personalized hypertension management

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297Per Med (2015) 12(3) 297ndash311 ISSN 1741-0541

part of

Review

102217PME1483 copy 2015 Future Medicine Ltd

Per Med

Review12

3

2015

The revolution occurring in genomic and personalized medicine is likely to have a significant impact on the management of hypertension However from the perspective of translating new knowledge into clinical practice progress has been slow This review article summarizes recent advances in hypertension-related diagnostics while also offering new perspective on hypertension management for the future Such new perspectives will likely require a paradigm shift toward more integrated and holistic approaches for better prevention and treatment of hypertension in both individuals and the population as a whole

Keywords feedback bull genomics bull hypertension bull lifestyle bull personalized

The first recording of blood pressure was made in 1733 in a horse but was not described as a disease in humans until 1808 The invention of cuff-based sphygmoma-nometry later in 1881 provided the means to measure blood pressure in the clinic [1] Over the early part of the 20th Century some of the causes of hypertension were discovered and the term lsquoessential hypertensionrsquo began to be used to specify that no cause could be found The consequences of chronic severe hypertension such as stroke retinopathy cardiac and renal failure soon became appar-ent to clinicians and was deemed lsquomalignantrsquo hypertension This often occurred in an accelerated fashion which without treat-ment often led to an early demise However at that time the long-term consequences of mild forms of hypertension were unknown and mild hypertension was generally consid-ered benign The continuous relationship of these lsquoend organrsquo diseases with milder forms of hypertension did not become known until longitudinal studies such as the Framing-ham study were performed [2] Despite its importance mild hypertension has continued to be under-recognized in part due to dif-ficulties with definition of the condition but also with its measurement

Moving forward to the 21st Century automated and miniaturized sphygmoma-nometry has democratized the measurement of blood pressure allowing home-based monitoring Home-based devices and ambu-latory monitoring are able to demonstrate diurnal blood pressure variation and aver-age blood pressure load which can identify mild hypertension and those with white coat and masked hypertension with greater accuracy [3] However office-based blood pressure measurements and centralized man-agement is still considered the standard of care Although the widespread use of sphyg-momanometry has aided in the recognition of hypertension in its present form the mea-surement and treatment of peripheral blood pressure may not be addressing the root cause of the condition

Increasing peripheral vascular resistance and in part arterial stiffness have been established as underlying causes for elevated blood pressure [4] Pulse wave reflections summated in large arterial vessels are the reason for the blood pressure waveform and its amplitude Arterial pulse wave veloc-ity and an augmentation index can now be measured using equipment once only avail-able within a research laboratory However

Personalized hypertension management in practice

Patrick A Gladding1 Alasdair Patrick2 Paul Manley2 Laura Mash2 Phillip Shepherd3 Rinki Murphy4 Silas Vilas-Boas5 amp Todd T Schlegel6

1Theranostics Laboratory North Shore Hospital Shakespeare Rd Auckland New Zealand 2MacMurray Hypertension Clinic Ltd Auckland New Zealand 3Sequenom Facility University of Auckland New Zealand 4Department of Medicine University of Auckland New Zealand 5Centre for Microbial Innovation University of Auckland New Zealand 6Nicollier-Schlegel Sagraverl Treacutelex Switzerland Author for correspondence Tel +6494861491 patrickgtheranosticslabcom

298 Per Med (2015) 12(3) future science group

Review Gladding Patrick Manley et al

complexity and an absence of therapies targeting arte-rial stiffness has limited its clinical utility However the information that arterial stiffness provides may be enhanced by combining its measurement with whole genome sequencing providing a more holistic view of cardiovascular health [5]

Addressing the underlying cause of hypertension in each individual patient using such a holistic approach is expected to usher in a era of early detection preven-tion and targeted treatments Tailored management for nonessential causes of hypertension such as Connrsquos syn-drome glucocorticoid remediable hyperaldosteronism Cushingrsquos syndrome and renal artery stenosis has been the driver to elucidating the cause of secondary forms of hypertension leaving the bulk of essential hyper-tension (95 of all cases) still without an underlying cause Glucocorticoid remediable hyperaldosteronism although rare provides a prototype for personalized medicine where a chimeric CYP11B1CYP11B2 genersquos function can be in part rectified with administration of physiological glucocorticoid treatment [6]

The rapid advances in genomic technologies are beginning to deliver on some of these hopes for essential hypertension Although further research is required for many discoveries to become part of daily routine there is emerging evidence which can be applied in contem-porary practice As this evidence often falls short of a randomized controlled megatrial the barrier to wide-spread adoption remains high With the rapid pace of change emergence of lsquobigrsquo data science and an inabil-ity to test all potential hypotheses it is arguable that the randomized megatrial as we know it has passed its use by date Tradition needs to be supplanted by a new model of care This review article hopes to address these issues from a new perspective

Genomics of hypertensionThe heritability of essential hypertension is estimated to be between 63 and 68 indicating a significant genetic component [7] Despite this the underlying molecular mechanisms have not been readily appar-ent The era of nonhypothesis driven genome wide association studies (GWAS) has identified a number of genes and single nucleotide polymorphisms (SNPs) associated with essential hypertension [7ndash9] However the contribution of these individual gene variants to blood pressure is small accounting for differences of only approximately 1 mmHg Such findings have been common to all GWAS studies of chronic dis-ease in part due to the nature of the variants tested These SNP variants by definition are common in the population and in isolation account for only small effects as they act in a complex interactive fashion with other genes This complexity is compounded by the

hypertensive phenotype being difficult to define influ-enced 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 start-ing 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 vari-ants which are more likely to contribute to the pres-ence of disease [1213] These rare variants however are often highly personal to an individual or a family and without previous description their functional rel-evance 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 num-ber of sequenced genomes is increasing rapidly and the richness of this information is being dramatically realized

Despite all of these issues early genomic stud-ies 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 polypep-tide1) [14] and 510-methylenetetrahydrofolate reduc-tase (MTHFR) [15] Many of the genes identified by these analyses were not previously linked to hyperten-sion revealing novel pathways and druggable targets for future study Some genes identified by GWAS had already been associated with hypertension in the pre-GWAS 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 conver-sion of 510 methylenetetrahydrofolate to 5-methyltet-rahydrofolate in the metabolism of methionine The loss of function gene variant C677T (rs1801133) within the MTHFR gene has been associated with elevated homo-

wwwfuturemedicinecom 299future science group

Personalized hypertension management in practice Review

cysteine coronary artery disease cancer and hyperten-sion in population studies However ethnicity and diet appear to be strong confounders and these results have not been consistently reproduced [16ndash19]

Unravelling the relevant SNPs associated with hypertension will require further observational longi-

tudinal studies Ideally randomized crossover studies would be performed however with the numerous per-mutations of genetic variants and the power required to conduct such studies testing treatment strategies based upon these variants may not always be feasi-ble [20] Biobanks self-tracking and observational stud-

Table 1 Emerging biomarkers in hypertension obesity and exercise physiology

Gene BiomarkerdbSNP position

Response Ref

Pharmacogenetics

PRKCA rs16960228 Hypertension and response to hydrochlorothiazide

[1278]

GNAS-EDN3 rs2273359

EBF1 rs4551053 Hypertension and in aggregate response to hydrochlorothiazide

[8]

SH2B3 rs3184504

FGF5 rs1458038

FGF5 rs1458038 Hypertension and in aggregate response to atenolol

[8]

CHIC2 rs871606

MOV10 rs2932538

HFE rs1799945

CAMK1D rs10752271 Response to Losartan [95]

