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hypertensive phenotype being difficult to define, influenced strongly by environmental factors and being
highly dynamic[10] . To reduce bias and noise, GWAS
studies often include large numbers of patients and
results are not always reproducible in other cohorts.
For these reasons SNP variants, identified by GWAS,
and their representative genes provide only a starting point and often carry no clinical utility when
actionable interventions and evidence-based (EBM)
outcomes are unavailable. GWAS has however been
highly successful in the identification of novel biology
in the pathogenesis of a condition, as is the case with
hypertension. In addition, GWAS may identify genes
related to behavioral attributes indirectly relevant to
an asymptomatic disease, such as hypertension. For
example nonadherence to drug therapy[11] .
Next-generation genome sequencing, on the other
hand, holds the promise of identifying causal rare variants, which are more likely to contribute to the presence of disease[12,13] . These rare variants, however,
are often highly personal to an individual or a family,
and without previous description, their functional relevance may be uncertain. Hence, the pressure to apply
next generation sequencing to ever increasing, broadly
phenotyped, populations to link causal effect, with
these variants of uncertain significance (VUS). As the
cost of next generation sequencing plummets the number of sequenced genomes is increasing rapidly and
the richness of this information is being dramatically
realized.
Despite all of these issues, early genomic studies have identified a number of genes that may have
clinical relevance in the management of hypertension
(Examples in Table 1) . Thirty nine SNPs have been
identified in genes such as ATP2B1 (encoding ATPase,
Ca++ transporting plasma membrane 1)[14] , CYP17A1
(cytochrome P450, family 17, subfamily A, polypeptide1) [14] and 5,10-methylenetetrahydrofolate reductase (MTHFR) [15] . Many of the genes identified by
these analyses were not previously linked to hypertension, revealing novel pathways and druggable targets
for future study. Some genes identified by GWAS had
already been associated with hypertension in the preGWAS era, thereby validating their significance and
highlighting the power of GWAS methodology.
Two genes of interest include CYP17A1, which
encodes a key enzyme in a steroidogenic pathway[3] . Loss
of function of CYP17A1 can lead to an uncommon form
of congenital adrenal hyperplasia, with hypertension.
The protein encoded by MTHFR catalyzes the conversion of 5,10 methylenetetrahydrofolate to 5-methyltetrahydrofolate in the metabolism of methionine. The loss
of function gene variant C677T (rs1801133), within the
MTHFR gene, has been associated with elevated homo-
cysteine, coronary artery disease, cancer and hypertension in population studies. However ethnicity and diet
appear to be strong confounders and these results have
not been consistently reproduced[1619] .
Unravelling the relevant SNPs associated with
hypertension will require further observational longi-
Review
Biomarker/dbSNP
position
Response
Ref.
PRKCA
rs16960228
[12,78]
GNAS-EDN3
rs2273359
EBF1
rs4551053
SH2B3
rs3184504
FGF5
rs1458038
FGF5
rs1458038
CHIC2
rs871606
MOV10
rs2932538
HFE
rs1799945
CAMK1D
rs10752271
Response to Losartan
[95]
TCF7L2
rs7917983
[79]
SLC22A11 SLC2A9
rs2078267
rs13129697
[80]
TAS2R38
rs1726866, rs713598,
rs10246939
[96]
CYP1A2
rs762551
[52,53]
MTHFR
rs1801133
[44,45]
IsoP
F2-isoprostanes
[55,56]
MPO
Myeloperoxidase,
rs2333227
[57,60]
SLC4A5
rs7571842, rs10177833
[47]
4-hydroxyhippurate
[40]
Pharmacogenetics
[8]
[8]
Nutrigenetics
rs1801282
[97]
FTO
rs9930506
[98]
Non-SNP biomarker, in other words, metabolite or plasma protein. Please see[100] under projects for an up-to-date list of hypertension
related SNP/genes as well as open-source Sequenom iPLEX primers (Supplementary Data).
dbSNP:Database of short genetic variation.
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Although the pharmacological options for hypertension appear to be limited, lifestyle options that
involve nutrition are likely to become more sophisticated and effectivein the future. There is a growing
appreciation that the microbiome (gut flora) has profound clinical significance, as it is integrally involved
in absorption and metabolism of drugs, nutrition and
the health of an individual. In the context of hypertension, this has been demonstrated through the study
of metabolomics. This technology uses NMR or mass
spectroscopy to profile small molecules, produced by
host metabolism and microorganisms. Although this
method has not been applied to many hypertensive
populations, an association has been made between
blood pressure and varying metabolites such as sex steroid metabolites, 4-hydroxyhippurate and alanine[40] .
Interestingly 4-Hydroxyhippurate is produced by gut
flora, the metabotype of which differs between individuals and is modifiable by dietary intake of fish and
other nutrients[41,42] . This raises the distinct possibility of using this or similar biomarkers, in personalized
dietary programs and as a monitoring tool for dietary
intake, including the use of functional foods, listed in
Table 2 [43] . The MTHFR 677TT (rs1801133) variant
is of particular interest in nutrigenomics as the folate
pathway is modified with the administration vitamin B2 (riboflavin)[44,45] . A randomized trial, using
genomic enrichment for hypertensive patients with
the TT genotype, has shown that blood pressure can
be reduced by approximately 6 mmHg systolic with
administration of riboflavin[45] .
