Table 1.

Summary of variants with pharmacogenetic interactions for RAAS-modulating agents in HF.

Drug	Gene	Polymorphism	rs number	Molecular phenotype	Clinical phenotype	Reference
ACE inhibitors	ACE	Intron 16 I/D	rs4646994	Increased ACE level associated with D-allele	D-allele homozygotes with HF had lower event-free survival on low-dose ACE inhibitor therapy.	[14, 91]
	TACR2	Gly231Glu		Coding SNP of unknown function	In patients (n = 91) receiving ACE inhibitor therapy, only Gly231 carriers developed chronic cough.	[22]
Angiotensin receptor blockers	ACE	Intron 16 I/D	rs4646994	Increased ACE level associated with D-allele	Faster reduction of LVH in D-allele carriers with angiotensin receptor blocker therapy.	[26,91]
	AGTR1	A1166C	rs5186	3′ Untranslated region SNP located in a microRNA binding site	C-allele carriers had better BP and NT-proBNP responses with the addition of candesartan to treatment including an ACE inhibitor.	[27,28]
	AGTR1	A-480G	rs1492078	Located 5′ to gene in the promoter region	A significant interaction between irbesartan treatment and BP reduction was observed.	[29]
	CYP2C9	Arg144Cys (CYP2C9* 2)	rs1799853	Reduced catalytic capacity for certain angiotensin receptor blockers compared with CYP2C9*1	CYP2C9*2 genotype increased BP response to irbesartan treatment.	[30,31]
Aldosterone antagonists	ACE	Intron 16 I/D	rs4646994	Increased ACE level associated with D-allele	Among patients with HF, only carriers of the I-allele demonstrated improvements in EF, EDV and ESV with spironolactone treatment.	[37,91]

ACE Angiotensin 1-converting enzyme, AGTR1 angiotensin II receptor type 1, BP blood pressure, CYP2C9 cytochrome P450 family 2 subfamily C polypeptide 9, EDV end diastolic volume, EF ejection fraction, ESV end systolic volume, HF heart failure, I/D insertion/deletion, LVH left ventricular hypertrophy, NT-proBNP N-terminal proB-type natriuretic peptide, RAAS renin-angiotensin-aldosterone system, TACR2 tachykinin receptor 2