TCF7L2 rs7917983 Risk of developing diabetes with hydrochlorothiazide

[79]

SLC22A11 SLC2A9 rs2078267 rs13129697

Risk of developing thiazide-associated gout

[80]

Nutrigenetics

TAS2R38 rs1726866 rs713598 rs10246939

Bitter taste receptor control of eating [96]

CYP1A2 rs762551 Caffeine metabolism and association with hypertension

[5253]

MTHFR rs1801133 Hypertension and response to riboflavin

[4445]

IsoP F2-isoprostanesdagger Risk of renal failure in hypertensives and cardiovascular risk

[5556]

MPO Myeloperoxidasedagger rs2333227

Hypertension and cardiovascular risk [5760]

SLC4A5 rs7571842 rs10177833 Salt sensitivity on blood pressure [47]

4-hydroxyhippuratedagger Hypertension diet and gut microbiome

[40]

Obesity and exercise physiology

PPARG rs1801282 Improved glucose homeostasis in response to exercise

[97]

FTO rs9930506 Obesity and response to exercise [98]

daggerNon-SNP biomarker in other words metabolite or plasma protein Please see [100] under projects for an up-to-date list of hypertension related SNPgenes as well as open-source Sequenomreg iPLEXreg primers (Supplementary Data)dbSNP Database of short genetic variation



ies embedded in electronic medical records (EMRs) may provide the most rational solution to this prob-lem [921] Citizen science that assesses dietary as well as pharmacological interventions and integrates genomics and social networks is an untapped route to progress in the field of hypertension management [2223]

Treatment strategiesThe first option for the management of essential hyper-tension remains lifestyle intervention where possible Public health policy over recent years has been impor-tant in identifying and educating the public on healthy foods (including salt restriction) and lifestyle behaviors (increased physical activity) Government legislature worldwide of food labeling and regulating food con-stituents has made significant achievements in improv-ing access to healthy foods and environmental plan-ning However market forces and individual choice are two impediments to achieving universal adoption of healthy lifestyle options and adherence to those treat-ment plans It is important therefore to realize that personalized medicine includes not only genomics but also delivering personalized care plans relating to diet and lifestyle It is worth noting that industries outside of medicine have utilized personalization for years to influence behavior increase efficiency and lower cost in the delivery of services

Personalized medicine also means personalized careThe concept of personalization is not limited to the field of genomics and is in wide use in industries other than medicine There are a number of underlying principles to personalization though one of the most important is the focus on patient-centered principles Using personalization in clinical care can be simple and inexpensive to administer such as targeting a screening program based on a family history A study performed by Hovell et al in the 1980s demonstrated the value of such simple interventions in the management of hyper-tension and emphasized the importance of lsquopersonal-ized carersquo which is not to be confused with its subset of lsquopersonalized (genomic) medicinersquo [2425] In the quasi experimental design in this study patients were man-aged either with specialized individualized attention which included courteous service and appointments made at the patientrsquos convenience This included feed-back on blood pressure values progress and attainment of goals Patients in the control arm were treated with a more business-like approach wherein patients did not receive any feedback on their own measurements progress or achievements Interestingly in those receiv-ing personalized care blood pressure values reduced by 8 mmHg systolic and 5 mmHg diastolic equivalent to

the effect of a single antihypertensive drug compared with those who received a business-like approach [24]

An important aspect to personalized care includes the respect of a patientrsquos autonomy including not only the delivery of care appropriate to the individual patient which may differ based on age religion and other preferences but also their willingness to receive it [2627] The desire to opt for nonpharmacological treatment options for mild hypertension needs to be respected particularly in an era where alternative and complementary health options are beginning to chal-lenge traditional dogma [2829] Transcendental medi-tation for instance has been shown to reduce both blood pressure and cardiovascular outcomes in African Americans Although time consumptive this approach should not be underestimated particularly given its wide range of psychosocial benefits which contem-porary treatment cannot provide [30] Counter to this however is the need for contemporary input in cases of hypertension where end-organ damage has occurred or in cases of life-threatening accelerated hypertension

Renal denervation (RDN) has become an emerg-ing option for patients with refractory hypertension though is now complicated by the result of an appar-ently negative randomized trial The SIMPLICITY-3 trial compared RDN with a sham procedure and showed no difference in blood pressure when results were averaged across each treatment group [31] From a one-size-fits-all perspective this appears to be a failed treatment though it would seem probable that RDN may be effective when reserved for selected patients such as those with neurally mediated renovascular hypertension [3233] Similarly manipulation of the autonomic nervous system through baropacing of the carotid sinus may also be appropriate in some individuals [34] Sophisticated computational model-ing has already demonstrated some of the underlying mechanisms behind the hypertension for instance the importance of baroreceptor and autonomic dys-function in the long-term regulation of arterial pres-sure [35] Supporting that view is the observation that heart rate variability a measure of autonomic function becomes abnormal prior to the development of hyper-tension [3637] In the future randomized clinical trials may be supplanted by simulations and the use of com-putational modeling of physiology to select the best treatment strategy for an individual

Rather than SIMPLICITY-3 denoting failure this result should be a reminder that reductionistic practices and uniform population-based approaches to prob-lems often seem to fail This particularly appears the case where a single intervention is undertaken which ignores the wide variability in human response and adaptive nature of biological systems Individualized

wwwfuturemedicinecom 301

Figure 1 Feedback loops motivation and behavior change Personally relevant actionable information is delivered to patients to support behavioral change

Action

Choices Relevance

Personalized data

Personally relevant actionable information is delivered to patients to support behavioral change

future science group


multidisciplinary care by contrast has been shown repeatedly to be far more effective at both an individ-ual and population level [38] As it is too complex to test multiple management strategies in a single clinical trial randomized registries and biobanks will be the best method to demonstrate that this methodology is efficacious and cost effective [39]

This patient-centered approach to care respects autonomy and understands that in a world of finite resources and limited access to healthcare profession-als patients must be engaged in monitoring and man-aging their own health With the advent of pervasive wireless connectivity ubiquitous health monitoring and cloud computing it will be possible for patients to experience greater independence feedback and sense of attainment from managing their own health with the options they choose (Figure 1)

Nonpharmacological management Metabolomics the gut microbiome amp nutrigeneticsAlthough the pharmacological options for hyper-tension appear to be limited lifestyle options that involve nutrition are likely to become more sophisti-cated and effective in the future There is a growing appreciation that the microbiome (gut flora) has pro-found clinical significance as it is integrally involved in absorption and metabolism of drugs nutrition and the health of an individual In the context of hyper-tension 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 ste-roid metabolites 4-hydroxyhippurate and alanine [40] Interestingly 4-Hydroxyhippurate is produced by gut flora the metabotype of which differs between indi-viduals and is modifiable by dietary intake of fish and other nutrients [4142] This raises the distinct possibil-ity 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 vita-min B2 (riboflavin) [4445] 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 stud-ies to blood pressure and populations with a low intake

are relatively free of hypertensive disease However the reduction of dietary salt at a population level has met with mixed success [46] This in part may be due to genetic variants influencing the variable response to salt loading and restriction not only throughout life but also in utero [4748] Recent reports have indicated that the salt intake targets recommended by guide-lines are too low for some patients and may in fact increase cardiovascular risk [49] A J-shaped effect is also evident with blood pressure indicating that strict population targets cannot be applied to the individ-ual patient and hence the Joint National Committee (JNC8) guidelines have relaxed blood pressure targets in some patient groups particularly the elderly [50] In this regard biological age rather than chronological age should be factored into treatment decisions when managing the hypertensive patient [51]

