|Year : 2022 | Volume
| Issue : 1 | Page : 1-6
Pharmacogenomics of adrenergic receptors from bench to bedside: Potential clinical implications in critical care
Jude Howaidi1, Hani MS Lababidi2
1 Department of Clinical Pharmacy, Pharmacy Administration, King Fahad Medical City, Riyadh, Saudi Arabia
2 Critical Care Medicine Administration, King Fahad Medical City, Riyadh, Saudi Arabia; MGH-Institute of Health Professions, Boston, MA, USA, Saudi Arabia
|Date of Submission||30-May-2021|
|Date of Acceptance||11-Oct-2021|
|Date of Web Publication||31-May-2022|
Department of Clinical Pharmacy, Pharmacy Administration, King Fahad Medical City, Riyadh 11564
Source of Support: None, Conflict of Interest: None
Distinctions in the DNA sequence of the genes pertaining to α and β adrenergic receptors can result in genetic polymorphisms. These variations can potentially impact response to treatment with adrenergic agonists and antagonists that likely warrant medical intervention. Pharmacogenomics is conceptualized as “the right drug to the right patient,” which implies that pharmacogenomics is entirely personalized. Given that adrenoreceptors play a fundamental role in regards to the pharmacogenetic interaction between catecholamines with α and β adrenergic receptors, it is, therefore, pivotal to highlight and further analyze variants amongst adrenergic receptors to improve the management of diseases pertaining to catecholamine dysfunction. In this review, we highlight the pharmacogenomics of adrenergic receptors and their potential clinical implications in critical care. It is evident that there are several variants associated with the adrenergic receptor alpha 1A (ADRA1A), adrenergic receptor alpha 2A (ADRA2A), adrenergic receptor beta-1 (ADRB1), adrenergic receptor beta-2 genes for α and β adrenergic receptors that were observed among different populations and ethnic groups including the Arg347Cys and Arg389Gly in ADRA1A and ADRB1, respectively. These polymorphisms have resulted in interindividual variability in drug responses for epinephrine, dexmedetomidine, and salbutamol, which concludes that pharmacogenomics of adrenergic receptors have proven immense variability in candidate genes amongst populations that lead to different drug responses.
Keywords: Adrenergic receptors, alpha receptors, beta receptors, critical care, genes, pharmacogenomics
|How to cite this article:|
Howaidi J, Lababidi HM. Pharmacogenomics of adrenergic receptors from bench to bedside: Potential clinical implications in critical care. Saudi Crit Care J 2022;6:1-6
|How to cite this URL:|
Howaidi J, Lababidi HM. Pharmacogenomics of adrenergic receptors from bench to bedside: Potential clinical implications in critical care. Saudi Crit Care J [serial online] 2022 [cited 2022 Jul 4];6:1-6. Available from: https://www.sccj-sa.org/text.asp?2022/6/1/1/346350
| Introduction|| |
The nervous system is a highly regulated system of the human body. It functions as a coordinator of sensory impulses that are mediated through signal transmission, which are interrelated with several body systems. As neurotransmitters of the sympathetic nervous system, norepinephrine and epinephrine play a fundamental role in the regulation of involuntary functions through their requisite binding with adrenergic receptors. Adrenergic receptors are composed of alpha and beta receptors. These receptors are cardinal mediators of signal transduction involved in the activation of sympathetic effects such as vasoconstriction of blood vessels and heart rate elevation., As part of the G-protein-coupled receptor target family, alpha and beta receptors are classified according to their location and functioning. Alpha-receptors comprise alpha-1 (α1) and alpha-2 (α2) with six subtypes (α1A, α1B, α1C, α2A, α2B, and α2C) while beta-receptors comprise beta-1 (β1), beta-2 (β2), and beta-3 (β3), which has not been studied well.
The sympathetic nervous system plays a vital role in the septic shock state. It allows the host to defend itself against the vasodilatation caused by the invading pathogens. Current practice guidelines of septic shock include the use of norepinephrine as the first-line vasopressor. Norepinephrine acts on vascular α1 adrenergic receptors, inducing vasoconstriction, and on cardiac β1 receptors inducing chronotropic effect. The exact mechanism of action of the alpha agonists remains controversial with variations in the response of the host to these powerful agents. On the other hand, Dobutamine acts on the myocardial β1 receptors to enhance cardiac contractility and has α1 receptors and β2 receptors stimulatory effect as well.
