Gene-Drug Interaction in Stroke

Table 1

Antihypertensive agents.

Name	Outcome	Gene and variant	Sample size/drugs used	Effect estimates and significance levels
INVEST-GENES [8]	Death/MI or stroke	GRK2 SNPs (rs1894111 G > A); GRK5 Gln41Leu	48/Verapamil SR, atenolol	GRK5 41Leu decreased the risk of adverse cardiovascular outcome adjusted independently of treatment (OR 0.535, 95% CI: 0.313–0.951)
INVEST-GENES [9]	Death/MI or stroke	KCNMB1 Glu65Lys; KCNMB1 Val110Leu	5979 with HTN/Verapamil SR, atenolol	KCNMB1 110Leu had reduced risk of composite outcome (HR 0.68 (95% CI 0.47–0.998); this effect was higher in Verapamil SR (HR 0.587, 95% CI 0.33–1.04) than atenolol-treated patients (HR 0.946, 95% CI 0.56–1.59)
LIFE substudy [10]	Cardiovascular events	13 polymorphisms (angiotensin-converting enzyme I/D, α-adducin Gly460Trp, β1-adrenergic receptor Gly389Arg, β2-adrenergic receptor Arg16Gly, β2-adrenergic receptor Gln27Glu, β3-adrenergic receptor Trp64Arg, angiotensinogen Met235Thr, aldosterone synthase promoter C-344T, type 1 angiotensinogen receptor A1166C, bradykinin 2 receptor I/D, CYP2C9∗2 versus CYP2C9∗1,CYP2C9∗3 versus CYP2C9∗1, G protein β3-subunit C825T)	3503/Losartan, atenolol	No significant genotype-drug interaction on the outcome
GEN-HAT [11]	Primary: fatal CHD/nonfatal MI. Secondary: stroke, all-cause mortality, combined CHD, and combined cardiovascular disease	ACE I/D	37,939/chlorthalidone, amlodipine, lisinopril, or doxazosin	No significant association with the outcome was reported; no significant gene-drug interaction was found
GEN-HAT [12]	Primary: fatal CHD/nonfatal MI. Secondary: stroke, all-cause mortality, combined CHD, and 6-mos systolic and diastolic BP changes	NPPA SNP T2238C (rs5065) NPPA SNP G664A (rs5063)	38,462 with HTN/chlorthalidone, amlodipine, lisinopril, or doxazosin	NPPA T2238C TT variant 𝑥“chlorthalidone versus amlodipine” interaction was significantly associated stroke (HR 1.09 95% CI 0.95–1.26).; NPPA T2238C TT variant 𝑥 “chlorthalidone versus amlodipine + lisinopril” interaction was significantly associated with stroke (HR 1.09 95% CI 0.95–1.26).; NPPA T2238C CC variant 𝑥 “chlorthalidone versus amlodipine” interaction was significantly associated with stroke (HR 1.18 95% CI 0.72–1.90). Either NPPA T2238C variant or NPPA G664A was not significantly associated with stroke and “chlorthalidone versus lisinopril,” “chlorthalidone versus doxazosin”
GEN-HAT [13]	Primary: fatal CHD/nonfatal MI. Secondary: stroke, heart failure, all-cause mortality, end-stage renal disease	FGB G455A	30 076 with HTN/chlorthalidone, amlodipine, lisinopril	Common GG homozygotes had higher stroke risk on lisinopril versus amlodipine (HR 1.38, 𝑃<0.001); variant A allele carriers had slightly lower risk on lisinopril versus amlodipine (HR 0.96, P value for interaction = 0.03)
Lemaitre et al. [14]	MI, ischemic stroke	ADRB1 (Seven SNPs plus haplotype), ADRB2 (five SNPs plus haplotypes)	938 cases with MI or stroke/beta blocker	beta1-AR gene variation and beta-blocker use showed a positive interaction on ischemic stroke risk (𝑃=0.04). Homozygosis or heterozygosis for rs#2429511 variant was associated with higher MI/stroke combined risk in beta-blocker users (OR 1.24 95% CI 1.03–1.50).; No interaction of ADRB2 with beta-blocker use and outcomes
Rotterdam study [15]	MI, stroke	AGT (M235T)	4097 with HTN/ACEI, BB	No significant gene-drug interaction was found on stroke
Rotterdam study [16]	MI, stroke	AGTR1 (C573T); ACE (I/D)	4097 with HTN/ACEI, BB	No significant AGTR1 and ACE I/D interaction on stroke risk with ACEI or BB
INVEST-GENES [17]	Death/nonfatal MI/nonfatal stroke	ADRB1 (Ser49GLy, Arg389Gly) and ADRB2 (Gly16Arg, Gln27Glu, 523 C > A)	5,895 CAD patients/Verapamil SR, atenolol	No association between any haplotype and treatment on stroke
INVEST-GENES [18]	Death/nonfatal MI/nonfatal stroke	NOS3-786T > C (rs2070744), NOS3 Glu298 > Asp (rs1799983)	258 death/MI/stroke versus 774 control	No genetic interaction with drugs and composite outcome
Psaty et al. [19]	MI/nonfatal stroke	ADD1 (Gly460Trp)	Cases versus controls	ADD1 Trp460 variant had lower stroke risk on diuretics (OR, 0.49; 95% CI, 0.32–0.77). The point estimate of diuretic-adducin interaction was SI 0.45 (95% CI 0.26–0.79) for the combined outcome MI and stroke; separate analyses yielded similar results: MI (SI 0.41 95% CI 0.21–0.80) and stroke (SI 0.53 95% CI 0.24–1.19)
INVEST-GENES [20]	Death/nonfatal MI/nonfatal stroke	ADD1 Gly460Trp	5,979 CAD patients/Verapamil SR, atenolol	ADD1 Trp460 black carriers had higher combined outcome risk (aHR 2.62, 95% CI 1.23–5.58), compared to whites (aHR 1.24 95% CI 0.90–1.71) and Hispanics (aHR 1.43 95% CI 0.86–2.39). No significant interaction between the ADD1 polymorphism and diuretic use for either primary outcome or secondary outcomes
PROGRESS [21]	Fatal and nonfatal stroke (ischemic or hemorrhagic), nonfatal MI/coronary death, composite nonfatal stroke/nonfatal MI/vascular death, all-cause mortality, dementia, and cognitive decline	ACE I/D	5688 with stroke or TIA/perindopril	No associations between ACE genotypes and cerebrovascular disease history or cardiovascular risk factors was demonstrated. The ACE genotype was not associated with the long-term risks of stroke. The ACE genotype did not modify the relative benefits of perindopril over placebo