Salt intake has been linked in epidemiological studies to blood pressure, and populations with a low intake
Action
Choices
Review
Personalized data
Relevance
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Table 2. Functional foods and nutriceuticals with antihypertensive properties, categorized by antihypertensive class.
Antihypertensive
therapeutic class
Angiotensin converting Egg yolk, Fish (specific): bonito, dried salted fish, fish
enzyme inhibitors
sauce, sardine muscle/protein, tuna, garlic, gelatin,
hawthorne berry, Milk products (specific): casein sour
milk, whey (hydrolyzed) sake, sea vegetables (kelp),
sea weed (wakame), wheat germ (hydrolyzed), zein
(corn protein)
Angiotensin receptor
blockers
Beta blockers
Vitamin D
Direct vasodilators
Celery, cooking oils with monounsaturated fats, fiber, Alpha linolenic acid, Arginine, calcium,
garlic, MUFA soy
flavonoids, magnesium Omega-3 fatty
acids, Potassium, taurine, vitamin C,
vitamin E
Diuretics
some patients. This highlights the need for personalized management planning, addressing the underlying
cause with problem-focused interventions. This may
include tailored diet and exercise advice. For example,
in diabetes and the metabolic syndrome, genetic variants have been identified which influence the response
to exercise, risk of obesity and weight gain associated
with certain foods[66] . Given the widespread deliverability of genomics, metabolomics and other personalized measures, including personalized nutrition, these
sciences have a greater chance of turning the tide on the
obesity epidemic than do surgical interventions[67,68] .
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Pharmacological management
Since the introduction of hydralazine in the 1950s
there has been a steady addition of other antihypertensive agents to the clinicians armamentarium[69] .
These pharmaceuticals historically emerged in the
order of diuretics, -blockers, calcium channel blockers (CCHB), -1 blockers, angiotensin converting
enzyme inhibitors (ACE-I) and angiotensin-1 receptor blockers (ARB). Centrally acting agents such as
clonidine and methyldopa are also included in this
list, but often considered last line. Of historic interest
is the fact that clonidine was originally developed as a
nasal decongestant but drug repurposing found its use
in hypertensive management[70] . The pace of discovery has slowed with the most recent addition of direct
renin inhibitors to this list. Existing within each class
are a number of agents and for the individual patient
the options are multiplied further by the permutations
of preferred drug combinations. Although numerous,
randomized clinical trials have tested the efficacy of
monotherapy and combination therapy, they have
been unable to test all possible therapeutic iterations.
Despite this, important conclusions can be extrapolated from trials such as ACCOMPLISH, ASCOT and
its substudy the CAF trial, which have cumulatively
shown that combination therapy with a CCHB/ACE-I
is preferable to a drug combination which includes a
diuretic, and that -blockers have less efficacy than
other agents[69,71] .
Due to the inaccurate nature of office based blood
pressure assessment and the long-term relationship
with adverse events, clinical trials have required large
numbers of patients and have been difficult to perform.
Despite the impediments, a number of lessons have
been learned from large trials. First, the response to any
single agent is on average 9.1 mmHg systolic and 5.5
mmHg diastolic; however, the variability in response
to a single agent in the population varies widely across
a range of 2030 mmHg, with some experiencing no
benefit at all or even a rise in blood pressure[69] . The
heritability and consistency of response of an individual to a single agent would suggest that it should be
possible to predict who is likely to benefit most from a
particular agent[72] . However, in the absence of such
a predictive test the question then arises whether one
should trial cycling monotherapy testing numerous
agents, sequentially in a single patient; or stepped care
where single agents are titrated to effect before the
additional agents are included or to give low-dose combination therapy. With the knowledge that blood pressure targets are rarely met in those who present with
moderate to high blood pressure and that drug side
effects become more apparent with increasing dose of
single agents, the most logical and practical approach
would be low dose combination therapy. This approach
has been tested in the STRATHE trial, where introducing low-dose combination therapy, as a first line,
appeared superior to sequential monotherapy and
stepped care[73] . The STRATHE trial enrolled only
patients with mean blood pressures of 160 mmHg
systolic and 95 mmHg diastolic. As it was only a
Review
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Figure 2. Diagnostic patterns obtained from standard clinical data. (A) A 43-year-old male who presented
with accelerated hypertension and a nonspecifically abnormal conventional ECG showing sinus tachycardia
and ventricular ectopy. Biomarker testing suggested possible heart failure (NT-BNP = 333 pmol/l [reference
<35pmol/l]). (B) Echocardiography showed left ventricular hypertrophy (LVH), a severely dilated left ventricle
(LV) with systolic dysfunction. (C) A cardiac MRI confirmed NICM. A coronary angiogram (not shown) showed mild
coronary artery disease. The presumed diagnosis was severe hypertensive cardiomyopathy.
