Asthma pharmacogenetics and the development of genetic profiles for personalized medicine

Figures & data

Figure 1 Premise of pharmacogenetics research in complex diseases.

Notes: Pharmacogenetics research studies a gene-by-environment interaction, by analyzing the effect of genotype and exposure to a medication in determining interindividual responses to pharmacologic therapies. Reprinted from Immunol Allergy Clin North Am. 2007;27(4). Ortega VE, Hawkins GA, Peters SP, Bleecker ER. Pharmacogenetics of the beta 2-adrenergic receptor gene. 665–684; vii. Copyright © 2007 with permission from Elsevier.⁸³
Abbreviation: SNP, single nucleotide polymorphism.

Table 1 Pharmacogenetic candidate genes for inhaled glucocorticoid response in asthma

Drug class	Gene	Associated loci	Study design	Response phenotype	Reference
Inhaled glucocorticoids (fluticasone, budesonide, flunisolide, triamcinolone)	CRHR1	rs242941, rs1876828	Candidate gene study	FEV1 response	^Citation17
	STIP1	rs2236647, rs6591838, rs1011219	Candidate gene study	FEV1 response	^Citation18
	TBX21	rs2240017 (His^33Gln)	Candidate gene study	Bronchoprotection	^Citation21,Citation22
	GLCCI1	rs37972=rs37973	GWAS	FEV1 response	^Citation24
	T gene	rs3127412, rs6456042, rs3099266, rs2305089	GWAS	FEV1 response	^Citation26
	ADCY9	rs2230739 (Met^772Ile)	Candidate gene study	FEV1 response	^Citation19
	CYP3A4	CYP3A4*22 allele	Candidate gene study	Symptom control	^Citation23

Notes: Biological candidate genes are summarized by associated genetic loci (rs number and coding change, if relevant), study design, and response phenotype for which a pharmacogenetic association has been described. Reproduced from Ortega VE and Wechsler ME. Curr Opin Allergy Clin Immunol. 2013;13(4):399–409. Promotional and commercial use of the material in print, digital or mobile device format is prohibited without the permission from the publisher Lippincott Williams & Wilkins. Please contact [e-mail] for further information.⁷⁰

Abbreviations: FEV₁, forced expiratory volume in 1 second; GWAS, genome-wide association studies.

Table 3 Pharmacogenetic candidate genes for β₂-adrenergic receptor response in asthma

β2-adrenergic receptor agonists drug classes	Gene	Associated loci	Study design	Response phenotype	Reference
Short-acting beta agonists (albuterol)	CRHR2	rs7793837	Candidate gene study	Acute FEV1 bronchodilation	^Citation58,Citation64
	ADCY9	rs2230739 (Ile^772Met)	Candidate gene study	Acute FEV1 bronchodilation	^Citation19,Citation64
	ADRB2	rs1042713 (Gly^16Arg)	Candidate gene study and genotype-stratified Candidate gene study	Acute FEV1 bronchodilation Long-term PEFR response Long-term PEFR response	^Citation48,Citation85 ^Citation9 ^Citation50
	ARG1	rs2781659, rs2781667	Candidate gene study	Acute FEV1 bronchodilation	^Citation60^–^Citation62,Citation64
	ARG2	rs7140310, rs10483801	Candidate gene study	Acute FEV1 bronchodilation	^Citation61
	NOS3	rs1799983 (Asp^298Glu)	Candidate gene study	Acute FEV1 bronchodilation	^Citation63
	THRB	rs892940	Candidate gene study	Acute FEV1 bronchodilation	^Citation73
	SLC24A4	rs77441273 (Arg^585Gln)	GWAS	Acute FEV1 bronchodilation	^Citation59
	SLC22A15	rs1281748, rs1281743	Admixture mapping	Acute FEV1 bronchodilation	^Citation59
	SPATS2L	rs295137	GWAS	Acute FEV1 bronchodilation	^Citation64
Long-acting beta agonists (salmeterol and formoterol)	ADCY9	rs2230739 (Met^772Ile)	Candidate gene study	Long-term FEV1 response	^Citation20
	ADRB2	rs1042713 (Gly^16Arg)	Candidate gene study and genotype-stratified Genotype-stratified Genotype-stratified	Long-term PEFR response No effect on PEFR response Bronchoprotection Preference for montelukast or LABA as add-on to ICS	^Citation86 ^Citation50,Citation53,Citation54,Citation87,Citation88 ^Citation53,Citation89 ^Citation90
	ADRB2	rs1800888 (Thr^164Ile), −376 insertion-deletion	Candidate gene study	Exacerbation requiring hospitalization	^Citation46

