Table 2.
Pharmacologically active gene loci from genome-wide association studies (GWAS), their pleiotropic associations, and key drug-gene interactions with their indications and blood pressure (BP) effects
| GWAS locus | Pleiotropic associations | Antihypertensive license | BP reduction as side-effect | Effect on BP | Therapeutic context/indication |
|---|---|---|---|---|---|
| ACE | Nonpleiotropic | Angiotensin-converting enzyme inhibitors | ↓↓↓↓ | Hypertension; Heart failure; Diabetes mellitus nephropathy | |
| Omapatrilat | ↓↓ | (Hypertension; Heart failure—failed because of adverse drug reactions) | |||
| ACVR2A | Basophils, Eosinophils, Neutrophils, Renal function, Urate | Sotatercept | ↓ | (Pulmonary hypertension—phase II) | |
| ADORA1 | Nonpleiotropic | Adenosine | ↓↓ | Supraventricular tachycardias | |
| Pentoxifylline | ↓↓ | Peripheral vascular disease | |||
| ADRB1 | Birth weight | Bethanidine | ↓↓ | (Sympatholytic) | |
| β-Blockers | ↓↓↓↓ | Hypertension; Angina; Arrhythmia; Heart failure | |||
| Dobutamine | ↓↓ | Inotropic support; Cardiac stress testing | |||
| Amiodarone | ↓↓ | Arrhythmia | |||
| AKR1A1 | Basophils, Granulocytes, Height, Hematocrit, Hemoglobin, Neutrophils, Platelet traits, RBC traits, Reticulocytes, WBC | Tolrestat | ↓ | (Diabetes complications—failed trials) | |
| AKR1B10 | Nonpleiotropic | (Diabetes complications—failed trials) | |||
| BCL2 | Adiposity, BMI, BMR, CAD, Glycemia, Hematocrit, RBC traits, Reticulocytes, T2DM, Visceral.fat, Weight | Docetaxel | ↓↓ | Solid tumours | |
| CACNA1C | Hematocrit, Hemoglobin, RBC traits | Cinnarizine | ↓ | Ménière disease | |
| Spironolactone | ↓↓↓↓ | Hyperaldosteronism; Oedema; Heart failure; Hypertension | |||
| Drotaverine | ↓↓ | Antispasmodic | |||
| Topiramate | ↓ | Epilepsy; Migraine | |||
| Calcium channel blockers | ↓↓↓↓ | Angina; Hypertension | |||
| CACNA1D | Monogenic, Nonpleiotropic | Cinnarizine | ↓ | Ménière disease | |
| Spironolactone | ↓↓↓↓ | Hyperaldosteronism; Oedema; Heart failure; Hypertension | |||
| Calcium channel blockers | ↓↓↓↓ | Angina; Hypertension | |||
| CACNB2 | Nonpleiotropic | Spironolactone | ↓↓↓↓ | Hyperaldosteronism; Oedema; Heart failure; Hypertension | |
| Calcium channel blockers | ↓↓↓↓ | Angina; Hypertension | |||
| CHRM2 | Heart rate | Pizotifen | ↓↓ | Migraine | |
| Disopyramide | ↓↓ | Arrhythmia | |||
| Cinnarizine | ↓ | Ménière’s disease | |||
| Acetylcholine | ↓↓ | ||||
| Amitriptyline | ↓↓ | Depression; Neuropathic pain; Migraine | |||
| CSK | Cholesterol, Granulocytes, Hematocrit, Monocytes, Platelet traits, RBC traits, Renal function | Dasatinib | ↓↓ | Chronic myeloid leukemia | |
| CYP11B2 | Height | Spironolactone | ↓↓↓↓ | Hyperaldosteronism; Oedema; Heart failure; Hypertension | |
| DBH | Nonpleiotropic | Ascorbic acid | ↓ | Scurvy | |
| DDAH1 | Adiposity | Esomeprazole | ↓ | Peptic ulcer disease | |
| EDNRA | CAD | Ambrisentan | ↓↓ | Pulmonary hypertension | |
| ESR1 | Adiposity, Height | Dobutamine | ↓↓ | Inotropic support; Cardiac stress testing | |
| FGR | BMI | Dasatinib | ↓↓ | Chronic myeloid leukemia | |
