Current pharmacogenomic recommendations in chronic respiratory diseases: Is there a biomarker ready for clinical implementation?

Figures & data

Table 1. Clinical implication of pharmacogenomic biomarkers for respiratory diseases included by the Food and Drug Administration.

Drug	Pharmacogene biomarker	Main clinical implication
Arformoterol	UGT1A1 CYP2D6	There was no impact on systemic exposure to arformoterol comparing subjects with different CYP2D6 and/or UGT1A1 enzyme activities.
Elexacaftor, Ivacaftor, and Tezacaftor	CFTR	The treatment is indicated in patients with at least one F508del mutation in the CFTR gene or a mutation in the CFTR that is responsive based on in vitro assay data.
Ivacaftor		It is indicated for patients with one CFTR mutation responsive to ivacaftor based on clinical or in vitro assay data. Trials studies performed in Caucasians.
Ivacaftor and Lumacaftor		It is indicated for patients homozygous for the F508del mutation in the CFTR. Clinical trials performed in a 99% Caucasian population.
Ivacaftor and Tezacaftor		It is indicated for homozygous patients for the F508del mutation or have at least one CFTR mutation responsive to tezacaftor/ivacaftor based on in vitro data and/or clinical evidence.
Formoterol	CYP2D6 CYP2C19	Whether a deficiency in one or both of CYP2D6 or CYP2C19 results in elevated systemic exposure to formoterol or systemic adverse effects has not been adequately explored. The report was performed in a population mostly Caucasian (88%).
Indacaterol	UGT1A1	Studies in Caucasians suggest no relevant effect of the UGT1A1 genotype on indacaterol exposure.
Umeclidinium	CYP2D6	No clinically meaningful difference in systemic exposure to umeclidinium was observed following repeat daily inhaled dosing to normal (ultrarapid, extensive, and intermediate metabolizers) and CYP2D6 poor metabolizer subjects. The study included a population described as 89% white.

Table 2. Annotations of pharmacogenetic variants included for respiratory diseases in PharmGKB.

Drug	PGx variant	Annotation	Biogeographical group ^a	Level of evidence ^b
Warfarin	CYP4F2 rs2108622	Genotype TT is associated with an increased warfarin dose in people with atrial fibrillation, heart valve replacement, pulmonary hypertension, pulmonary embolism, and venous thrombosis.	East Asian	1A
	CYP2C9 rs1057910	Genotypes AC + CC are associated with a decreased warfarin dose in people with atrial fibrillation, heart valve replacement, pulmonary hypertension, pulmonary embolism, and venous thrombosis.	East Asian
	VKORC1 rs9923231	Genotypes AC + CC are associated with a decreased warfarin dose in people with atrial fibrillation, heart valve replacement, pulmonary hypertension, pulmonary embolism, and venous thrombosis.	East Asian
	rs7196161	Allele A is associated with dosage in people with atrial fibrillation, pulmonary embolism, stroke, and venous thrombosis.	Chinese, Malay, Indian, Other	3
	rs9934438	Genotype AG is associated with increased dose in people with atrial fibrillation, cardiomyopathies, heart valve replacement, peripheral vascular diseases, pulmonary embolism, and venous thrombosis.	Sub-Saharan African	1B
	APOE rs7412	Genotype CC is associated with increased dose in people with atrial fibrillation, pulmonary embolism, or venous thrombosis.	East Asian	NA
Theophylline	CYP1A2 rs35694136	Genotypes TT + T/del are associated with increased severity of COPD when treated with theophylline.	Near Eastern	NA
N-acetylcysteine	TOLLIP rs3750920	Patients have different responses according to CC, CT, or TT genotypes and pulmonary fibrosis.	European	3
	EPHX1	EPHX1 poor metabolizer is associated with increased response in people with COPD.	East Asian	NA
Ivacaftor	CFTR rs75527207	When treated with ivacaftor, allele A is associated with a decreased likelihood of cystic fibrosis pulmonary exacerbation.	Not reported	1A
	rs113993960	Genotype del/del is associated with decreased cystic fibrosis pulmonary exacerbation when treated with ivacaftor and tezacaftor.	Multiple groups	NA
Captopril	ACE rs1799752	Genotype del/del is associated with different responses in men with COPD.	East Asian	2A
Nintedanib	DSP rs2076295	Genotype TT is associated with decreased overall survival in people with pulmonary fibrosis	European	NA
Nitroglycerin	ALDH2 rs671	Genotypes AA + AG are associated with increased drug concentrations in children with congenital heart defects and pulmonary hypertension.	East Asian	NA
Fluticasone/ salmeterol	CRHR1 rs242941	Genotype CC is associated with increased mean change in FEV when treated with this combination in people with COPD.	East Asian	NA
ACE inhibitors	CLASP1 rs62151109	Allele C is associated with an increased likelihood of cough in people with asthma, diabetes mellitus, heart failure, hypertension, and COPD.	European	NA

^aPharmGKB uses a system of nine biogeographical groups to indicate racial and ethnicity information about participants in pharmacogenomic studies, for further information please visit https://www.pharmgkb.org/page/biogeographicalGroups; ^b Clinical Annotations Levels of Evidence [42]: Level 4, unsupported; Level 3, Low; Level 2, Moderate (2A: variant found in PharmGKB’s Tier 1 Very Important Pharmacogenes, 2B: variant not found in PharmGKB’s Tier 1 Very Important Pharmacogenes); Level 1, High (1A: with a variant-specific prescribing guidance available, 1B: no available variant-specific prescribing guidance). ACE, angiotensin-converting enzyme; COPD, Chronic obstructive pulmonary disease; FEV, forced expiratory volume; NA, this annotation has not been used as evidence for any clinical annotations

Table 3. Gene/drug pairs related to chronic respiratory diseases reported by the clinical pharmacogenetics implementation consortium [50].

Drug	Gene	CPIC level^a	PharmGKB level of evidence ^b	PGx on FDA label
Ivacaftor	CFTR	A	1A	Testing required
Warfarin	CYP2C9, CYP4F2, VKORC1	A	1A	Actionable PGx
	CALU, GGCX,	D	3	NA
	PROC, PROS1	D	NA
Budesonide	CRHR1	D	NA	NA
Fluticasone propionate	CRHR1	D	NA	NA
Fluticasone/ salmeterol	CRHR1	D	NA	NA
Salbutamol	ADRB2, COL22A1, CRHR2	D	3	NA
Salmeterol	ADRB2	D	2A	NA
Triamcinolone	CRHR1	D	NA	NA

^aCPIC level A and B gene/drug pairs have sufficient evidence for at least one prescribing action to be recommended, meanwhile CPIC level C and D gene/drug pairs are not considered to have adequate evidence or actionability to have prescribing recommendations. ^b Clinical Annotations Levels of Evidence reported by PharmGKB: Level 4, unsupported; Level 3, Low; Level 2, Moderate (2A: variant found in PharmGKB’s Tier 1 Very Important Pharmacogenes, 2B: variant not found in PharmGKB’s Tier 1 Very Important Pharmacogenes); Level 1, High (1A: with a variant-specific prescribing guidance available, 1B: no available variant-specific prescribing guidance). NA; not available information; PGx, pharmacogenomics.

Clinical annotation levels of evidence [Internet]. cited 2022 Oct 10]. Available from 2022 Oct 10: https://www.pharmgkb.org/page/clinAnnLevels.

 Google Scholar

Genes-Drugs CPIC [Internet]. cited 2022 Oct 11]. Available from 2022 Oct 11: https://cpicpgx.org/genes-drugs/.

 Google Scholar