Current concepts and molecular mechanisms in pharmacogenetics of essential hypertension

Abstract

Hypertension is a leading age-related disease in our society and if left untreated, leads to fatal cardiovascular complications. The prevalence of hypertension has increased and becomes a significant global health economic burden, particularly in lower-income societies. Many loci associated with blood pressure and hypertension have been reported by genome-wide association studies that provided potential targets for pharmacotherapy. Pharmacogenetic research had shown interindividual variations in drug efficacy, safety, and tolerability. This could be due to genetic polymorphisms in the pharmacokinetics (genes involved in a transporter, plasma protein binding, and metabolism) or pharmacodynamic pathway (receptors, ion channels, enzymes). Pharmacogenetics promises great hope toward targeted therapy, but challenges remain in implementing pharmacogenetic aided antihypertensive therapy in clinical practice. Using various databases, we analyzed the underlying mechanisms between the candidate gene polymorphisms and antihypertensive drug interactions and the challenges of implementing precision medicine. We review the emergence of pharmacogenetics and its relevance to clinical pharmacological practice.

Introduction

Hypertension is commonly diagnosed in primary care and if not managed appropriately, may lead to complications such as myocardial infarction, stroke, renal failure, and death. The American College of Cardiology/American Heart Association (ACC/AHA) have defined hypertension, when the systolic blood pressure (SBP) is 130 mmHg or greater and/or diastolic blood pressure (DBP) is 80 mmHg or greater. The ACC/AHA guidelines state that pharmacotherapy should be started when SBP is 140 mmHg or greater and/or DBP is 90 mmHg or greater [Table 1].[1] The WHO (World Health Organization) has reviewed the hypertension trends since 1975 and found an increase in the prevalence of hypertension in adults from 594 million in 1975 to 1.13 billion in 2015. It was also observed that high-income countries have a lower prevalence of hypertension when compared with low-income countries. However, the prevalence of hypertension is not only due to low or middle-income status but also based on increase population growth, aging, lifestyle habits, and interaction of multiple genetic and epigenetic factors.[2] For years, it has been debated that hypertension is inherited, and the genetic contribution of BP ranges from 30% to 50%.[3] Many genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) and deoxyribonucleic acid variants that are associated with BP regulation. Even though there are challenges in conducting GWAS, these studies have extended our knowledge about genetic polymorphisms and its impact on hypertension.[4]

Table 1.

Classification of blood pressure

Blood pressure	SBP (mm Hg)	DBP (mm Hg)
Normal	<120	<80
Elevated	120-129	<80
Stage 1 hypertension	130-139	80-89
Stage 2 hypertension	≥140	≥90

BP=Blood pressure, SBP=Systolic BP, DBP=Diastolic BP

Pharmacogenetic studies focus on the understanding of the genetic nature of drug response based on the interaction of individuals' genetic constitution. In 2003, the sequencing of the human genome was a major development in the medical field. It shows a new approach in tailoring antihypertensive treatment to specific hypertensive individuals to improve drug efficacy and effectiveness.[5] Genetic linkage and association between marker loci and candidate genes have been demonstrated in many studies that potentially influence BP. These candidate genes code for proteins, channels, drug transporters, drug metabolism enzymes, etc., and regulate BP of an individual. Despite various published articles on genetic linkage and diseases, studies on pharmacogenetics regarding BP response to antihypertensive medication are sparse. Hence, we aimed to review current pharmacogenetics concepts in the treatment of hypertension and the mechanism of action of gene-drug interactions.

The objectives of this review are to (1) discuss some of the critical genes and its polymorphisms associated with hypertension, (2) analyze genetic polymorphisms and it's interactions on antihypertensive drug response, (3) summarize the current concept of pharmacogenetics in the treatment of hypertension and how it could be useful for physicians in optimizing drug selection for individual hypertensive patients.