The association between hypertension caffeine intake and cardiovascular events in epidemiological studies has also been shown to be equivocal How-ever when a genotype related to caffeine metabolism is considered a clear dose responsive association of cof-fee consumption hypertension and clinical outcomes is demonstrated [5253] In addition GWAS studies of high-caffeine consumers have identified genes related to smoking initiation higher adiposity and fasting insulin and glucose levels [54]

Biomarkers of oxidative stress and inflammation complete the axis linking nutrition obesity hyperten-sion and cardiovascular risk F2 isoprostane and myelo-peroxidase exemplify such biomarkers F2 isoprostane has been shown to predict the development of renal failure in patients with hypertension and is a prognos-tic marker of cardiovascular risk [5556] The inflam-matory biomarker plasma myeloperoxidase (MPO) is also deeply involved the cardiovascular system and hypertension Myeloperoxidase is a strong independent



predictor of cardiovascular risk [57] and identifies the presence of endothelial dysfunction [58] which may be the cause or consequence of chronic hypertension [59] Furthermore a polymorphism within the MPO gene (rs2333227) is associated with hypertension [60] and cancer risk with the latter genetic relationship being mitigated through diet [61] Conversely the associa-tion between plasma levels of MPO and hypertension is strengthened in the presence of hyperglycemia-induced oxidative stress which could be targeted in a personalized nutritional program [6263]

Obesity sleep amp lifestyle diseasesDisordered sleep is an underappreciated cause for hypertension Not only have abnormal breathing pat-terns been associated with hypertension for example due to obstructive sleep apnea but also abnormal slow wave sleep and sleep architecture [6465] Obesity itself is also associated with hypertension and abnormal sleep may be a potential root cause for both conditions in

some patients This highlights the need for personal-ized 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 vari-ants have been identified which influence the response to exercise risk of obesity and weight gain associated with certain foods [66] Given the widespread deliver-ability of genomics metabolomics and other personal-ized measures including personalized nutrition these sciences have a greater chance of turning the tide on the obesity epidemic than do surgical interventions [6768]

Pharmacological managementSince the introduction of hydralazine in the 1950s there has been a steady addition of other antihyper-tensive agents to the clinicianrsquos armamentarium [69] These pharmaceuticals historically emerged in the order of diuretics β-blockers calcium channel block-ers (CCHB) α-1 blockers angiotensin converting

Table 2 Functional foods and nutriceuticals with antihypertensive properties categorized by antihypertensive class

Antihypertensive therapeutic class

Foods and ingredients listed by therapeutic class Nutrients and supplements listed by therapeutic class

Angiotensin converting enzyme inhibitors

Egg yolk Fish (specific) bonito dried salted fish fish sauce sardine muscleprotein 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)

Melatonin omega-3 fatty acids pomegranate pycnogenol zinc

Angiotensin receptor blockers

Celery fiber garlic MUFA Coenzyme Q10 gamma linolenic acid N-acetyl cysteine oleic acid resveratrol potassium taurine vitamin C vitamin B6 (pyridoxine)

Beta blockers Hawthorne berry Celery garlic MUFA Alpha lipoic acid calcium magnesium N-acetyl cysteine oleic acid omega-3 fatty acids eicosapentaenoic acid docosahexaenoic acid taurine vitamin B6 vitamin C vitamin E

Central alpha agonists (reduce SNS activity)

Celery fiber garlic protein Coenzyme Q 10 gamma linolenic acid potassium restriction of sodium taurine vitamin C vitamin B6 zinc

Direct renin inhibitors Vitamin D

Direct vasodilators Celery cooking oils with monounsaturated fats fiber garlic MUFA soy

Alpha linolenic acid Arginine calcium flavonoids magnesium Omega-3 fatty acids Potassium taurine vitamin C vitamin E

Diuretics Celery hawthorn berry protein Calcium coenzyme Q 10 fiber gamma linolenic acid l-carnitine magnesium potassium taurine vitamin B6 vitamin C Vitamin E high gammadelta tocopherols and tocotrienols

MUFA Monounsaturated fatty acid SNS Sympathetic nervous system Reproduced with permission from [101] (Table also presented in [43])



enzyme inhibitors (ACE-I) and angiotensin-1 recep-tor 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 discov-ery 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 extrapo-lated from trials such as ACCOMPLISH ASCOT and its substudy the CAFEacute trial which have cumulatively shown that combination therapy with a CCHBACE-I is preferable to a drug combination which includes a diuretic and that β-blockers have less efficacy than other agents [6971]

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 91 mmHg systolic and 55 mmHg diastolic however the variability in response to a single agent in the population varies widely across a range of 20ndash30 mmHg with some experiencing no benefit at all or even a rise in blood pressure [69] The heritability and consistency of response of an individ-ual 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 ndash testing numerous agents sequentially in a single patient or stepped care ndash where single agents are titrated to effect before the additional agents are included or to give low-dose com-bination therapy With the knowledge that blood pres-sure 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 intro-ducing 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 ge160 mmHg systolic and ge95 mmHg diastolic As it was only a

small exploratory trial its results do not preclude the possibility of personalizing monotherapy for individ-ual patients with mild hypertension [74] Furthermore the permutations of combination therapy expand the universe of options to the individual patient It remains likely that combination therapy will also lend itself to personalization

This then leads to the concept of the polypill which in itself has been proven effective and might be par-ticularly beneficial where access to primary and sec-ondary care is limited [75] The polypill which cur-rently addresses a number of cardiovascular risk factors including hypertension is however reductionistic as are public health concepts of universal dietary supple-mentation or restrictions [7677] Although effective to a degree these measures cannot address the wide population variability in response to diet exercise and medication [46] To the individual the idea of taking a treatment with components that may not work or could possibly cause harm will be unpalatable espe-cially if low cost options for predicting response are available With the advent of mass customization and as pharmaceutical patents expire it is highly prob-able that personalized combination polytherapy pos-sibly delivered in a single pill could be tailored to an individualrsquos needs

Pharmacogenomics amp chronotherapyGWAS-identified and other SNPs have been associated with response to antihypertensive drug therapy [1278] However the effect size for each individual SNP is small and insufficient to recommend use with high-cost geno-typing As the cost of genotyping is reducing exponen-tially the costndasheffectiveness of using this information is improving More promising are the evolution of SNP panels which use cumulative scores based on a number of SNPs The Pharmacogenomic Evaluation of Antihy-pertensive Responses (PEAR) study has evaluated the response of various antihypertensives including hydro-chlorothiazide β-blockers and others and shown that an additive SNP panel may have clinical value in choos-ing optimal monotherapy for a patient [8] Conversely a gene variant associated with diabetes in other words a TCF7L2 SNP (rs7917983) is significantly associ-ated with diabetes associated with thiazide use [79] Thiazide-induced gout is also influenced by genendashdrug interactions (rs2078267 in SLC22A11 rs13129697 in SLC2A9) [80] Biomarkers to guide antihypertensive therapy need not always be genetic and plasma renin itself has been shown to predict blood pressure response to β-blockers and hydrochlorothiazide [81]

Genomics may also allow clinical trials of antihy-pertensive patients to be made smaller by prescreening patients for particular gene variants (genomic enrich-



ment) Conversely the number of patients required to show a pharmacogenomic effect can be reduced by using multiple methods of monitoring blood pressure particularly at-home which reduces the signal-to-noise ratio (SN) and provides greater precision [82] Studies of self-measured home blood pressure monitoring have shown a graded cardiovascular risk even among those with lsquonormalrsquo blood pressure recordings [83] This is in part due to circadian patterns of blood pressure vari-ability which has been strongly associated with early

atherosclerosis [84] An absence of a nocturnal dip in blood pressure is associated with an increased risk of a cardiovascular event equivalent to most traditional risk factors [8586] Furthermore blood pressure variation over many years is predictive of cardiovascular events which argues for lifelong blood pressure trajectories to be plotted against a personal baseline [87]