The genetic aspect of adrenergic receptors is an imperative component that determines the structural features as well as the action of alpha and beta receptors. The differences and similarities in the structure of adrenoreceptors arise from the genes encoding α and β. Adrenergic receptor alpha 1A (ADRA1A) and adrenergic receptor alpha 2A (ADRA2A) are genes encoding for α1A and α2A, respectively. ADRA1A is located on chromosome 8p21.2, while ADRA2A is located on chromosome 10q25.2. On the other hand, beta-receptors are encoded by adrenergic receptor beta-1 (ADRB1) gene, which is located on chromosome 10q25.3, and adrenergic receptor beta-2 (ADRB2) gene, which is located on chromosome 5q32. The structural similarity between alpha and beta receptors appears to be the presence of 400–500 amino acids with seven transmembrane domains. In contrast, the major structural difference includes the length of the C-terminal regions. The α2 subtypes have a shorter C-terminal compared to α1 and β. For instance, α2 subtypes have a C-terminus with 23 amino acid residues while β with 167 C-terminus residues.
Distinctions in the DNA sequence of the genes pertaining to α and β adrenergic receptors can result in genetic polymorphisms. These variations can potentially impact response to treatment with adrenergic agonists and antagonists that likely warrant medical intervention. Pharmacogenomics is a form of personalized medicine that deals with the utilization of appropriate medication based on the patient's genetic makeup. This branch of pharmacology is necessitated to improve patient health outcomes in terms of both efficacy and safety by narrowing drug selection tailored to genetic variants within the patient's genome. Given that adrenoreceptors play a fundamental role in regards to the pharmacogenetic interaction between catecholamines with α and β adrenergic receptors, it is, therefore, pivotal to highlight and further analyze variants amongst adrenergic receptors to improve the management of diseases pertaining to catecholamine dysfunction., In this review, we highlight the pharmacogenomics of adrenergic receptors and their potential clinical implications in critical care.
| The Importance of Pharmacogenomics|| |
Pharmacogenomics is conceptualized as “the right drug to the right patient,” which implies that pharmacogenomics is entirely personalized. Single nucleotide polymorphism (SNP) occurs when a single nucleotide (A, T, C, or G) is altered by insertion, deletion, or rearrangement in the genome sequence. It is the most common form of genetic variation amongst the human population with an estimated rate of 1 SNP in every 1300 base pairs of DNA. This form of variation in the human genome can result in different drug responses. Pharmacogenomics focuses on several genes encoding for proteins such as receptors, enzymes, signal pathways, and ion channels.,,, The study of pharmacogenomics serves multiple aspects in healthcare since administering the right drug to the right patient will subsequently lead to an enhanced drug response, a decrease in the incidence of adverse drug reactions, and an overall reduction in healthcare costs.,
Genes of alpha-adrenergic receptors
Adrenergic receptor alpha-1A
The ADRA1A encodes for the α1A adrenergic receptor which is responsible for the vasoconstriction of blood vessels in humans. The ADRA1A gene, located on chromosome 8p21.2, is highly expressed compared to the genes encoding for the remainder subtypes of alpha-1 receptors (α1B and α1C). The ADRA1A gene has four transcript variants (isoforms) as a result of alternative splicing that differs in the C-terminus region. In vitro studies have identified a variant in ADRA1A in which cysteine replaces arginine at codon 492 (Arg492Cys). When compared to the wild-type form, Arg492, the variant Cys492 was indifferent in terms of response to norepinephrine, which indicates that both wild-type and variant forms were equivalent in terms of binding affinity. The incidence of the Arg492Cys variant was more frequent in Japanese participants, followed by Caucasians, while African-Americans had the lowest incidence.
Adrenergic receptor alpha 2A
The ADRA2A are presynaptic autoinhibitory receptors responsible for the central regulation release of neurotransmitters such as norepinephrine, which subsequently leads to lowering blood pressure by inhibiting sympathetic activity. The ADRA2A gene is located on chromosome 10q25.2. One ADRA2A variant is Asn251 Lys which modifies the third intracellular loop of α2A. It has been postulated that people with this polymorphism may have an 'agonist-promoted” phenotype.
Candidate genes of beta-adrenergic receptors
Adrenergic receptor beta-1
The ADRB1 are prime receptors for the sympathetic activity of the heart necessitated for regulating heart rate and cardiac muscle contraction. The ADRB1 intron-less gene encoding is located on chromosome 10q25.3. The diversification of ADRB1 variants was identified, and possible alteration in β-blockers' response has been suggested. ADRB1 polymorphisms consist of three common variants resulting in amino acid substitutions in the amino sequence; these include Ser49Gly, Arg389Gly, and Arg389 Leu. Arg389Gly is the most frequently observed variant, which results in changes in the fourth loop intracellularly of ADRB1. In-vitro studies showed that Arg389Gly substitution consequently led to a reduced ADRB1 stimulation of adenylyl cyclase compared to wild-type Arg389. This form of substitution has consequently led to the limited coupling of G-protein, which further has caused a shift in dynamic response towards agonists and antagonists of ADRB1.