Current Concepts of Pharmacogenetics in the Treatment of Hypertension

It is known that various mechanisms determine the antihypertensive drug response. These mechanisms are influenced by drug absorption, distribution, excretion, and metabolism and are called pharmacokinetic mechanisms. Variation in genes encoding proteins is responsible for absorption, distribution, excretion, and metabolism and alters the drug-metabolizing enzyme leading to normal, reduced, increased, or absence of activity. Initially, pharmacogenetics or pharmacogenomics studies on antihypertensive drugs focused on drug-metabolizing enzymes and genes encoding them. Slowly pharmacogenetic studies gain momentum, and by the year 2000, articles started publishing on the genetic linkage of different genes other than the drug-metabolizing gene.[6] Pharmacodynamic mechanisms that could account for variation in antihypertensive response are (i) receptor mechanism, where drugs bind to the receptor to initiate pharmacodynamic effect, (ii) efficacy and potency of a drug, determine by dose-response curve, (iii) therapeutic index, a relationship between therapeutic and toxic dose which provides relative measures for safety and toxicity of a drug, (iv) lag time, delay in the therapeutic effect of a given drug. The reason for the delay in therapeutic effect could be either pharmacodynamic or pharmacokinetics, (v) desensitization and tachyphylaxis due up or downregulation of receptors.[7]

Genetic Polymorphisms Involved in Antihypertensive Therapy

The goal of pharmacogenetics in the treatment of a disease is to develop nobel ways of maximizing therapeutic efficacy and minimizing the adverse effects of a drug in an individual. Candidate genes linked to hypertension interact with antihypertensive drugs to modify the BP response to treatment or increase the risk of adverse effects. We used various databases such as PubMed, PharmGKB, dbSNP, and GenBank NCBI NIH for literature search, gene, and SNP-related pieces of information. Candidate genes and their variants affecting antihypertensive response are shown in Table 2.

Table 2.

Candidate gene for antihypertensive drugs

Gene	Polymorphism(s)	Antihypertensive drug	Allele and genotype association	References
NEDD4L	rs4149601	HCTZ	G allele carrier is associated with greater BP reduction. It is also associated with risk of CVS adverse outcomes if HCTZ is not added in the regime	[8]
	rs4149601-rs292449		G-C haplotype associated with greater BP reduction
ADD1	rs4961	HCTZ	Trp460 allele associated with greater BP reduction	[9]
AGT	Rs7079	Benazepril	CC homozygotes associated with decrease in DBP	[10]
AGTR1	haplotypes H2, H3	Benazepril	H2 associated with decrease in SBP and H3 with DBP	[10]
ACE	I/D	Enalapril, Lisinopril	DD homozygotes associated with lowering of BP	[11]
FUT4	rs11020821	Candesartan	Associated with lowering of BP	[12]
ADRB1	rs1801252	Metoprolol	CC genotype associated with reduction of BP	[13,14]
GKR4	rs2960306	Atenolol	65L allele - no therapeutic response	[15]
	rs1024323	Atenolol	142V allele - no therapeutic response	[15]
	rs2960306-rs1024323	Atenolol	Haplotypes - no therapeutic response	[15]
PTPRD	rs12346562, rs1104514	Atenolol	A allele is associated with lowering of BP in whites	[16]
	rs10739150	Atenolol	G allele is associated with lowering of BP in blacks
KCNH2	rs17424631	Celiprolol, atenolol, bisoprolol, doxazosin	CC genotypes associated with BP reduction	[17]
	rs17424631	Azelnidipine and nitrendipine	CT/TT genotypes in male associated with BP reduction
KCNMB1	rs11739136	Verapamil	Lys65 allele achieved control of BP more rapidly than Glu65 homozygotes	[18]
CACNA1C	rs1051375	Verapamil	AA genotype associated with good control of BP	[19]
GNB3	rs5433	Clonidine	TT genotypes associated with BP reduction	[20]
CYP2D6	rs1065852	Metoprolol	CC, CT, TT genotypes - no therapeutic response	[13]
CYP2D6	rs3892097	Metoprolol	AA genotypes associated with reduction of BP	[21]
CYP2C9	rs1057910	Losartan	CYP2C9*3 allele associated with BP reduction	[22]
CYP2C9	Ala477Thr	Losartan	CYP2C9*30 allele - no therapeutic response	[22]
CYP3A5	rs776746	Amlodipine	CYP3A5*3 allele associated with reduction in DBP	[23]
CYP3A4	rs2242480	Amlodipine	CYP3A4*1G allele associated with reduction in DBP	[23]
CES1	rs71647871	Enalapril, ramipril, perindopril, moexipril, and fosinopril	Therapeutic failure	[24]
NAT2	rs1801279	Hydralazine	NAT2*14 allele associated with decrease in BP with increased risk of lupus erythematosus	[25]
	rs1801280	Hydralazine	NAT2*5 allele associated with decrease in BP with increased risk of lupus erythematosus	[25]
ABCB1	rs1045642	Amlodipine	TT genotypes associated with reduction of BP	[26]