Self-monitoring and self-directed treatment of hyper-tension at home using an algorithm has been shown to be more effective than traditional office-based prac-

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 pmoll [reference lt35 pmoll]) (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

A

B C


Figure 3 20th century Organ-focused and reductionistic



tice [88] Altering the timing of medication adminis-tration or chronotherapy is also showing promise in improving the response to medication for example dos-ing with an ARB at night time [89] though these find-ings 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 telemoni-toring 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 diur-nal variation environmental and stressful stimuli and should reveal otherwise imperceptible patterns in clini-cal data (Figure 2) [92] These integrated biobank ini-tiatives need to be collaborative locally supported and viewed as part of clinical care rather than research [21]

Conclusion amp the future of hypertension managementThe management of hypertension has changed sig-nificantly over the last century It is worth noting that

Figure 2 Diagnostic patterns obtained from standard clinical data (cont) (D amp E) Shows advanced ECG (A-ECG) results at presentation (marker 1) using linear discriminant analysis against a large pre-existing clinical ECG database [9299] Thus A-ECG correctly diagnosed the nonischemic cardiomyopathy (ie 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

D E

35

40

-14 -12 -10 -8

1

-6

ICM

12

3

NIC

MCA

D

LVH

+

+

+

+

Canonical 1

Can

on

ical

2

Canonical PlotCanonical Plot 3D

Hea

lthy

+

HO

CM

+

2

3

Canonical 1

Can

on

ical

2

306 Per Med (2015) 12(3)

Figure 4 21st century Molecular and network-based

Liddle syndromeECE1

HSBD PTGIS

NR3C2

GNB3

CYP3A5

AGT

Nos3

Coronary spasRenal tubular dysgenesis

Alzheimer diseaseACE

PSEN1

HyperproreninemiaAngiotensin I-coverting enzyme

SARS progression ofPick diseasehistiocyte disease

MPO

PAXIP1

MH

AGTR1 KCNMB1RETN

Supranuclear palsy

DementiaITM2BMAPT

SNCBPallidopontonigral degeneration

Placental abruption

TJP2

BAATEPHX1

STOX1 Preeclampsia

HypertensionHypercholanemia

Apparent mineralocorticoid excess hypertension due toSCNN1B

SCNN1G

SCNN1AWNK1

WNK4

Pseudohypoaldosteronism



definitions surrounding the condition have been dic-tated by methods of measurement and the emergence of new pharmaceutical agents As these methods and treatment strategies change so too will the percep-tion of the condition Compared with other tradi-tional risk factors hypertension contributes the most to the burden of cardiovascular disease in the popula-tion 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

These issues highlight a significant failure of the technologies of the 20th Century to provide feed-back to patients an essential component to behav-ioral change programs A convergence of genomics biosensors ubiquitous computing and home-based monitoring are beginning to provide a wealth of patient-specific data never before attainable This information will hopefully be able to identify pat-terns of behavior and better target of interventions (Figure 3 Figure 4 amp Table 3) Although seemingly the antithesis of population-based approaches to health-care personalization has shown extraordinary effi-

Table 3 Future perspective of hypertension management

20th century 21st century

Organ based and reductionistic Molecular and network based

Defined by the methods of measurement and treatment class options Evidence-base provided by averaging patient data

Defined by identifying patterns in multiple heterogenous diagnostic inputs and managed by addressing the underlying cause Evidence provided by response in the individual patient

Clinician centric Pharmacologically driven model of care and delivered in the office

Patient-centric with clinician guidance Systems-based driven model of care delivered in the office and by telemedicine



Executive summary

Backgroundbull Current definitions of hypertension are dictated by methods of measurement rather than identification of

the underlying causebull Contemporary management of hypertension is based on reductionist pharmacologyGenomics of hypertensionbull Genomics is providing insights into the underlying mechanisms of essential hypertension and can be used to

predict treatment efficacy and adverse reactionsTreatment strategies nonpharmacologicalbull Personalized medicine also means personalized care

ndash Personalized care can be used to motivate patients using individualized feedback and treatment strategies

Metabolomics the gut microbiome amp nutrigeneticsbull Obesity sleep amp lifestyle diseases

ndash A number of emerging genetic metabolite and cytokine biomarkers can be used to risk stratify patients with hypertension

Treatment strategies pharmacologicalbull Pharmacogenomics amp chronotherapy

ndash Sleep architecture chronobiology diet and lifestyle are important considerations in a holistic personalized approach to hypertension management

Conclusionbull 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 of care

ciency in the delivery of services in nonhealthcare related sectors

As discussed in this review article there are a number of practical approaches that can be used to personalize the management of hypertension to the individual patient The plethora of options and dearth of random-ized evidence begs the question whether the current model of evidence-based medicine and burden of proof required before implementation is outdated With the volume of data now at hand it is more a matter of implementing monitoring learning and adapting [93] This should particularly be the case with information that is already collected as current standard of care but also with genomic information which has become increasingly cheaper to obtain Emerging genetic and metabolite biomarkers are showing promise in the ability to personalize both dietary and pharmacological inter-ventions Some of these should now be put into prac-tice (Supplementary Data see online at wwwfuture-medicinecomdoifull102217PME1483) [94] In

addition new procedural technologies need to be incor-porated 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 amp competing interests disclosurePA Gladding holds an issued patent on the use of pharmaco-

genetic technology and is the founder of Theranostics Labora-

tory which receives licensing fees from Cleveland HeartLab

TT Schlegel is principal inventor on several NASA patents re-

lated 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

ReferencesPapers of special note have been highlighted asbullbull of considerable interest

1 Postel-Vinay N A Century Of Arterial Hypertension 1896ndash1996 Wiley NJ USA (1996)

2 Kannel WB Fifty years of Framingham Study contributions to understanding hypertension J Hum Hypertens14(2) 83ndash90 (2000)

3 Fagard RH Cornelissen VA Incidence of cardiovascular events in white-coat masked and sustained hypertension versus true normotension a meta-analysis J Hypertens 25(11) 2193ndash2198 (2007)

4 Payne RA Wilkinson IB Webb DJ Arterial stiffness and hypertension emerging concepts Hypertension 55(1) 9ndash14 (2010)



5 Patel CJ Sivadas A Tabassum R et al Whole genome sequencing in support of wellness and health maintenance Genome Med 5(6) 58 (2013)

bullbull Futuristicviewofahealthriskassessment

6 Rich GM Ulick S Cook S Wang JZ Lifton RP Dluhy RG Glucocorticoid-remediable aldosteronism in a large kindred clinical spectrum and diagnosis using a characteristic biochemical phenotype Ann Intern Med 116(10) 813ndash820 (1992)

7 Ehret GB Genome-wide association studies contribution of genomics to understanding blood pressure and essential hypertension Curr Hypertens Rep 12(1) 17ndash25 (2010)

8 Gong Y Mcdonough CW Wang Z et al Hypertension susceptibility loci and blood pressure response to antihypertensives results from the pharmacogenomic evaluation of antihypertensive responses study Circ Cardiovasc Genet 5(6) 686ndash691 (2012)

9 Kamide K Asayama K Katsuya T et al Genome-wide response to antihypertensive medication using home blood pressure measurements a pilot study nested within the HOMED-BP study Pharmacogenomics 14(14) 1709ndash1721 (2013)

