Treatment response heterogeneity in asthma: the role of genetic variation

Figures & data

Figure 1. Heterogeneity in improvement in asthma-control upon treatment with inhaled corticosteroids (ICS) or leukotriene receptor agonists (LTRA). Change in asthma-control days per week from baseline was measured in children with mild-to-moderate asthma participating in a cross-over NHLBI-CARE Network trial. Based on [5].

Figure 2. Candidate-gene approach versus Genome Wide Association Study (GWAS) approach to study genetic variants associated with treatment response in asthma.

Table 1. GWAS studies assessing genetic variants associated with asthma medication response.

Study	Drug	Study population	Outcome	Identified loci in or near gene	Genome-wide significant p<5×10(-8)
Brehm et al., 2015 [19]	SABA	447 Puerto Rican children with asthma. Replication: 568 children with asthma (mainly European decent), 556 children with asthma (Costa Rican) and 1858 children with asthma (Latino American)	BDR	FGF14	No
Israel et al., 2015 [16]	SABA	724 asthmatics (adults and children) from two pediatric populations and one adult population. Replication: 439 asthmatics	BDR	ASB3, SOCS	Yes
Duan et al., 2014 [15]	SABA	403 non-Hispanic white asthmatic children and their parents. Replication: 2747 individuals (adults and children) participating in 8 asthma trials.	BDR	PRKCQ, IL15RA, IL2RA, COL22A1 and CLOCK genes	No
Padhukasahasram et al., 2014 [18]	SABA	328 Healthy African Americans. Replication in African American asthmatics (n=1968), healthy African American (n=149) and one European Americans with asthma (n=658).	BDR	SPATA13-AS1	~
Drake et al., 2014 [17]	SABA	1782 Latino children with asthma. Replication: 531 Latinos.	BDR	SLC22A15	Yes
Himes et al., 2012 [14]	SABA	1644 Caucasian adults from 6 drug clinical trials. Replication in 501 white adults	BDR	SPATS2L	No
Mosteller et al., 2017 [36]	ICS	2672 patients (children and adults) from 7 industry-sponsored RCTs from diverse ethnic backgrounds (70% European)	Lung function	None	No
Dahlin et al., 2015 [33]	ICS	806 Caucasian patients (children and adults) from 2 population-based biobanks	Asthma exacerbations	CMTR1	No
Wang et al., 2015 [35]	ICS	120 asthmatic patients (discovery), 467 patients of 3 independent trials studies (replication)	Lung function	chr6 rs6924808 and chr11 rs1353649	Yes
Park et al., 2014 [34]	ICS	189 Korean asthmatic patients (children and adults)	Lung function	ALLC	No
Park et al., 2014 [30]	ICS	124 Caucasian pediatric patients (discovery), 77 Caucasian pediatric patients and 220 adults (replication)	Asthma symptoms	FBXL7 (in children)	~
Tantisira et al., 2012 [32]	ICS	418 Caucasian pediatric and adult patients (discovery), 407 Caucasian adult patients (replication)	Lung function	T gene	No
Tantisira et al., 2011 [31]	ICS	118 child-parent trios (discovery), four replication populations with asthmatic patients (n= 935)	Lung Function	GLCCI1	No
Dahlin et al., 2016 [63]	LTM	160 asthmatic patient who received zileuton, three replication populations with asthmatic patients using zileuton or montelukast	Lung function	GLT1D1, MRPP3	Yes
Dahlin et al., 2015 [62]	LTM	133 asthmatic patients (discovery) using montelukast and 184 patients using montelukast (replication)	Lung function	MLLT3	Yes

BDR, bronchodilator response; ICS, inhaled corticosteroids; LTM, leukotriene modifiers; SABA, short-acting beta-2 agonists.

Figure 3. Children with an ADRB2 Arg16 genotype have an increased risk of exacerbations when using LABA. Results of a meta-analysis of 5 studies participating in the Pharmacogenomics in Childhood Asthma (PiCA) consortium. OR and corresponding 95%CI for exacerbation for each copy of the Arg16 variant in children using ICS and LABA. The increased risk was not observed in children using ICS solely or ICS + LTRA. Based on [25].

LABA: long-acting beta-2 agonists, ICS: inhaled corticosteroids, LTRA: leukotriene receptor antagonists, OR: odds ratio, CI: confidence intervals

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