ADD1=Adducins 1, AGT=Angiotensin, AGTR1=Angiotensin receptor 1, ACE=Angiotensin-converting enzyme, FUT4=Fucosyltransferase 4, ADRB1=Adrenoceptor beta 1, KCNH=Potassium voltage-gated channel subfamily H member 2, KCNMB1=Potassium calcium-activated channel subfamily M regulatory beta subunit 1, CACNA1C=Calcium voltage-gated channel subunit alpha 1 C, CYP=Cytochrome P, CES1=Carboxylesterase 1, NAT=N-acetyltransferase, ABCB1=ATP-binding cassette subfamily B member 1, HCTZ=Hydrochlorothiazide, BP=Blood pressure, DBP=Diastolic BP, SBP=Systolic BP, CVS - cardiovascular system, GC - Please change to G-C haplotype

Antihypertensive pharmacodynamic interactions on genetic polymorphisms

Diuretics

Neural precursor cell expressed, developmentally downregulated 4-like, E3 ubiquitin-protein ligase (NEDD4 L) is an ubiquitin ligase. NEDD4 L gene is vital for the maintenance of proper sodium reabsorption.[27] Adducins 1 (ADD1) are a family of cytoskeleton proteins found in the renal tubule and thought to regulate ion transport. The protein encoded by this gene represents the alpha unit. A scientist experimenting on Milan hypertensive rats reported that the mutant adducin gene increases the activity of Na-K pump on the basolateral membrane of renal epithelial cells.[28]

A prospective, multicenter, randomized, open-level study done on 768 hypertensive patients suggested that NEDD4 L gene polymorphisms (rs4149601, rs4149601-rs292449) had a better response with hydrochlorothiazide (HCTZ) in lowering high BP. The study also predicted that NEDD4 L rs4149601 (G allele carrier) could be a predictor of cardiovascular adverse effects when HCTZ is not included in the antihypertensive regimen.[8] Hypertensive patients with ADD1 gene polymorphism rs4961 were evaluated for BP response to HCTZ therapy, and it was observed that there was a fall in BP in these patients.[9] Genetic polymorphisms of NEDD4 L and ADD1 gene are associated with increase sodium reabsorption.[27,28] Hydrochlorothiazide inhibits the Na+/Cl− cotransporter and decreases sodium reabsorption in the renal tubule.[29] This might explain the response of decrease BP with hydrochlorothiazide in patients with NEDD4 L and ADD1 gene polymorphisms.

Angiotensin-converting enzyme inhibitors

Angiotensinogen is expressed in the liver and encoded by the AGT gene on chromosome 1. In the renin-angiotensin pathway, AGT gene is one of the significant genes which has association with pathophysiology of hypertension. Randomized clinical trial of the Chinese population showed a correlation of AGT SNP rs7079 CC genotype in lowering DBP. With benazepril, an ACEI, the same Chinese population with angiotensin receptor 1 haplotypes H2 showed a decrease in SBP and haplotype H3 in DBP.[10] Another gene, ACE which encodes an angiotensin-converting enzyme (ACE), also known to regulates BP. Genetic polymorphism of ACE gene, insertion/deletion (I/D) is the most widely studied gene associated with hypertension. Nevertheless, very few pharmacogenetic studies have been conducted with ACE I/D gene polymorphism, hypertension, and ACE inhibitors (ACEIs). After literature research, a study was done on Malay hypertensive population with ACE I/D polymorphism (ACE genotype DD) which was found to have a better BP-lowering response when treated with ACEIs, enalapril, and lisinopril.[11]

A sole precursor of angiotensin peptides, angiotensinogen, secreted from the hepatocytes is converted to angiotensin I decapeptide by renin. ACE attached to endothelial membrane cleaved angiotensin I decapeptide to generate angiotensin II octapeptide.[30] AGT gene encodes angiotensinogen and overexpression of the AGT gene (KAP-AGT transgene) in the animal model,[31] and ACE gene polymorphism in hypertensive patients had a higher level of circulating angiotensinogen and ACE in the plasma. This leads to an increase in the generation of angiotensin II and sodium reabsorption.[32] As it is known that ACEIs blocks the conversion of angiotensin I to angiotensin II by inhibiting ACE, ACEIs might interact with ACE gene polymorphism and reduces blood pressure.