10 Padmanabhan S Melander O Hastie C et al Hypertension and genome-wide association studies combining high fidelity phenotyping and hypercontrols J Hypertens 26(7) 1275ndash1281 (2008)

11 Seo I Suh SI Suh MH Baek WK Genome-wide association study of medication adherence in chronic diseases in the Korean population Genomics Inform 12(3) 121ndash126 (2014)

12 Manolio TA Collins FS Cox NJ et al Finding the missing heritability of complex diseases Nature 461(7265) 747ndash753 (2009)

13 Polimanti R Iorio A Piacentini S Manfellotto D Fuciarelli M Human pharmacogenomic variation of antihypertensive drugs from population genetics to personalized medicine Pharmacogenomics 15(2) 157ndash167 (2014)

14 Levy D Ehret GB Rice K et al Genome-wide association study of blood pressure and hypertension Nat Genet 41(6) 677ndash687 (2009)

15 Newton-Cheh C Johnson T Gateva V et al Genome-wide association study identifies eight loci associated with blood pressure Nat Genet 41(6) 666ndash676 (2009)

16 Qian X Lu Z Tan M Liu H Lu D A meta-analysis of association between C677T polymorphism in the methylenetetrahydrofolate reductase gene and hypertension Eur J Hum Genet 15(12) 1239ndash1245 (2007)

17 Yang Z Zhang XF Liu HX Hao YS Zhao CL MTHFR C677T polymorphism and colorectal cancer risk in Asians a meta-analysis of 21 studies Asian Pac J Cancer Prev 13(4) 1203ndash1208 (2012)

18 Jamison RL Shih MC Humphries DE et al Effect of the MTHFR C677T and A1298C polymorphisms on survival in patients with advanced CKD and ESRD a prospective study Am J Kidney Dis 53(5) 779ndash789 (2009)

19 Klerk M Verhoef P Clarke R Blom HJ Kok FJ Schouten EG MTHFR 677C--gtT polymorphism and risk of coronary heart disease a meta-analysis JAMA 288(16) 2023ndash2031 (2002)

20 Chatellier G Day M Bobrie G Menard J Feasibility study of N-of-1 trials with blood pressure self-monitoring in hypertension Hypertension 25(2) 294ndash301 (1995)

21 Hirsch BR Abernethy AP Leveraging informatics mobile health technologies and biobanks to treat each patient right J Pers Med 9(8) 849ndash857 (2012)

bullbull ExcellentarticleoutliningtheimportanceofbiobanksandtheirintersectionwithHealth

22 Do CB Tung JY Dorfman E et al Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinsonrsquos disease PLoS Genet 7(6) e1002141 (2011)

23 Swan M Hathaway K Hogg C Mccauley R Vollrath A Citizen science genomics as a model for crowdsourced preventive medicine research wwwjopmorg

bullbull Outliningthepotentialforcrowd-sourceddatagathering

24 Hovell MF Black DR Mewborn CR et al Personalized versus usual care of previously uncontrolled hypertensive patients an exploratory analysis Prev Med 15(6) 673ndash684 (1986)

25 Pokorska-Bocci A Stewart A Sagoo GS Hall A Kroese M Burton H lsquoPersonalized medicinersquo whatrsquos in a name J Pers Med 11(2) 197ndash210 (2014)

26 Price JD Grimley Evans J N-of-1 randomized controlled trials (lsquoN-of-1 trialsrsquo) singularly useful in geriatric medicine Age Ageing 31(4) 227ndash232 (2002)

bullbull Practicalapproachtoofn=1trialsinclinicalmedicine

27 Cornetta K Brown CG Balancing personalized medicine and personalized care Acad Med 88(3) 309ndash313 (2013)

28 Lamas GA Goertz C Boineau R et al Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction the TACT randomized trial JAMA 309(12) 1241ndash1250 (2013)

29 Mori TA Omega-3 fatty acids and hypertension in humans Clin Exp Pharmacol Physiol 33(9) 842ndash846 (2006)

30 Schneider RH Grim CE Rainforth MV et al Stress reduction in the secondary prevention of cardiovascular disease randomized controlled trial of transcendental meditation and health education in Blacks Circ Cardiovasc Qual Outcomes 5(6) 750ndash758 (2012)

31 Bhatt DL Kandzari DE Orsquoneill WW et al A controlled trial of renal denervation for resistant hypertension N Engl J Med 370(15) 1393ndash1401 (2014)

bullbull Landmarkhypertensiontrialtestingrenaldenervationversusshamprocedure

32 Bertog SC Sobotka PA Sievert H Renal denervation for hypertension JACC Cardiovasc Interv 5(3) 249ndash258 (2012)

33 Lurz P Daehnert I Gutberlet M Desch S Renal sympathetic denervation in resistant hypertension late after surgical repair for aortic coarctation Eur Heart J 34(45) 3500 (2013)

34 Solti F Szabo Z Kerkovits G Budai G Bodor E Kalmar I Baropacing of the carotid sinus nerve for treatment of ldquoIntractablerdquo hypertension Z Kardiol 64(4) 368ndash374 (1975)



35 Beard DA Pettersen KH Carlson BE Omholt SW Bugenhagen SM A computational analysis of the long-term regulation of arterial pressure F1000Res 2 208 (2013)

36 Singh JP Larson MG Tsuji H Evans JC Orsquodonnell CJ Levy D Reduced heart rate variability and new-onset hypertension insights into pathogenesis of hypertension the Framingham Heart Study Hypertension 32(2) 293ndash297 (1998)

37 Schroeder EB Liao D Chambless LE Prineas RJ Evans GW Heiss G Hypertension blood pressure and heart rate variability the Atherosclerosis Risk in Communities (ARIC) study Hypertension 42(6) 1106ndash1111 (2003)

38 Mattila R Malmivaara A Kastarinen M Kivela SL Nissinen A Effectiveness of multidisciplinary lifestyle intervention for hypertension a randomised controlled trial J Hum Hypertens 17(3) 199ndash205 (2003)

39 James S Frobert O Lagerqvist B Cardiovascular registries a novel platform for randomised clinical trials Heart 98(18) 1329ndash1331 (2012)

40 Zheng Y Yu B Alexander D et al Metabolomics and incident hypertension among blacks the atherosclerosis risk in communities study Hypertension 62(2) 398ndash403 (2013)

41 Holmes E Loo RL Stamler J et al Human metabolic phenotype diversity and its association with diet and blood pressure Nature 453(7193) 396ndash400 (2008)

42 Heinzmann SS Merrifield CA Rezzi S et al Stability and robustness of human metabolic phenotypes in response to sequential food challenges J Proteome Res 11(2) 643ndash655 (2012)

43 Houston M The role of nutrition and nutraceutical supplements in the treatment of hypertension World J Cardiol 6(2) 38ndash66 (2014)

44 Horigan G Mcnulty H Ward M Strain JJ Purvis J Scott JM Riboflavin lowers blood pressure in cardiovascular disease patients homozygous for the 677C--gtT polymorphism in MTHFR J Hypertens 28(3) 478ndash486 (2010)

45 Wilson CP Mcnulty H Ward M et al Blood pressure in treated hypertensive individuals with the MTHFR 677TT genotype is responsive to intervention with riboflavin findings of a targeted randomized trial Hypertension 61(6) 1302ndash1308 (2013)

46 Mente M Mancia G PURE-Sodium Heterogeneity in the associations of urinary sodium and potassium with blood pressure The PURE sodium study Presented at The European Society of Cardiology Congress Amsterdam Netherlands 31 Augustndash04 September 2013

