Table 1.
Summary of recent pharmacogenetic studies of antihypertensives by drug class.
| First author | Year | Participants | Outcome | Gene (variant) | Treatment | Findings* | Comment |
|---|---|---|---|---|---|---|---|
| Diuretics | |||||||
| Maitland-van der Zee et al. [25] | 2005 | 195 cases with high DBP, 195 controls with low DBP | DBP at 4 weeks | 19 genes (total of 45 polymorphisms) | HCTZ | SNPs SCNN1G rs5729, rs5723 and NOS3 rs1799983 were associated with significant differences in DBP response | SCNN1G SNPs have no previously known PGx interactions with diuretics NOS3 was shown to have PGx association with diuretic [33], however, that was in the full cohort from which these nested cases and controls were drawn |
| Manunta et al. [35] | 2008 | 193 newly diagnosed with HTN | BP at 4 weeks | ADD1 (Gly460Trp), NEDD4L (rs4149601), WNK1 (5 SNPs) | HCTZ | In single-variant analysis, ADD1 T carriers had significantly greater BP reduction than GG individuals; no other variants were significantly associated. Individuals carrying specific combinations of alleles of these genes had significantly greater SBP-lowering than other combinations | Single-variant results consistent with a number of other studies [62,63]. The multiple-variant analysis conducted here is novel |
| Turner et al. [4] | 2008 | 194 blacks, 195 whites with HTN from opposite tertiles of DBP response to drug | DBP at 4 weeks | GWAS (100 k SNPs) | HCTZ | SNPs and haplotypes in LYZ and YEATS4 were associated with DBP response to drug | Findings may be consistent with gene-expression profiling study [34] |
| β-blockers | |||||||
| Lanfear et al. [24] | 2005 | 597 with ACS | Time to all-cause 3 year mortality | ADRB1 (Arg389Gly, Ser49Gly), ADRB2 (Gly16Arg, Gln27Glu) | BB | No associations for ADRB1 variants. The ADRB2 Gln27 allele was associated with higher mortality. The ADRB2 16Arg allele homozygotes had higher mortality. Risk was maximized when both genotypes were taken into account | Gln27Glu finding consistent with Kaye [64] No reported significant associations with Gly16Arg in this context |
| Liu et al. [7] | 2006 | 61 with HTN | BP and MAP at 4 weeks | ADRB1 (Gly389Arg, Ser49Gly) | Metoprolol | Drop in BP and MAP varied with Gly389Arg genotype. Drop in SBP varied with Ser49Gly genotype 49Ser389Arg/49Ser389Arg and 49Ser389Arg/49Gly389Arg patients were good responders; 49Ser389Arg/49Ser389Arg patients had a larger SBP drop than 49Ser389Arg/49Gly389Arg patients; 49Ser389Gly/49Gly389Arg and 49Ser389Gly/49Ser389Gly patients were nonresponders | Ser49Gly findings partially consistent with Johnson [65]. Gly389Arg findings consistent with some studies [65–67] but not others [23] Note, however, this is the first study of these variant-drug combinations in a Chinese population. Lack of previous treatment data and washout protocol for this study hinders comparisons |
| Lemaitre et al. [23] | 2008 | 938 cases with MI or stroke, 2249 controls | MI, Ischemic stroke | ADRB1 (seven SNPs plus haplotypes), ADRB2 (five SNPs plus haplotypes) | BBs | Two SNPs In ADRB1 interacted with treatment for MI and stroke risk BB treatment did not interact with ADRB2 variants for either outcome | For ADRB1, other studies [7,65] reported significant interaction between variants tested here and BB treatment for BP-lowering whereas no interactions were found here. For ADRB2, findings agree with previous observations [68] |
| ACE inhibitors | |||||||
| Filigheddu et al. [45] | 2008 | 191 with HTN | BP at 4 weeks | ACE (ID), AGTR1 (A1166C), CYP11B2 (-344 C/T), AGT (-6 A/G) | Fosinopril | No variants were significantly associated with BP response to fosinopril | Others have found significant associations between fosinopril and ACE (ID) for BP response [69]. Findings for these variants with other ACE inhibitors are contradictory |
| Gluszek et al. [40] | 2008 | 64 with essential HTN | BP, ambulatory, MAP at 8 weeks | AGTR1 (A1166C) | Perindopril | No significant associations | Findings of other studies of this polymorphism with various treatments have been inconsistent; these findings consistent with Hingorani et al. (with unspecified ACEI and untreated hypertensives versus this study's mixed treatment, 2-week washout hypertensives) [41] |
| Angiotensin II blockers | |||||||
| Kurland et al. [19] | 2008 | 42 with HTN and LVH | BP at 12 weeks | AGTR1 (C5245T) | Irbesartan | Plasma concentration of drug was related to the change In SBP in TT individuals but not for other genotypes | Polymorphism not previously studied in this context/study design |
| Calcium channel blockers | |||||||
| Bremer et al. [28] | 2006 | 120 Caucasians | BP at ≥6 mo | CACNA1C (62 SNPs) | CCBs | Three SNPs had significant associations with antihypertensive outcomes | This was the earlierst study reporting significant PGx interaction with a CCB and, to date, the only one reporting an association with CACNA1C |
