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Abstract
Essential hypertension is a complex trait where the underlying aetiology is not completely understood. Left untreated it increases the risk of severe health complications including cardiovascular and renal disease. It is almost 15 years since the first genome-wide association study for hypertension, and after a slow start there are now over 1000 blood pressure (BP) loci explaining ∼6% of the single nucleotide polymorphism-based heritability. Success in discovery of hypertension genes has provided new pathological insights and drug discovery opportunities and translated to the development of BP genetic risk scores (GRSs), facilitating population disease risk stratification. Comparing highest and lowest risk groups shows differences of 12.9 mm Hg in systolic-BP with significant differences in risk of hypertension, stroke, cardiovascular disease and myocardial infarction. GRSs are also being trialled in antihypertensive drug responses. Drug targets identified include NPR1, for which an agonist drug is currently in clinical trials. Identification of variants at the PHACTR1 locus provided insights into regulation of EDN1 in the endothelin pathway, which is aiding the development of endothelin receptor EDNRA antagonists. Drug re-purposing opportunities, including SLC5A1 and canagliflozin (a type-2 diabetes drug), are also being identified. In this review, we present key studies from the past, highlight current avenues of research and look to the future focusing on gene discovery, epigenetics, gene-environment interactions, GRSs and drug discovery. We evaluate limitations affecting BP genetics, including ancestry bias and discuss streamlining of drug target discovery and applications for treating and preventing hypertension, which will contribute to tailored precision medicine for patients.
Highlights
Hypertension is the leading global risk factor for morbidity and mortality, and studies have demonstrated a clear link between elevated systolic and diastolic blood pressure (BP) and cardiovascular disease (CVD) [1]
The current guidelines proposed by the European Society of Cardiology characterise grade 1 hypertension clinically as ≥140/90 mm Hg in patients below 80 years [4], while the clinical threshold defining hypertension in the United States is lower at ≥130/80 mm Hg, as stated by the American Heart Association [5]
95% of hypertensive cases are termed as essential hypertension (EH); hypertension with an unknown cause resulting from interplay of environmental and genetic factors
Summary
Hypertension is the leading global risk factor for morbidity and mortality, and studies have demonstrated a clear link between elevated systolic and diastolic blood pressure (BP) and cardiovascular disease (CVD) [1]. Various genome-wide linkage analyses were undertaken in relatively large cohorts including the Framingham Heart Study [24], the Family BP Program [25,26] and the British Genetics of Hypertension (BRIGHT) study [27] These studies successfully identified a number of quantitative trait loci (QTLs) (regions of DNA linked to variations in the phenotype) associated with hypertension, some of which were validated in follow-up studies [28,29,30]. A trans-ethnic meta-analysis of Exome chip data with replication in European and South Asian ancestries identified the first rare exonic variants associated with BP traits with effect sizes greater than that observed with common variants (>1.5 mm Hg per allele), mapped to four genes: RBM47, COL21A1, DBH and RRAS. Elucidating the causal SNPs remains a challenge; the majority map to noncoding regions of the genome, and variants are often in linkage disequilibrium (LD) with one or more other variants, in which they are nonrandomly associated in the population
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