CAD:Coronary artery disease; EDV:End diastolic volume; EF:Ejection fraction; ESV:End systolic volume;
FS:Fractional shortening; HOCM: Hypertrophic cardiomyopathy; ICM:Ischemic cardiomyopathy; LVIDd:Left
ventricular internal diastolic dimension; LVIDs:Left ventricular internal systolic dimension; LVPWd:Left ventricular
posterior wall dimension; NICM:Non-ischemic cardiomyopathy; SV:Stroke volume.
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Review
Canonical Plot 3D
Healthy
HOCM
Canonical Plot
NICM
CAD
Canonical 2
+ 2
Canonical 2
LVH
40
1
ICM
+
+
35
-14
-12
-10
-8
Canonical 1
-6
Canonical 1
Figure 2. Diagnostic patterns obtained from standard clinical data (cont.). (D & E)Shows advanced ECG (A-ECG)
results at presentation (marker 1) using linear discriminant analysis against a large, pre-existing clinical ECG
database[92,99] . Thus, A-ECG correctly diagnosed the nonischemic cardiomyopathy (i.e., marker 1 was nearest
the purple NICM population centroid at presentation), as well as the subsequent trajectory, with treatment
(sequential markers 2 and 3), through basal left ventricular hypertrophy (LVH, aqua centroid) toward a healthier
state (small green centroid). Red, orange and blue centroids:other centroids of advanced ECG results in patients
with CAD, ICM and HOCM, respectively.
CAD:Coronary artery disease; EDV:End diastolic volume; EF:Ejection fraction; ESV:End systolic volume;
FS:Fractional shortening; HOCM: Hypertrophic cardiomyopathy; ICM:Ischemic cardiomyopathy; LVIDd:Left
ventricular internal diastolic dimension; LVIDs:Left ventricular internal systolic dimension; LVPWd:Left ventricular
posterior wall dimension; NICM:Non-ischemic cardiomyopathy; SV:Stroke volume.
tice [88] . Altering the timing of medication administration, or chronotherapy, is also showing promise in
improving the response to medication, for example, dosing with an ARB at night time[89] , though these findings need further validation. As diurnal variation is itself
genetic, with variable individual metabolic variation, it
is not surprising that the timing of antihypertensive
medication can itself be personalized[90] .
Integrating clinical biobanks, EMRs and telemonitoring is already reducing the cost and complexities
of running pharmacogenetic clinical trials[91] . In the
future this is likely to demonstrate further links with
the autonomic nervous system, the importance of diurnal variation, environmental and stressful stimuli and
should reveal otherwise imperceptible patterns in clinical data (Figure 2) [92] . These integrated biobank initiatives need to be collaborative, locally supported and
viewed as part of clinical care rather than research[21] .
Conclusion & the future of hypertension
management
The management of hypertension has changed significantly over the last century. It is worth noting that
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Liddle syndrome
ECE1
SCNN1B
SCNN1G
WNK1
SCNN1A
WNK4
Pseudohypoaldosteronism
HSBD
PTGIS
NR3C2
GNB3
TJP2
BAAT
Hypercholanemia
EPHX1
CYP3A5
Hypertension
STOX1 Preeclampsia
AGT
Placental abruption
Nos3
AGTR1 KCNMB1
RETN
Coronary spas
Alzheimer disease
MH
PAXIP1
histiocyte disease
MPO
Hyperproreninemia
Angiotensin I-coverting enzyme
ACE
PSEN1
SARS, progression of
Pick disease
Supranuclear palsy
Dementia
ITM2B
MAPT
SNCB
Pallidopontonigral degeneration
definitions surrounding the condition have been dictated by methods of measurement and the emergence
of new pharmaceutical agents. As these methods and
treatment strategies change, so too will the perception of the condition. Compared with other traditional risk factors hypertension contributes the most
to the burden of cardiovascular disease in the population. However, despite evidence-based approaches to
care, hypertension continues to be under-recognized
and under-treated. This is compounded by the fact
that the disease is silent and treatment does not alter
symptoms.
21st century
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Review
addition new procedural technologies need to be incorporated into clinical decision trees and monitored as
they are implemented, targeting treatment to the right
patients. Given the complexity and rapid emergence
of new information in this field, an interdisciplinary
expert team is required to provide the best integrated,
holistic care for the individual patient.
Financial & competing interests disclosure
PA Gladding holds an issued patent on the use of pharmacogenetic technology and is the founder of Theranostics Laboratory, which receives licensing fees from Cleveland HeartLab.
TT Schlegel is principal inventor on several NASA patents related to advanced electrocardiography. The authors have no
other relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial
conflict with the subject matter or materials discussed in the
manuscript apart from those disclosed.
No writing assistance was utilized in the production of this
manuscript.
Executive summary
Background
Current definitions of hypertension are dictated by methods of measurement, rather than identification of
the underlying cause.
Contemporary management of hypertension is based on reductionist pharmacology.
Genomics of hypertension
Genomics is providing insights into the underlying mechanisms of essential hypertension and can be used to
predict treatment efficacy and adverse reactions.
Conclusion
The best method to generate the evidence base to support individualized care will be to implement the
technology, monitor its use, learn from the outcomes and if proven cost-effective, adapt to the new model
ofcare.
References
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