| Langaee et al. [21] | 2006 | 537 with CAD and HTN | BP, HTN risk | CYP3A5 (*3, *6) | Verapamil | Alleles marginally associated with treatment outcomes in blacks (p = 0.075) and Hispanics (p = 0.056). | Polymorphisms not previously studied in this context/study design |
| Beitelshees et al. [26] | 2007 | Overall n = 5979, but n varied by substudy | BP at 6 weeks treatment, time to BP control, number of drugs to control BP, death/MI/stroke | KCNMB1 (Glu65Lys, Val110Leu) | Verapamil, others as needed | SBP response did not differ by genotype Lys65 carriers achieved earlier control and required fewer drugs Leu110 carriers had reduced risk of death/MI/stroke | Findings consistent with the Kelley–Hedgepeth et al. study of BB and this variant [27]; however, incomplete information on previous antihypertensive treatment and washout for these studies hinders comparisons |
| Multiple drug classes | |||||||
| Milionis et al. [29] | 2007 | 132 untreated with HTN | BP after variable follow-up period | ACE (ID), AGT (M235T), AGTR1 (A1166C) | All classes, all combinations | AGTR1 C allele and AC genotype associated with more BP response, especially in individuals with MetS | Findings of other studies of AGTR1 A1166C with various treatments have been inconsistent [51,70] Undifferentiated treatment in this study and differences in washout protocols among studies make comparisons difficult |
| Schelleman et al. [37] | 2007 | 4097 with HTN | MI, stroke for approximately 10-year maximum follow-up | AGT (M235T) | ACEI, BB | MI risk with ACEI treatment increased for T allele carriers No AGT–ACEI associations for stroke; no AGT–BB associations for MI or stroke | Findings of other studies of this polymorphism with ACEIs have been Inconsistent [41,42] for BP lowering; present study is considerably larger and longer-termed than previous and tracks hard outcomes |
| Kelley–Hedgepeth et al. [27] | 2008 | 2594 without CVD | BP | KCNMB1 (Glu65Lys) | 4 HTN drug classes | BB treatment may be responsible for lower BP in Lys65 allele carriers | Findings consistent with those of the Beitelshees et al. study of CCB and this variant [26]; however, incomplete information on previous antihypertensive treatment and washout for these studies hinders comparisons |
| Lynch et al. [20] | 2008 | 38,462 with HTN | CHD, stroke, all-cause mortality, combined cardiovascular disease outcomes, and 6-month BP changes | NPPA (T2238C, G664A) | Chlorthalidone versus amlodipine, doxazosin, lisinopril | Only T2238C variant associated with modification of drug effects on outcomes Minor C allele carriers had more favorable CVD outcomes with diuretic; TT individuals had more favorable outcomes with CCB | Polymorphisms not previously studied in this context/study design |
| Pacanowski et al. [22] | 2008 | 5895 with CAD | death, nonfatal MI, nonfatal stroke for 2.8 year average follow-up | ADRB1 (Ser49Gly, Arg389Gly, haplotypes), ADRB2 (Gly16Arg, Gln27Glu, Arg175Arg, haplotypes) | Atenolol, verapami | Ser49-Arg389 haplotype carriers had higher death rates in verapamil but not atenolol group | For ADRB1, Ser49-Arg389 haplotype findings consistent with previous BB studies [7,66,71,72]. For ADRB2, associations that did not reach significance here did in other studies of BB treatment [24]. These polymorphisms and haplotypes not previously studied in the context of verapamil treatment Incomplete information on previous treatment and washout protocols makes comparisons among studies difficult |
| Schelleman et al. [38] | 2008 | 4097 with HTN | MI, stroke for ~ 10 year maximum follow-up | AGTR1 (C573T), ACE (ID) | ACEI, BB | MI risk with ACEI treatment reduced for AGTR1 C allele carriers No AGTR1–ACEI or BB associations for stroke No ACE–ACB or BB associations for MI or stroke | AGTR1 C573T polymorphism not previously studied in this context ACE ID findings consistent with previous study [44] |
*
Associations reported here met standards of significance as defined by each study, unless otherwise noted.
ACEI: Angiotensin converting enzyme inhibitor; ACS: Acute coronary syndrome; ADD1: α-adducin gene; AGT: Angiotensinogen; BB: β-blocker; BP: Blood pressure; CAD: Coronary artery disease; CCB: Calcium channel blocker; CHD: coronary heart disease; CVD: Cardiovascular disease; DBP: Diastolic blood pressure; GWAS: Genome-wide association study; HCTZ: Hydrochlorothiazide diuretic; HTN: Hypertension; LVH: Left ventricular hypertrophy; MAP: Mean arterial pressure; MetS: Metabolic syndrome; MI: Myocardial infarction; NOS: Nitric oxide synthase; PGx: Pharmacogenetic; SBP: Systolic blood pressure.