Angiotensin receptor blocker

We found only one study on FUT 4 gene polymorphism in association with hypertension and angiotensin receptor blocker after searching in various databases. American white (FUT4 gene rs11020821) hypertensive population showed a decrease in BP with candesartan therapy.[12] Protein involved in the fucosyltransferase 4 (FUT4) gene is alpha-(1,3)- fucosyltransferase 4 and involves in the expression of Lewis X/SSEA-1 and VIM-2 antigens,[33] but we were not clear how FUT 4 gene and candesartan interaction involve in lowering BP.

Beta 1-adrenergic blockers

Beta 1-adrenergic blocker acts through G-protein coupled receptor, beta 1-adrenergic receptor and coded by the adrenoceptor beta 1 (ADRB1) gene. Among the polymorphisms of the ADRB1 gene, rs1801252 is associated with agonist-prompted downregulation of beta-receptor expression, which is distal to internalization and is associated with an altered N-glycosylation state,[34] and rs1801253 increases coupling of the β₁ adrenergic receptor to G-protein, leading to increase in adenylyl cyclase activity. These polymorphisms also increase the risk of cardiovascular diseases.[35] Heart failure was associated with increased sympathetic nervous stimulation resulting in the downregulation of myocardial β₁ receptors. Metoprolol, a cardioselective β₁ receptor blocker showed a better control of BP in two different hypertensive populations with ADRB1 gene polymorphisms.[13,14,36]

Studies suggested that there is an increase activity of G protein-coupled receptor kinase 4 (GRK4) in hypertensive patients with GRK4 gene variant. It was explained that dopamine produced from the proximal renal tubules decreases renal proximal tubular sodium reabsorption through D₁-like receptor, but this ability is impaired in essential human hypertension. It has been reported that GRK4 SNPs rs2960306 and rs1024323 desensitized the D₁-like receptor by serine phosphorylation of the receptor.[37,38] A pharmacogenetic study was done in hypertensive patients with GRK4 gene variants rs2960306, rs1024323, and rs2960306-rs1024323 haplotypes; it was observed therapeutic failure with atenolol therapy.[15]

A novel locus (PTPRD gene variants) associated with BP was found to have a better response to atenolol. SNPs of PTPRD rs12346562 and rs1104514 in caucasian and rs10739150 in African population were associated with lower BP with atenolol therapy.[16] After an experiment done on various vasculature, it was observed that angiotensin II increases cytokine levels (interleukin [IL]-1 β, IL-6, IL-8, IL-17, IL-23, transforming growth factor [TGF]β, and TNFα) leading to activation of JAK (Janus kinase)-STAT (signal transducers and activators of transcription). PTPRD gene dephosphorylates STAT3 and genetic variations in PTPRD gene abolish the ability to regulate STAT3, which elevates BP.[39] After a literature search,[40] we concluded that beta-blockers might inhibit the cytokines and be responsible for lowering BP levels.

Many studies indicated that multiple drugs such as adrenergic blockers and calcium channel blockers are involved in the modulation of KCNH2 gene. This potassium voltage-gated channel subfamily H member 2 (KCNH2) gene channel (Kv11.1) is the family of the pore-forming subunit that encodes for α subunit of the delayed rectifier of the potassium voltage-gated channels (I_kr). G protein-coupled receptor, such as the β₁ receptor, regulates the expression of KCNH2 gene through activation of Gs-adenylate cyclase-cAMP-PKA-14-3-3 pathway. Fazhong He et al., 2013 stated that patients treated with β blockers (celiprolol, atenolol, bisoprolol) showed hypotensive effect with all the β blockers in patients (below 55 years of age) with KCNH2 rs17424631 genetic variation (CC genotypes).[17]

Calcium channel blockers

In the US, the hypertensive population with KCNMB1 rs11739136 genetic polymorphism response well to verapamil monotherapy.[18] The protein encoded by KCNMB1 (potassium calcium-activated channel subfamily M regulatory beta subunit 1) gene regulates the arterial tone through calcium signal in the vascular smooth muscle through an influx of Ca+ ion and voltage-gated K+ channels (BK_Ca). β₁ subunit of this gene increases the activity of Ca+ and voltage-gated K+ channel, which prevents the further influx of Ca+ by a negative feedback mechanism.[41]

