863, rs17226566	Endotoxin	34
# In this case-control study, 417 asthmatic children and 407 non-asthmatic controls (age 5-18 yr) were recruited in Croatia. Endotoxin exposure was measured in dust samples collected from homes. CD14 SNP rs5744455 (FDR P=0.02) and LY96 SNP rs17226566 (FDR P=0.04) were significantly associated with AEs.
ER visit or hospitalization	TGFB1	rs2241712	Dust mite allergen	35
# The association between 9 SNPs in TGFB1 and AE was tested in 2 cohorts; 416 Costa Rican parent-child trios and 465 families of non-Hispanic white children in the CAMP trial. Exposure to dust mite allergen (Der p 1 level) was dichotomized at 10 mg/g or greater. Dust mite exposure significantly modified the effect of the A allele of the promoter SNP rs2241712 on AEs in both cohorts (Pinteraction=0.008 in Costa Rica and Pinteraction=0.03 in CAMP).
ER visit or hospitalization	IL9	rs11741137, rs2069885	Dust mite allergen	43
# Investigators used differential genome-wide expression profiles from a longitudinal birth cohort study in response to Der f 1 allergen (sensitized vs nonsensitized) to inform a gene-environment study of dust mite exposure and asthma severity. Home dust mite allergen levels (<10 or ≥ 10 mg/g dust) were assessed at baseline. IL9 polymorphisms (rs11741137, rs2069885, and rs1859430) showed evidence for interaction with dust mite in the CAMP trial (Pinteraction=0.02 to 0.03), with replication in the Costa Rica Study (Pinteraction=0.04)
Moderate exacerbation*			Picorna virus infection	36
# Investigators followed exacerbation-prone childhood asthmatics prospectively and evaluated differential gene expressions in nasal lavage samples obtained during an acute, moderate, picornavirus-induced exacerbation, and 7 to 14 days later. They found that more than 1,000 genes was upregulated during AEs in comparison with 7 to 14 days later and revealed that interferon regulatory factor 7 was one of the hyperconnected hub nodes using coexpression network analysis.
ER visit or hospitalization	CRTAM	rs2272094	Circulating Vitamin D level	40
# Investigators conducted a genome-wide study of gene-vitamin D interaction on AEs using population-based and family-based approaches on 403 subjects and t rios from the CAMP trial. Vitamin D levels were obtained at the time of randomization and were dichotomized as low (≤ 30 ng/mL) or high (>30 ng/mL). Three common variants in the CRTAM were associated with an increased rate of AEs based on the presence of a low circulating vitamin D level. These results were replicated in a second independent population from Costa Rica.

^*Lack of symptom relief after 3 treatments, low peak flow readings (<80% of personal best), or both.

AE, Asthma exacerbation; ER, Emergency room; FDR, False discovery rate; NA, Not applicable; SNP, Single nucleotide polymorphism.