47 Carey RM Schoeffel CD Gildea JJ et al Salt sensitivity of blood pressure is associated with polymorphisms in the sodium-bicarbonate cotransporter Hypertension 60(5) 1359ndash1366 (2012)

48 Yan L Yao X Bachvarov D Saifudeen Z El-Dahr SS Genome-wide analysis of gestational gene-environment interactions in the developing kidney Physiol Genomics 46(17) 655ndash670 (2014)

49 Orsquodonnell M Mente A Rangarajan S et al Urinary Sodium and Potassium Excretion Mortality and Cardiovascular Events N Engl J Med 371(7) 612ndash623 (2014)

bullbull Researchdemonstratinganincreasedcardiovascularriskwithbothlowandhighsaltintake

50 James PA Oparil S Carter BL et al 2014 evidence-based guideline for the management of high blood pressure in adults Report from the panel members appointed to the eighth joint national committee (JNC 8) JAMA 311(5) 507ndash520 (2014)

bullbull LatestJointNationalCommittee(JNC)guidelinesonhypertension

51 Post Hospers G Smulders YM Maier AB Deeg DJ Muller M Relation between blood pressure and mortality risk in an older population role of chronological and biological age J Intern Med doi101111joim12284 (2014) (Epub ahead of print)

52 Palatini P Ceolotto G Ragazzo F et al CYP1A2 genotype modifies the association between coffee intake and the risk of hypertension J Hypertens 27(8) 1594ndash1601 (2009)

53 Cornelis MC El-Sohemy A Kabagambe EK Campos H Coffee CYP1A2 genotype and risk of myocardial infarction JAMA 295(10) 1135ndash1141 (2006)

54 The Coffee and Caffeine Genetics Consortium Cornelis MC Byrne EM et alGenome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption Mol Psychiatry doi101038mp 2014107 (2014) (Epub ahead of print)

55 Cottone S Mule G Guarneri M et al Endothelin-1 and F2-isoprostane relate to and predict renal dysfunction in hypertensive patients Nephrol Dial Transplant 24(2) 497ndash503 (2009)

56 Davies SS Roberts Ii LJ F2-isoprostanes as an indicator and risk factor for coronary heart disease Free Radic Biol Med 50(5) 559ndash566 (2011)

57 Nicholls SJ Hazen SL Myeloperoxidase and cardiovascular disease Arterioscler Thromb Vasc Biol 25(6) 1102ndash1111 (2005)

58 Vita JA Brennan ML Gokce N et al Serum myeloperoxidase levels independently predict endothelial dysfunction in humans Circulation 110(9) 1134ndash1139 (2004)

59 Quyyumi AA Patel RS Endothelial dysfunction and hypertension cause or effect Hypertension 55(5) 1092ndash1094 (2010)

60 Liu YC Chung CJ Shiue HS et al Genetic polymorphisms of myeloperoxidase and their effect on hypertension Blood Press 22(5) 282ndash289 (2013)

61 Ahn J Gammon MD Santella RM et al Myeloperoxidase genotype fruit and vegetable consumption and breast cancer risk Cancer Res 64(20) 7634ndash7639 (2004)

62 Van Der Zwan LP Scheffer PG Dekker JM Stehouwer CD Heine RJ Teerlink T Hyperglycemia and oxidative stress strengthen the association between myeloperoxidase and blood pressure Hypertension 55(6) 1366ndash1372 (2010)

63 Minich DM Bland JS Personalized lifestyle medicine relevance for nutrition and lifestyle recommendations ScientificWorldJournal 2013 129841 (2013)

64 Fung MM Peters K Redline S et al Decreased slow wave sleep increases risk of developing hypertension in elderly men Hypertension 58(4) 596ndash603 (2011)

310 Per Med (2015) 12(3)

65 Dopp JM Reichmuth KJ Morgan BJ Obstructive sleep apnea and hypertension mechanisms evaluation and management Curr Hypertens Rep 9(6) 529ndash534 (2007)

66 Ash GI Eicher JD Pescatello LS The promises and challenges of the use of genomics in the prescription of exercise for hypertension the 2013 update Curr Hypertens Rev 9(2) 130ndash147 (2013)

67 Christakis NA Fowler JH The spread of obesity in a large social network over 32 years N Engl J Med 357(4) 370ndash379 (2007)

68 Barabaacutesi AL Network medicine mdash from obesity to the ldquodiseasomerdquo N Engl J Med 357(4) 404ndash407 (2007)

69 Sever PS Messerli FH Hypertension management 2011 optimal combination therapy Eur Heart J 32(20) 2499ndash2506 (2011)

70 Staumlhle H A historical perspective development of clonidine Best Pract Res Clin Anaesthesiol 14(2) 237ndash246 (2000)

71 Bloch MJ Basile J Analysis of recent papers in hypertension differences in central aortic blood pressure explain outcome differences in ASCOT the CAFE substudy and rimonabant improves multiple cardiometabolic parameters in overweight and obese individuals J Clin Hypertens 8(5) 376ndash380 (2006)

72 Padmanabhan S Paul L Dominczak AF The pharmacogenomics of anti-hypertensive therapy Pharmaceuticals 3(6) 1779ndash1791 (2010)

73 Zannad F Managing hypertension a question of STRATHE J Hum Hypertens 19(Suppl 1) S3ndashS7 (2005)

74 Kochar MS Trottier D Kotecki G Forbes M Bamrah VS Sequential monotherapy of hypertension J Clin Pharmacol 34(12) 1173ndash1176 (1994)

75 Lafeber M Spiering W Van Der Graaf Y et al The combined use of aspirin a statin and blood pressure-lowering agents (polypill components) and the risk of vascular morbidity and mortality in patients with coronary artery disease Am Heart J 166(2) 282ndash289 (2013)

76 Joseph J Loscalzo J Methoxistasis integrating the roles of homocysteine and folic acid in cardiovascular pathobiology Nutrients 5(8) 3235ndash3256 (2013)

77 Joseph J Loscalzo J Selenistasis epistatic effects of selenium on cardiovascular phenotype Nutrients 5(2) 340ndash358 (2013)

78 Turner ST Boerwinkle E Orsquoconnell JR et al Genomic association analysis of common variants influencing antihypertensive response to hydrochlorothiazide Hypertension 62(2) 391ndash397 (2013)

79 Karnes JH Gong Y Pacanowski MA et al Impact of TCF7L2 single nucleotide polymorphisms on hydrochlorothiazide-induced diabetes Pharmacogenet Genomics 23(12) 697ndash705 (2013)

80 Mcadams-Demarco MA Maynard JW Baer AN Kao LW Kottgen A Coresh J A urate gene-by-diuretic interaction and gout risk in participants with hypertension results from the ARIC study Ann Rheum Dis 72(5) 701ndash706 (2013)

81 Turner ST Schwartz GL Chapman AB et al Plasma renin activity predicts blood pressure responses to beta-blocker

and thiazide diuretic as monotherapy and add-on therapy for hypertension Am J Hypertens 23(9) 1014ndash1022 (2010)

82 Turner ST Schwartz GL Chapman AB et al Power to identify a genetic predictor of antihypertensive drug response using different methods to measure blood pressure response J Transl Med 10 47 (2012)

83 Asayama K Thijs L Brguljan-Hitij J et al Risk stratification by self-measured home blood pressure across categories of conventional blood pressure a participant-level meta-analysis PLoS Med 11(1) e1001591 (2014)