The calcium voltage-gated channel subunit alpha 1 C (CACNA1C) gene encodes the α1c subunit of the L-type calcium channel. This is one of the critical binding sites for calcium channel blockers (CCBs). Genetic variation of CACNA1C, rs1051375 (AA genotype) individuals of the United States, and Puerto Rico had better control of BP with verapamil (phenylalkylamines) sustained-release base treatment than with atenolol (β adrenergic blocker). CACNA1C gene encodes the α1c subunit of the L-type calcium channel. This voltage-dependent Ca+ channels mediate the entry of Ca+ into excitable cells, which help regulate BP.[19]

KCNH2 gene rs17424631 genetic polymorphism, which we have discussed earlier, has shown an effective hypotensive response with azelnidipine and nitrendipine (dihydropyridines) therapy in CT/TT genotypes male patients.[17]

L-type Ca²⁺ (Ca_L) channels, voltage-gated K+ (K_V) channels, and high-conductance voltage- and Ca²⁺-sensitive K+ (BK_Ca) channels are voltage-sensitive channels. These channels play an important role in the regulation of arterial smooth muscle tone. Evidence suggested that the upregulation of Ca_L channels (overexpression of _1c) and/or loss of K_v channels (downregulation of K_v gene expression) results in opening up of these channels and causes depolarization. This results in increased voltage-gated Ca+ influx in arteries leading to vasoconstriction and high BP.[42] CCBs bind to α1 subunit and interferes with the voltage-dependent cycling of the channel. Phenylalkylamines bind to open and inactivated state with high affinity and reduce inward Ca² + currents through L-type Ca²+ channels (LTCCs), mainly Cav. 1.2 channels are found in arterial smooth muscles.[43] Kv2.1 channels carry delayed rectifier K+ currents, which display outward rectification with slow inactivation.[44] It was demonstrated in rabbit atria that dihydropyridines inhibit transient outward K+ current (I_to).[45]

Alpha-1 adrenergic receptor blockers

He et al. also evaluate the genetic polymorphism of KCNH2 gene rs17424631 with adrenergic blocker along with blockers and CCBs in hypertensive patients. It was observed that doxazosin, an adrenergic blocker, lowers DBP in hypertensive patients.[17] In various experiments, it was seen that the expression of KCNH2 gene is also regulated by receptor through protein kinase C (PKC) and protein kinase A (PKA) and adrenergic blockers inhibit the rapidly activating delayed rectifier potassium current (I_kr) through PKC and PKA.[46]

Centrally acting antihypertensive drugs

Clonidine, an α_2A adrenergic receptor agonist, lowers BP in hypertensive patients with TT genotypes of GNB3 gene rs5433 genetic polymorphism.[20] The genetic abnormality in guanine nucleotide-binding proteins might involve various clinical conditions, and essential hypertension is also one of them. Gigantocellular depressor area (GiDA) is located in a region of the reticular formation, and the researcher examined that α_2A adrenergic receptors were abundantly found in GiDA. After stimulation of α_2A receptors by clonidine, it was observed that clonidine produced a decrease in arterial BP in hypertensive rats.[47]

