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Genomics of Blood Pressure and Hypertension: Extending the Mosaic Theory Toward Stratification.

ABSTRACT: The genetic architecture of blood pressure (BP) now includes more than 30 genes, with rare mutations resulting in inherited forms of hypertension or hypotension, and 1477 common single-nucleotide polymorphisms (SNPs). These signify the heterogeneity of the BP phenotype and support the mosaic theory of hypertension. The majority of monogenic syndromes involve the renin-angiotensin-aldosterone system and the adrenal glucocorticoid pathway, and a smaller fraction are due to rare neuroendocrine tumours of the adrenal glands and the sympathetic and parasympathetic paraganglia. Somatic mutations in genes coding for ion channels (KCNJ5 and CACNA1D) and adenosine triphosphatases (ATP1A1 and ATP2B3) highlight the central role of calcium signalling in autonomous aldosterone production by the adrenal gland. The per-SNP BP effect is small for SNPs according to genome-wide association studies (GWAS), and all of the GWAS-identified BP SNPs explain ? 27% of the 30%-50% estimated heritability of BP. Uromodulin is a novel pathway identified by GWAS, and it has now progressed to a genotype-directed clinical trial. The majority of the GWAS-identified BP SNPs show pleiotropic associations, and unravelling those signals and underpinning biological pathways offers potential opportunities for drug repurposing. The GWAS signals are predominantly from Europe-centric studies with other ancestries underrepresented, however, limiting the generalisability of the findings. In this review, we leverage the burgeoning list of polygenic and monogenic variants associated with BP regulation along with phenome-wide studies in the context of the mosaic theory of hypertension, and we explore potential translational aspects that underlie different hypertension subtypes.

SUBMITTER: Lip S

PROVIDER: S-EPMC7237883 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Genomics of Blood Pressure and Hypertension: Extending the Mosaic Theory Toward Stratification.

Lip Stefanie S Padmanabhan Sandosh S

The Canadian journal of cardiology 20200305 5

The genetic architecture of blood pressure (BP) now includes more than 30 genes, with rare mutations resulting in inherited forms of hypertension or hypotension, and 1477 common single-nucleotide polymorphisms (SNPs). These signify the heterogeneity of the BP phenotype and support the mosaic theory of hypertension. The majority of monogenic syndromes involve the renin-angiotensin-aldosterone system and the adrenal glucocorticoid pathway, and a smaller fraction are due to rare neuroendocrine tumo ...[more]

PMID: 32389342

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Project description:BackgroundThe Global Burden of Diseases Study 2010 reported that hypertension is worldwide the leading risk factor for cardiovascular disease, causing 9.4 million deaths annually. We examined to what extent self-measurement of home blood pressure (HBP) refines risk stratification across increasing categories of conventional blood pressure (CBP).Methods and findingsThis meta-analysis included 5,008 individuals randomly recruited from five populations (56.6% women; mean age, 57.1 y). All were not treated with antihypertensive drugs. In multivariable analyses, hazard ratios (HRs) associated with 10-mm Hg increases in systolic HBP were computed across CBP categories, using the following systolic/diastolic CBP thresholds (in mm Hg): optimal, <120/<80; normal, 120-129/80-84; high-normal, 130-139/85-89; mild hypertension, 140-159/90-99; and severe hypertension, ?160/?100. Over 8.3 y, 522 participants died, and 414, 225, and 194 had cardiovascular, cardiac, and cerebrovascular events, respectively. In participants with optimal or normal CBP, HRs for a composite cardiovascular end point associated with a 10-mm Hg higher systolic HBP were 1.28 (1.01-1.62) and 1.22 (1.00-1.49), respectively. At high-normal CBP and in mild hypertension, the HRs were 1.24 (1.03-1.49) and 1.20 (1.06-1.37), respectively, for all cardiovascular events and 1.33 (1.07-1.65) and 1.30 (1.09-1.56), respectively, for stroke. In severe hypertension, the HRs were not significant (p?0.20). Among people with optimal, normal, and high-normal CBP, 67 (5.0%), 187 (18.4%), and 315 (30.3%), respectively, had masked hypertension (HBP?130 mm Hg systolic or ?85 mm Hg diastolic). Compared to true optimal CBP, masked hypertension was associated with a 2.3-fold (1.5-3.5) higher cardiovascular risk. A limitation was few data from low- and middle-income countries.ConclusionsHBP substantially refines risk stratification at CBP levels assumed to carry no or only mildly increased risk, in particular in the presence of masked hypertension. Randomized trials could help determine the best use of CBP vs. HBP in guiding BP management. Our study identified a novel indication for HBP, which, in view of its low cost and the increased availability of electronic communication, might be globally applicable, even in remote areas or in low-resource settings.

Project description:BackgroundWhether cardiovascular risk is more tightly associated with central (cSBP) than brachial (bSBP) systolic pressure remains debated, because of their close correlation and uncertain thresholds to differentiate cSBP into normotension versus hypertension.MethodsIn a person-level meta-analysis of the International Database of Central Arterial Properties for Risk Stratification (n=5576; 54.1% women; mean age 54.2 years), outcome-driven thresholds for cSBP were determined and whether the cross-classification of cSBP and bSBP improved risk stratification was explored. cSBP was tonometrically estimated from the radial pulse wave using SphygmoCor software.ResultsOver 4.1 years (median), 255 composite cardiovascular end points occurred. In multivariable bootstrapped analyses, cSBP thresholds (in mm Hg) of 110.5 (95% CI, 109.1-111.8), 120.2 (119.4-121.0), 130.0 (129.6-130.3), and 149.5 (148.4-150.5) generated 5-year cardiovascular risks equivalent to the American College of Cardiology/American Heart Association bSBP thresholds of 120, 130, 140, and 160. Applying 120/130 mm Hg as cSBP/bSBP thresholds delineated concordant central and brachial normotension (43.1%) and hypertension (48.2%) versus isolated brachial hypertension (5.0%) and isolated central hypertension (3.7%). With concordant normotension as reference, the multivariable hazard ratios for the cardiovascular end point were 1.30 (95% CI, 0.58-2.94) for isolated brachial hypertension, 2.28 (1.21-4.30) for isolated central hypertension, and 2.02 (1.41-2.91) for concordant hypertension. The increased cardiovascular risk associated with isolated central and concordant hypertension was paralleled by cerebrovascular end points with hazard ratios of 3.71 (1.37-10.06) and 2.60 (1.35-5.00), respectively.ConclusionsIrrespective of the brachial blood pressure status, central hypertension increased cardiovascular and cerebrovascular risk indicating the importance of controlling central hypertension.

Dataset Information

Genomics of Blood Pressure and Hypertension: Extending the Mosaic Theory Toward Stratification.

Publications

Genomics of Blood Pressure and Hypertension: Extending the Mosaic Theory Toward Stratification.

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