84 Sander D Kukla C Klingelhofer J Winbeck K Conrad B Relationship between circadian blood pressure patterns and progression of early carotid atherosclerosis A 3 year follow-up study Circulation 102(13) 1536ndash1541 (2000)

85 Boggia J Li Y Thijs L et al Prognostic accuracy of day versus night ambulatory blood pressure a cohort study Lancet 370(9594) 1219ndash1229 (2007)

86 Ben-Dov IZ Kark JD Ben-Ishay D Mekler J Ben-Arie L Bursztyn M Predictors of all-cause mortality in clinical ambulatory monitoring unique aspects of blood pressure during sleep Hypertension 49(6) 1235ndash1241 (2007)

87 Allen NB Siddique J Wilkins JT et al Blood pressure trajectories in early adulthood and subclinical atherosclerosis in middle age JAMA 311(5) 490ndash497 (2014)

88 Mcmanus RJ Mant J Haque MS et al Effect of self-monitoring and medication self-titration on systolic blood pressure in hypertensive patients at high risk of cardiovascular disease the TASMIN-SR randomized clinical trial JAMA 312(8) 799ndash808 (2014)

bullbull Researcharticlesupportinghome-basedtitrationofantihypertensivemedication

89 Hermida RC Ayala DE Mojon A Fernandez JR Cardiovascular risk of essential hypertension influence of class number and treatment-time regimen of hypertension medications Chronobiol Int 30(1ndash2) 315ndash327 (2013)

90 Watanabe Y Halberg F Otsuka K Cornelissen G Toward a personalized chronotherapy of high blood pressure and a circadian overswing Clin Exp Hypertens 35(4) 257ndash266 (2013)

91 Gottesman O Kuivaniemi H Tromp G et al The Electronic Medical Records and Genomics (eMERGE) Network past present and future Genet Med 15(10) 761ndash771 (2013)

92 Schlegel TT Kulecz WB Feiveson AH et al Accuracy of advanced versus strictly conventional 12-lead ECG for detection and screening of coronary artery disease left ventricular hypertrophy and left ventricular systolic dysfunction BMC Cardiovasc Disord 10 28 (2010)

93 Krumholz HM Big data and new knowledge in medicine the thinking training and tools needed for a learning health system Health Aff 33(7) 1163ndash1170 (2014)

bullbull Excellentpaperidentifyingthedatawasteinthecurrenthealthsystem

94 Ginsburg G Medical genomics gather and use genetic data in health care Nature 508(7497) 451ndash453 (2014)

95 Frau F Zaninello R Salvi E et al Genome-wide association study identifies CAMKID variants involved in blood




pressure response to losartan the SOPHIA study Pharmacogenomics 15(13) 1643ndash1652 (2014)

96 Dotson CD Shaw HL Mitchell BD Munger SD Steinle NI Variation in the gene TAS2R38 is associated with the eating behavior disinhibition in Old Order Amish women Appetite 54(1) 93ndash99 (2010)

97 Ruchat SM Rankinen T Weisnagel SJ et al Improvements in glucose homeostasis in response to regular exercise are influenced by the PPARG Pro12Ala variant results from the HERITAGE Family Study Diabetologia 53(4) 679ndash689 (2010)

98 Karoly HC Stevens CJ Magnan RE Harlaar N Hutchison KE Bryan AD Genetic influences on

physiological and subjective responses to an aerobic exercise session among sedentary adults J Cancer Epidemiol 540563 (2012 )

99 Gladding P Cave A Zareian M et al Open access integrated therapeutic and diagnostic platforms for personalized cardiovascular medicine J Pers Med 3(3) 203ndash237 (2013)

100 Theranostics About us wwwtheranosticsconz

101 Houston M Nutrition and nutraceutical supplements for the treatment of hypertension Part I J Clin Hypertens 15(10) 752ndash757 (2013)





complexity and an absence of therapies targeting arte-rial stiffness has limited its clinical utility However the information that arterial stiffness provides may be enhanced by combining its measurement with whole genome sequencing providing a more holistic view of cardiovascular health [5]

Addressing the underlying cause of hypertension in each individual patient using such a holistic approach is expected to usher in a era of early detection preven-tion and targeted treatments Tailored management for nonessential causes of hypertension such as Connrsquos syn-drome glucocorticoid remediable hyperaldosteronism Cushingrsquos syndrome and renal artery stenosis has been the driver to elucidating the cause of secondary forms of hypertension leaving the bulk of essential hyper-tension (95 of all cases) still without an underlying cause Glucocorticoid remediable hyperaldosteronism although rare provides a prototype for personalized medicine where a chimeric CYP11B1CYP11B2 genersquos function can be in part rectified with administration of physiological glucocorticoid treatment [6]

The rapid advances in genomic technologies are beginning to deliver on some of these hopes for essential hypertension Although further research is required for many discoveries to become part of daily routine there is emerging evidence which can be applied in contem-porary practice As this evidence often falls short of a randomized controlled megatrial the barrier to wide-spread adoption remains high With the rapid pace of change emergence of lsquobigrsquo data science and an inabil-ity to test all potential hypotheses it is arguable that the randomized megatrial as we know it has passed its use by date Tradition needs to be supplanted by a new model of care This review article hopes to address these issues from a new perspective

Genomics of hypertensionThe heritability of essential hypertension is estimated to be between 63 and 68 indicating a significant genetic component [7] Despite this the underlying molecular mechanisms have not been readily appar-ent The era of nonhypothesis driven genome wide association studies (GWAS) has identified a number of genes and single nucleotide polymorphisms (SNPs) associated with essential hypertension [7ndash9] However the contribution of these individual gene variants to blood pressure is small accounting for differences of only approximately 1 mmHg Such findings have been common to all GWAS studies of chronic dis-ease in part due to the nature of the variants tested These SNP variants by definition are common in the population and in isolation account for only small effects as they act in a complex interactive fashion with other genes This complexity is compounded by the

hypertensive phenotype being difficult to define influ-enced 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 start-ing 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 vari-ants which are more likely to contribute to the pres-ence of disease [1213] These rare variants however are often highly personal to an individual or a family and without previous description their functional rel-evance 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 num-ber of sequenced genomes is increasing rapidly and the richness of this information is being dramatically realized

Despite all of these issues early genomic stud-ies 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 polypep-tide1) [14] and 510-methylenetetrahydrofolate reduc-tase (MTHFR) [15] Many of the genes identified by these analyses were not previously linked to hyperten-sion revealing novel pathways and druggable targets for future study Some genes identified by GWAS had already been associated with hypertension in the pre-GWAS 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 conver-sion of 510 methylenetetrahydrofolate to 5-methyltet-rahydrofolate in the metabolism of methionine The loss of function gene variant C677T (rs1801133) within the MTHFR gene has been associated with elevated homo-








Response Ref

Pharmacogenetics


[1278]

GNAS-EDN3 rs2273359


[8]

SH2B3 rs3184504

FGF5 rs1458038


[8]

CHIC2 rs871606

MOV10 rs2932538

HFE rs1799945



[79]

SLC22A11 SLC2A9 rs2078267 rs13129697


[80]

Nutrigenetics

TAS2R38 rs1726866 rs713598 rs10246939



[5253]


[4445]


[5556]





[40]



[97]