Antihypertensive pharmacokinetic interactions on genetic polymorphisms

Drug metabolizing enzymes

Drug metabolizing enzymes are either microsomal such as cytochrome P450 (CYP), epoxide hydrolases, or nonmicrosomal such as UDP-glucuronosyltransferases, sulfotransferases, glutathione-S-transferase, N-acetyl transferases conjugate. These drug-metabolizing enzymes are primarily expressed in the liver but also express in small quantity in the small intestine, lungs, placenta, and kidneys. In Phase I drug metabolism, oxidative biotransformation of most of the drugs is catalyzed by 1, 2, and 3 CYPs enzyme families.[48] Over 100 allelic variants and subvariants of the CYP2D6 gene have been documented by the Pharmacogene Variation Consortium (Pharm Var). Therapeutic drug response, adverse effects, and tolerability of an individual can be explained due to allelic variants and subvariants of the CYP2D6 gene.[49] In the Chinese Han hypertensive population, CYP2D6 rs1065852 did not show any significant therapeutic outcome with metoprolol therapy.[13] However, hypertensive patients from Netherland who are homozygous for CYP2D6 rs3892097 (CYP2D6FNx014 AA) gene variation had better control with metoprolol.[21] In Caucasian, CYP2D6FNx014 was found to be the most common variant allele, and this variant leads to poor metabolism (PM) of metoprolol.[50] Lennard et al. observed that the PM phenotype of this gene is associated with more intense and sustained receptor blockade as there was an increase in metoprolol plasma concentration[51] but due to increase plasma concentration of metoprolol in PM phenotype patients had a higher risk of bradycardia as an adverse effect when compared with non-PMs.[52] CYP2C9 gene, another member from the CYP gene family, also metabolizes various drugs and interindividual variability in drug response can be seen due to genetic polymorphisms. In the Japanese hypertensive population, the CYP2C9 gene variation showed varied drug response with losartan. Patients with CYP2C9 rs1057910 (A1075C) or CYP2C9FNx013 gene variation showed lowered SBP when treated with losartan but not effective with CYP2C9FNx0130 (Ala477Thr) genetic polymorphism patients. Yin et al. explained the therapeutic failure due to insufficient conversion of losartan to E-3174 in CYP2C9FNx0130 genetic polymorphism patients.[22] CYP3A4FNx011GFNx011G SNP of the CYP3A4 gene and CYP3A5FNx013FNx013 SNP of the CYP3A5 gene also significantly reduces DBP when treated with amlodipine.[23] Carboxylesterase 1 (CES1) is a hydrolase enzyme that metabolizes ACEIs (80%-95%) to active metabolites in the liver. CES1 gene encodes for carboxylesterase 1. It was speculated in vitro that CES1 gene polymorphism, rs71647871 is a loss of function variant for activation of prodrug of ACEIs (enalapril, ramipril, perindopril, moexipril, and fosinopril) resulting in therapeutic failure in patients with ACEIs.[24]

The Phase II drug-metabolizing enzymes, arylamine N-acetyltransferase 2 encoded by NAT2 gene, mediate the metabolism of hydralazine through acetylation. Genetic polymorphisms of NAT2 gene give rise to either slow or fast acetylator phenotypes. Pharmacogenetic study shows that slow acetylators such as NAT2 rs1801279 (191G>A; Arg64Gln) in NAT2FNx0114 allele and NAT2 rs1801280 (341T>C; Ile114Thr) in NAT2FNx015 allele significantly lower BP with hydralazine. However, these patients also had a higher incidence of adverse effects such as drug-induced lupus erythematosus.[25]

Drug transporters

Drug transporters are also significant determinants of the absorption, distribution, and elimination of many drugs. Genetic variation of drug transporters may cause individual and ethnic differences in pharmacokinetics or pharmacodynamic characteristics. P-glycoprotein (P-gp) drug transporters determine the range of drugs that have to be uptake and efflux from or into the lumen. ATP-binding cassette subfamily B member 1 (ABCB1) or MDR1 gene encodes P-gp drug efflux pump, and genetic polymorphism of this gene alters the interindividual differences in bioavailability. MDR1 or ABCB1 gene rs1045642 TT genotype was associated with hypotensive effect (patients obtained target BP, <140/90 mmHg) of amlodipine in hypertensive Chinese Han population. It was explained that a better effect of amlodipine among TT genotype was due to decreased expression of ABCB1 gene and decreased synthesis of P-gp.[26]

Discussion

Numerous antihypertensive drugs were recommended according to the guidelines of ACC/AHA for the management of hypertension. Even though specific treatment protocols are approached, there is interindividual variability between patients in response to drugs or is experiencing adverse effects. This is due to the complex trait of BP, which is influenced by genetics and environmental factors. Genome-wide association study (GWAS) has helped in identifying many Novel loci involved in BP regulation and lengthen our knowledge of genetic regulation of BP such as molecular pathway involved in ACE, voltage-dependent calcium channel, adrenergic ₂ receptor, etcetera. GWAS findings also help in determining risk and targeted treatment for hypertension.[53] Human genome sequencing aims to diagnose and understand the pathology of a disease and help in developing Nobel ways of maximizing therapeutic efficacy and minimizing adverse effects for an individual patient. Our review article has restricted our discussion to the pharmacodynamic and pharmacokinetic mechanism and impact of genetic polymorphism on drug response.