Adrenergic receptor beta-2
The ADRB2 is G-protein coupled receptors that are primarily found in lung bronchial smooth muscles in addition to arteries of skeletal muscles. Upon activation of ADRB2, cellular signal transduction pathways transpire, leading to dilation of bronchial smooth muscles of the lungs and vasodilation of arteries of skeletal muscles. The ADRB2 gene is an intron-less gene located on chromosome 5q32. Three ADRB2 polymorphisms were identified: Gly16Arg, Gln27Glu, and Thr164Ile. Similar to ADRB1, the fourth loop of ADRB2 is modified in the presence of these variants. In-vitro studies have demonstrated a lack of signaling in adenylyl cyclase activation in transgenic mice with Ile164 ADRB2., In addition, the Gly16Arg variant was examined in transfected cells. The result of this in vitro analysis showcased that transfected cells with wild-type Gly16 ADRB2 were more responsive towards down-regulation induced by agonistic effects compared to Arg16 transfected cells.
| Clinical Implications of Adrenoreceptor Pharmacogenomics|| |
Adrenergic receptor alpha 1A
Although there is a major dissimilarity in terms of vasoconstriction among the human population, inter-individual variability in ADRA1A expression is highly incidental.,, Therefore, inter-individual variability in terms of response to cardiovascular drug therapy is highly anticipated. A previous study assessing genetic variability in terms of the vasoconstrictive property of epinephrine in 12 families have shown that parents had a higher ED50 compared to their children. Moreover, in another study, epinephrine administration in 15 unrelated subjects have demonstrated much phenotypic variance with ED50 ranging between 3.9 and 120.5 ng/min in terms of vein diameter constriction. The results of these studies indicate different responses to epinephrine-induced vasoconstriction are genetically linked.
Studies assessing genetic polymorphisms of the ADRA1A gene in terms of drug response are limited. The sensitivity to phenylephrine, an alpha-1 agonist, is examined in 74 participants for three different genotypes of ADRA1A: Arg347Arg, Arg347Cys, and Cys347Cys. The majority of the participants had the Arg347Cys genotype. The sensitivity to phenylephrine is expressed as dose resulting of 50% vasoconstriction (ED50). The ED50 range for Arg/Arg, Arg/Cys, and Cys/Cys genotypes are 287–918, 274–680, and 197–1124 ng/min, respectively, with no statistical significance. A comparable outcome is reported in a study performed on the dorsal hand vein response to assess the effect of phenylephrine on 106 participants with 32 ADRA1A SNPs. The study found no differences in terms of response among the ADRA1A variants.
Adrenergic receptor alpha 2A
The effect of ADRA2A polymorphism of dexmedetomidine, a highly selective α2-adrenergic receptor agonist, has been studied on the blood pressure response of 73 participants (black and white subjects). All nine identified ADRA2A genotypes SNPs are present in both ethnicities. The three homozygous participants for the A > G SNP (rs553668) had major reductions in systolic blood pressure, diastolic blood pressure, and heart rate compared to heterozygous participants. However, participants who are homozygous or heterozygous for the C > G SNP (rs2484516) had a much less reduction in systolic blood pressure (44% reduction).
Adrenergic receptor beta-1
Several studies assessed the clinical implications of ADRB1 in animal and human studies. For instance, transgenic mice with two human receptors of β1Arg389 and β1Gly389 variants were studied. Following the administration of the β-agonist, dobutamine, stimulation of Arg389 β1 AR in transgenic mice was higher compared to mice with Gly389 β1 AR. Furthermore, the homozygosity for Arg389 is associated with greater hemodynamic responses to β-receptor blockade, and is associated with improvement in ventricular function during carvedilol treatment in heart failure patients.
Moreover, in vitro analysis of two groups of heart mice with Gly389 β1 AR and Arg389 β1 AR were further assessed. Propranolol, a nonselective β-blocker, was administered to examine cardiac function. In this analysis, mice with Arg389 β1 AR had a greater response in terms of the negative inotropic effects of Propranolol. These findings highlight a more likely response to therapy in Arg389 β1ARs (ADRB1) subjects; however, clinical studies are required to support these findings.