Action

Choices Relevance

Personalized data















































A

B C









D E

35

40

-14 -12 -10 -8

1

-6

ICM

12

3

NIC

MCA

D

LVH

+

+

+

+

Canonical 1

Can

on

ical

2


Hea

lthy

+

HO

CM

+

2

3

Canonical 1

Can

on

ical

2

306 Per Med (2015) 12(3)


Liddle syndromeECE1

HSBD PTGIS

NR3C2

GNB3

CYP3A5

AGT

Nos3



PSEN1



MPO

PAXIP1

MH

AGTR1 KCNMB1RETN

Supranuclear palsy

DementiaITM2BMAPT


Placental abruption

TJP2

BAATEPHX1

STOX1 Preeclampsia



SCNN1G

SCNN1AWNK1

WNK4















Executive summary
























manuscript













































































310 Per Med (2015) 12(3)























































Response Ref

Pharmacogenetics


[1278]

GNAS-EDN3 rs2273359


[8]

SH2B3 rs3184504

FGF5 rs1458038


[8]

CHIC2 rs871606

MOV10 rs2932538

HFE rs1799945



[79]

SLC22A11 SLC2A9 rs2078267 rs13129697


[80]

Nutrigenetics

TAS2R38 rs1726866 rs713598 rs10246939



[5253]


[4445]


[5556]





[40]



[97]














Action

Choices Relevance

Personalized data















































A

B C









D E

35

40

-14 -12 -10 -8

1

-6

ICM

12

3

NIC

MCA

D

LVH

+

+

+

+

Canonical 1

Can

on

ical

2


Hea

lthy

+

HO

CM

+

2

3

Canonical 1

Can

on

ical

2

306 Per Med (2015) 12(3)


Liddle syndromeECE1

HSBD PTGIS

NR3C2

GNB3

CYP3A5

AGT

Nos3



PSEN1



MPO

PAXIP1

MH

AGTR1 KCNMB1RETN

Supranuclear palsy

DementiaITM2BMAPT


Placental abruption

TJP2

BAATEPHX1

STOX1 Preeclampsia



SCNN1G

SCNN1AWNK1

WNK4















Executive summary
























manuscript













































































310 Per Med (2015) 12(3)



























































Action

Choices Relevance

Personalized data















































A

B C









D E

35

40

-14 -12 -10 -8

1

-6

ICM

12

3

NIC

MCA

D

LVH

+

+

+

+

Canonical 1

Can

on

ical

2


Hea

lthy

+

HO

CM

+

2

3

Canonical 1

Can

on

ical

2

306 Per Med (2015) 12(3)


Liddle syndromeECE1

HSBD PTGIS

NR3C2

GNB3

CYP3A5

AGT

Nos3



PSEN1



MPO

PAXIP1

MH

AGTR1 KCNMB1RETN

Supranuclear palsy

DementiaITM2BMAPT


Placental abruption

TJP2

BAATEPHX1

STOX1 Preeclampsia



SCNN1G

SCNN1AWNK1

WNK4















Executive summary
























manuscript













































































310 Per Med (2015) 12(3)


















































Action

Choices Relevance

Personalized data















































A

B C









D E

35

40

-14 -12 -10 -8

1

-6

ICM

12

3

NIC

MCA

D

LVH

+

+

+

+

Canonical 1

Can

on

ical

2


Hea

lthy

+

HO

CM

+

2

3

Canonical 1

Can

on

ical

2

306 Per Med (2015) 12(3)


Liddle syndromeECE1

HSBD PTGIS

NR3C2

GNB3

CYP3A5

AGT

Nos3



PSEN1



MPO

PAXIP1

MH

AGTR1 KCNMB1RETN

Supranuclear palsy

DementiaITM2BMAPT


Placental abruption

TJP2

BAATEPHX1

STOX1 Preeclampsia



SCNN1G

SCNN1AWNK1

WNK4















Executive summary
























manuscript













































































310 Per Med (2015) 12(3)




















































































A

B C









D E

35

40

-14 -12 -10 -8

1

-6

ICM

12

3

NIC

MCA

D

LVH

+

+

+

+

Canonical 1

Can

on

ical

2


Hea

lthy

+

HO

CM

+

2

3

Canonical 1

Can

on

ical

2

306 Per Med (2015) 12(3)


Liddle syndromeECE1

HSBD PTGIS

NR3C2

GNB3

CYP3A5

AGT

Nos3



PSEN1



MPO

PAXIP1

MH

AGTR1 KCNMB1RETN

Supranuclear palsy

DementiaITM2BMAPT


Placental abruption

TJP2

BAATEPHX1

STOX1 Preeclampsia



SCNN1G

SCNN1AWNK1

WNK4















Executive summary
























manuscript













































































310 Per Med (2015) 12(3)






























































A

B C









D E

35

40

-14 -12 -10 -8

1

-6

ICM

12

3

NIC

MCA

D

LVH

+

+

+

+

Canonical 1

Can

on

ical

2


Hea

lthy

+

HO

CM

+

2

3

Canonical 1

Can

on

ical

2

306 Per Med (2015) 12(3)


Liddle syndromeECE1

HSBD PTGIS

NR3C2

GNB3

CYP3A5

AGT

Nos3



PSEN1



MPO

PAXIP1

MH

AGTR1 KCNMB1RETN

Supranuclear palsy

DementiaITM2BMAPT


Placental abruption

TJP2

BAATEPHX1

STOX1 Preeclampsia



SCNN1G

SCNN1AWNK1

WNK4















Executive summary
























manuscript













































































310 Per Med (2015) 12(3)






















































A

B C









D E

35

40

-14 -12 -10 -8

1

-6

ICM

12

3

NIC

MCA

D

LVH

+

+

+

+

Canonical 1

Can

on

ical

2


Hea

lthy

+

HO

CM

+

2

3

Canonical 1

Can

on

ical

2

306 Per Med (2015) 12(3)


Liddle syndromeECE1

HSBD PTGIS

NR3C2

GNB3

CYP3A5

AGT

Nos3



PSEN1



MPO

PAXIP1

MH

AGTR1 KCNMB1RETN

Supranuclear palsy

DementiaITM2BMAPT


Placental abruption

TJP2

BAATEPHX1

STOX1 Preeclampsia



SCNN1G

SCNN1AWNK1

WNK4















Executive summary
























manuscript













































































310 Per Med (2015) 12(3)
























































D E

35

40

-14 -12 -10 -8

1

-6

ICM

12

3

NIC

MCA

D

LVH

+

+

+

+

Canonical 1

Can

on

ical

2


Hea

lthy

+

HO

CM

+

2

3

Canonical 1

Can

on

ical

2

306 Per Med (2015) 12(3)


Liddle syndromeECE1

HSBD PTGIS

NR3C2

GNB3

CYP3A5

AGT

Nos3



PSEN1



MPO

PAXIP1

MH

AGTR1 KCNMB1RETN

Supranuclear palsy

DementiaITM2BMAPT


Placental abruption

TJP2

BAATEPHX1

STOX1 Preeclampsia



SCNN1G

SCNN1AWNK1

WNK4















Executive summary
























manuscript













































































310 Per Med (2015) 12(3)
















































306 Per Med (2015) 12(3)


Liddle syndromeECE1

HSBD PTGIS

NR3C2

GNB3

CYP3A5

AGT

Nos3



PSEN1



MPO

PAXIP1

MH

AGTR1 KCNMB1RETN

Supranuclear palsy

DementiaITM2BMAPT


Placental abruption

TJP2

BAATEPHX1

STOX1 Preeclampsia



SCNN1G

SCNN1AWNK1

WNK4















Executive summary
























manuscript













































































310 Per Med (2015) 12(3)


















































Executive summary
























manuscript













































































310 Per Med (2015) 12(3)























































































































310 Per Med (2015) 12(3)


















































































310 Per Med (2015) 12(3)
















































310 Per Med (2015) 12(3)



























































Documents

personalized hypertension management