In recent years, genetic polymorphism influencing the pharmacodynamic mechanism gains more popularity. Drug response of a particular drug depends on its interaction with a specific molecular receptor as it is influenced by factors such as upregulation or downregulation of receptors. The NEDD4 L gene and ADD1 gene regulate homeostasis of sodium balance in the renal tubule. Hydrochlorothiazide decreases sodium reabsorption in the renal tubule suggesting BP reduction in patients with genetic variation of NEDD4 L and ADD1 gene. Overexpression of the AGT gene or ACE gene correlates with an increase in circulating angiotensinogen and vasoconstriction. Arterial vasodilatation and BP reduction could be obtained through ACEIs. Downregulation of the β₁ receptor by the ADRB1 gene variant increases the risk of hypertension, while GKR4 gene variation leads to therapeutic failure. KCNH2 gene variation with CC genotypes showed a better BP-lowering effect with β₁ blockers, and adrenergic blocker and CT/TT genotypes respond well with CCBs. In hypertensive patients with overexpression or upregulation CACNA1C gene and downregulation of the KCNMB1 gene, phenylalkylamines and dihydropyridines mediate dilatation of blood vessels and BP reduction.

The pharmacokinetic mechanism of a drug influencing genetic polymorphism was the initial pharmacogenetics studies. Initially, CYP genes and their genetic variation were studied in response to drug-metabolizing enzymes. Researchers found that within a given population, there was variability in the allele distribution and these individuals could be categorized as ultrarapid, extensive, intermediate, and poor metabolizers.[54] Pharmacogenetic studies of CYP genes such as CYP3A4/5, CYP2D6, and CYP2C9 metabolize 30.2%, 20%, and 12.8% of the drug, respectively.[55] CYP genes, CES1, NAT2 also involve in antihypertensive drug metabolism. Polymorphism of these drug-metabolizing genes influences the regulation of BP. There could be an increase in the efficacy of a drug if the polymorphic gene is a loss of function variants and a decrease in drug efficacy when there is a gain of function variant.

Significant advances in pharmacogenetic studies on hypertension could be seen the past decade which facilitates our understanding of individualized drug therapy. In the present day, there has been an increase in research interest in pharmacogenetics studies in India. However, as hypertension is a complex medical condition, hypertension pharmacogenetics often generates conflicting and inconsistent results with regard to genetic polymorphisms, BP response, and use of antihypertensive drugs. Sometimes, bringing the valuable genetic information from bench to clinical practice remains challenging. Awareness of pharmacogenetic testing among the primary health-care physician as they are the first group of physicians in treating hypertension, cost of pharmacogenetic testing, inconsistent regulatory and reimbursement policies, and availability of testing centers challenges implementation of pharmacogenetic testing in clinical practice.[56] Evidence-based practice resources are required to overcome the barriers while implementing pharmacogenetic testings which would help us to have a standard approach while interpreting and applying genetic test results.[57] Hence, this would lead to a better quality, safety, and efficacy of patient care by improving BP control and prevent cardiovascular risk.

Conclusions

Ethnic variability, diet, age, gender, environment, and geographical factors are indicators responsible for the complexity of hypertension disease. Evidence suggested that research in pharmacogenetics has advanced our knowledge of targeted therapy and promises great hope on precision medicine. FDA has revised some of the drug levels and included pharmacogenetic information and recommendation for certain drugs after a genetic association of specific variants and drug response phenotypes has been identified. Pharmacogenetic information in the drug level for antihypertensive drugs is latent. Research works on pharmacogenetics, which promises precision medicine still rested on academics. The transition for pharmacogenetics to clinical practice is necessary, and this would be effective when there are sufficient knowledge and awareness among physicians to understand the influence of genetic variations and drug responses. It is also necessary for physicians to interpret the rationale of pharmacogenetic tests for specific genotypes. Pharmacogenetic tests would become easier to implement if the patients also have an optimistic view of the benefit-risk balance. Lack of cost-effectiveness studies to assess the economic benefit of managing a patient with pharmacogenetic aided medication could also be a barrier to precision medicine implementation. At present, insurance coverage for pharmacogenetic testing is not a rational process, but the scenario of health-care reimbursement and drug regulation is continuously changing. Several variations in results can be seen in pharmacogenetics hypertension studies. Conducting extensive collaborative GWAS studies of hypertension genome and antihypertensive drug response among various ethnic groups would have a higher likelihood of success. By investigating and solving the complexity of genetics and environmental factors, understanding the pharmacodynamics and pharmacokinetics principles would help us overcome the roadblocks and manage hypertension better.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.