Several in vivo studies have been conducted to analyze responsiveness to β-blockers that are considered genotype-dependent. One study determined genotypes of β1ARs that included: rs1801252 and rs1801253 which are correlated with Ser49Gly and Arg389Gly variants, respectively, in ethnic groups of unrelated black and white participants with exercise-induced tachycardia. Both black and white ethnic groups had the Ser49Gly and Arg389Gly variants. In addition, atenolol, a selective β1-blocker was administered in both groups. The study confirmed that there was a 1.75 fold decrease in heart rate in white participants compared to blacks (P < 0.001) with a mean reduction of 7.3 beats per minute after administering atenolol. Following the inclusion of variants of ADRB1 in the analysis, it was determined that participants with Arg389Gly variants were fairly responsive to atenolol. The homozygous group had a greater response compared to the heterozygote group. On the contrary, there was a minimal reduction in heart rate in participants with the Ser49 allele compared to the participants with the Arg389Gly variants. To support the findings of the previous study, 34 participants with homozygous Arg389Gly variants (21 had the Arg389 allele and 13 had the Gly389 allele) were given atenolol to assess the extent of heart rate reduction in both groups. Participants who were homozygous for the Arg389 allele had a greater reduction in hemodynamic responses. A genotype-based study assessed the efficacy of metoprolol in participants with heart failure. The study concluded that patients with the Gly389 variant had minimal improvement with metoprolol compared to placebo. These clinical findings suggest that ADRB1 variants (with the exception of Arg389) could possibly lead to insufficient response to β1-blockers in the management of heart failure and hypertension.
Adrenergic receptor beta-2
The inter-individual variability pertaining to ADRB2 (β2-ARs) has been determined in humans as well. Nine ADRB2 polymorphisms were identified as point mutations that are present in Caucasian asthmatic subjects. The Arg16Gly and Gln27Glu polymorphisms are present in 53% and 24% of asthmatic and nonasthmatic participants; however, participants with asthma being homozygous for Arg16Gly and Gln27Glu. Around 24% of the subjects with asthma have both variants occur simultaneously. Asthmatic subjects with the Arg16Gly variant are more likely to be resistant towards β2-agonists. On the contrary, a study on 854 participants (398 asthmatics and 456 nonasthmatics) could not confirm the association between response to salbutamol and Arg16Gly variants in ADRB2. The same group of researchers identified a different variant of ADRB2 Thr164Ile (rs1800888) with several allelic frequencies. The study implies that the Thr164Ile variant could potentially alter response to β2-agonists.
| Future Research on Adrenoreceptor Pharmacogenomics in Critical Care Medicine|| |
While there has been a considerable body of research on the application of genomics to medicine in general, studies on personalized medicine in critical care have been scarce. The main reasons reside in the heterogeneity and poor characterization of critical illnesses compared to other domains such as oncological diseases, where precision medicine has been evolving rapidly. Until now, we are typifying diseases and syndromes in critical illnesses based on general parameters such as physiological variables, hemodynamics, oxygen requirement, lung compliance, and physical signs. Moreover, the time factor of critical care illnesses plays a hindering role in precision medicine in intensive care unit (ICU). The results of any genomic testing should be promptly given the acuteness and rapid deterioration of these illnesses. In general, the necessary factors needed for pharmacogenomics to result in a clinically important change in drug effect include (1) considerable effect of the polymorphism on the active drug moiety, (2) a relationship between drug concentration and response, (3) if severe adverse effects exist, they need to be concentration-dependent, and (4) the therapeutic window is narrow. In view of these challenges, we hereby describe two approaches to promote future research on adrenoreceptor pharmacogenomics in critical care medicine.
Genome mining involves studying the whole genome data to better understand the biology and treatment response to a critical care illness. This approach is based on microarray technology to discover the involved genetic intricacies of complex diseases. An example of such an approach is that the study carried out on the PROWESS population. Sepsis prognostic markers and treatment response markers were identified in 1446 patients. Genome mining can be applied to adrenoreceptor pharmacogenomics by testing all patients with septic shock through microarray technology to determine markers for response to a specific inotropic medicine.
Single marker analysis
This approach involves determining the association between a single genetic polymorphism and a critical care illness or condition. There are many examples of this approach in determining the susceptibility of patients to sepsis and septic shock, such as by checking polymorphisms for CD14 and Interleukin-10 genes., The same approach can be applied for specific adrenoceptor gene polymorphisms similar to what we are presented in [Table 1].
|Table 1: Candidate gene polymorphism for adrenoreceptors in critical care setting|
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| Conclusion|| |
The pharmacogenomics of adrenergic receptors have proven immense variability in candidate genes amongst populations that lead to different drug responses. In vivo pharmacogenomic-based studies pertaining to adrenergic receptors in ICU are needed to identify the variants in adrenergic receptors responsible for the differences in drug response.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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