Notes: Biologic candidate genes are summarized by drug class, associated genetic loci (rs number and coding change, if relevant), study design, and response phenotype for which a pharmacogenetic association has been described. Reproduced from Ortega VE and Wechsler ME. Curr Opin Allergy Clin Immunol. 2013;13(4):399–409. Promotional and commercial use of the material in print, digital or mobile device format is prohibited without the permission from the publisher Lippincott Williams & Wilkins. Please contact [e-mail] for further information.⁷⁰

Abbreviations: FEV₁, forced expiratory volume in 1 second; GWAS, genome-wide association studies; ICS, inhaled corticosteroids; LABA, long-acting beta agonist; PEFR, peak expiratory flow rate.

Table 2 Pharmacogenetic candidate genes for leukotriene modifier response in asthma

Drug classes	Gene	Associated loci	Study design	Response phenotype	Reference
Leukotriene receptor modifiers: 5-lipooxygenase inhibitors (ABT-761 and zileuton)	ALOX5	Promoter repeat, rs892690, rs2029253, rs2115819	Candidate gene study	FEV1 response	^Citation27,Citation28
	LTC4S	rs272431	Candidate gene study	FEV1 response	^Citation31
	MRP1	rs215066, 119774	Candidate gene study	FEV1 response	^Citation31
Cysteinyl leukotriene antagonists (montelukast)	ALOX5	Promoter repeat, rs2115819	Candidate gene study	FEV1 response	^Citation29,Citation30
	LTC4S	rs730012	Candidate gene study	Exacerbation risk	^Citation30
	LTA4H	rs266845	Candidate gene study	Exacerbation risk	^Citation30
	MRP1	rs119774	Candidate gene study	FEV1 response	^Citation30
	SLCO2B1	rs12422149 (Arg^312Gln)	Candidate gene study	Symptom control and drug levels	^Citation33

Notes: Biologic candidate genes are summarized by associated genetic loci (rs number and coding change, if relevant), study design, and response phenotype for which a pharmacogenetic association has been described. Reproduced from Ortega VE and Wechsler ME. Curr Opin Allergy Clin Immunol. 2013;13(4):399–409. Promotional and commercial use of the material in print, digital or mobile device format is prohibited without the permission from the publisher Lippincott Williams & Wilkins. Please contact [e-mail] for further information.⁷⁰

Abbreviation: FEV₁, forced expiratory volume in 1 second.

Figure 2 ACRN Beta Agonist Response by Genotype (BARGE) trial.

Notes: In the BARGE trial, Arg¹⁶ homozygotes experienced no change in PEFR during albuterol treatment while Gly¹⁶ homozygotes experienced an improvement in PEFR during regular albuterol therapy. In addition, Arg¹⁶ homozygotes experienced an improvement in PEFR during placebo treatment. Reprinted from The Lancet. 2004;364(9444). Israel E, Chinchilli VM, Ford JG, et al. Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial. 1505–1512. Copyright © 2004, with permission from Elsevier.⁹
Abbreviations: ACRN, Asthma Clinical Research Network; PEFR, peak expiratory flow rate.

Figure 3 Impact of genetic variants in human disease.

Notes: Multiple common genetic variants with small to modest effect sizes contribute to common disease susceptibility and therapeutic responsiveness in an additive fashion. Genome-wide association studies have identified common variants associated with risk for asthma, response to short-acting beta agonists, and response to inhaled corticosteroids. In contrast, rare genetic variants contribute to susceptibility for common diseases and, potentially, response to pharmacologic therapies with a large effect size. Adapted from Tsuji S. Genetics of neurodegenerative diseases: insights from high-throughput resequencing. Hum Mol Genet. 2010;19(R1):R65–R70.⁸⁴

Figure 4 Two rare ADRB2 variants and asthma-related hospitalization with LABA treatment.

Notes: Thr¹⁶⁴Ile is shown in (A) and a 25 base-pair insertion-deletion at position −376 in relation to the start codon (−376 In-Del) is shown in (B). Reprinted from Lancet Respir Med. 2014;2(3). Ortega VE, Hawkins GA, Moore WC, et al. Effect of rare genetic variants in ADRB2 on risk of severe exacerbations and symptom control during longacting beta agonist treatment in a multiethnic asthma population. 204–213. Copyright © 2014 with permission from Elsevier.⁴⁶
Abbreviations: LABA, long-acting beta agonist; CI, confidence interval; OR, odds ratio.

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