| FRK | Adiposity, Cholesterol, C-reactive protein, Height, Low-density lipoprotein | Dasatinib | ↓↓ | Chronic myeloid leukaemia | |
| GUCY1A2 | CAD | Riociguat | ↓↓ | Pulmonary hypertension | |
| HDAC7 | Allergy, Asthma, Platelet traits, Reticulocytes | Belinostat | ↓ | (T-cell lymphoma) | |
| HDAC9 | Adiposity, CAD, CVA | ||||
| HDAC9 | Adiposity, CAD, CVA | Valproic acid | ↓ | Epilepsy; Bipolar disorder; Migraine | |
| HRH1 | Adiposity, BMD, Neoplasm | Mirtazapine | ↓↓ | Depression | |
| Pizotifen | ↓↓ | 5-HT, Muscarinic, H1, Alpha-adrenergic antagonist | |||
| Dimenhydrinate | ↓ | Vertigo | |||
| Histamine | ↓↓ | ||||
| Cinnarizine | ↓ | Ménière’s disease | |||
| Amitriptyline | ↓↓ | Depression; Neuropathic pain; Migraine | |||
| INSR | Adiposity, High-density lipoprotein, Height, Triglycerides, Urate, Visceral.fat | Insulin | ↓ | Diabetes mellitus | |
| KCNJ11 | Adiposity, BMI, Glycemia, Height, T2DM | Diazoxide | ↓↓ | Hypoglycemia | |
| LIMK1 | Lung function | Dabrafenib | ↓↓ | Melanoma | |
| MTHFR-NPPB | CAD, RBC traits, Visceral fat | Carvedilol | ↓ | Hypertension; Angina; Heart failure | |
| NPR3 | Adiposity, BMR, Height, Lung function, Visceral fat, Weight | Nesiritide | ↓↓ | (Heart failure—failed clinical trial) | |
| PDE10A | Nonpleiotropic | Dipyridamole | ↓↓ | Adenosine deaminase and phosphodiesterase Inhibitor | |
| Papaverine | ↓↓ | (Antispasmodic) | |||
| PDE1A | Adiposity, BMR, Weight | Calcium channel blockers | ↓↓↓↓ | Angina; Hypertension | |
| Bepridil | ↓↓ | Angina (withdrawn) | |||
| PDE3A | CAD, Monogenic | Amrinone | ↓ | Heart failure | |
| PDE5A | Basophils, CAD, Granulocytes, Platelet traits, WBC | Dipyridamole | ↓↓ | Antiplatelet | |
| Pentoxifylline | ↓↓ | Peripheral vascular disease | |||
| SCN10A | Heart rate, Neoplasm | Tetracaine | ↓ | Local anaesthetic | |
| Lidocaine | ↓↓ | Local anaesthetic; Ventricular arrhythmia | |||
| Valproic acid | ↓ | Epilepsy; Bipolar disorder; Migraine | |||
| Brivaracetam | ↓ | Epilepsy | |||
| SCN2A | Adiposity | Zonisamide | ↓↓ | Epilepsy | |
| Tetracaine | ↓ | Local anaesthetic | |||
| Valproic acid | ↓ | Epilepsy; Bipolar Disorder; Migraine | |||
| Brivaracetam | ↓ | Epilepsy | |||
| VEGFA | Hematocrit, Hemoglobin, RBC traits, Renal function, Urate | Carvedilol | ↓↓↓↓ | Hypertension; Angina; Heart failure | |
| YES1 | Nonpleiotropic | Dasatinib | ↓↓ | Chronic myeloid leukaemia |
All pleiotropic associations of GWAS BP single-nucleotide polymorphisms (SNPs) were extracted and categorised into groups of correlated traits. Some SNPs did not show any non-BP associations and were classified as nonpleiotropic. The genes linked to GWAS SNPs were determined by proximity to the SNP and cardiovascular plausibility. Only 1 gene per loci was included. Drug-gene interactions were obtained from the DrugBank and Comparative Toxicogenomics Database, and drug indications were obtained from the British National Formulary and Food and Drug Administration labelled indications.
BMI, body mass index; BMD, bone mineral density; BMR, basal metabolic rate; RBC, red blood cells; CAD, coronary artery disease; CVA, cerebrovascular accident; T2DM, type 2 diabetes mellitus; WBC, white blood cells.