Do Polymorphisms Of Adrenergic Receptor Signaling Pathways Affect Outcomes Of Patients Report Example

- Abstract
Cardiovascular diseases such as heart failure are some of the leading causes of mortality and morbidity with Australia being one of the country’s most greatly affected (McLean, Esclick & Coats, 2006). An area of interest in the pathology of heart failure is the significance that polymorphisms of adrenergic receptor genes have on the outcomes of patients with heart failure. Single-nucleotide polymorphisms or SNPs that occur in the genes that encode for adrenergic receptors are known to have various physiological and functional consequences. Specifically, the β1-adrenergic receptors have a crucial role in the regulation of heart rate and heart contractility and have been found to be a predictor of exercise capacity. Some of the SNPs that have been identified include twelve of the coding SNPs in the β1-adrenergic receptor gene and nine coding SNPs in the β2-adrenergic receptor gene (O'Shaughnessy & Sandilands, 2005). Ultimately, such pharmacogenetic variables can possibly impinge upon the pharmacokinetics and pharmacodynamics of drugs in the treatment of heart failure, and so the fundamental mechanisms of polymorphisms of β1-adrenergic receptor signalling pathway polymorphisms and their clinical significance will be reviewed in this report.
- Fundamental mechanisms of polymorphism of adrenergic receptor signalling pathway polymorphisms
Adrenergic receptors work as targets for adrenaline and noradrenaline, as well as various therapeutic agents, currently being used, agonists and antagonists. The human adrenergic receptors (AR) belong to the family of the cell surface receptors involved in carrying out signalling through coupling the guanine nucleotide binding proteins. As a family are made up of nine members or subtypes. These subtypes include α1A-, α1B-, α1DAR; α2A-, α2B-, α2CAR; and β1-, β2-, and β3AR. The classical coupling pathways for α1AR, α2AR, and βAR are through Gq, which results to the stimulation of phopholipase C, Gi, which causes adenylyl cyclase inhibition, and Gs, which causes adenylyl cyclase stimulation, respectively. β-adrenergic receptors mainly activate the Gs pathway, however, Gi pathway activation can also be implemented by β2-adrenergic receptors. In the human heart, there is an expression of β1 and β2 adrenergic receptors which take place at a ratio of about 75:25. The two subtypes are known to increase the force of cardiac contraction and frequency of heart rate. Desensitisation and downregulation of β-adrenergic cardiac receptors occurs in heart failure, and β1 receptor antagonism has been shown to improve the symptoms of heart failure to a great degree (Small, McGraw, & Liggett, 2003).
When catecholamines such as adrenaline and noradrenaline bind to β1-adrenergic receptors, the stimulatory G-protein (Gs) that is coupled to it, exchanges guanosine diphosphate (GDP) for guanosine triphosphate (GTP). This activates the G-protein and the Gs-GTP unit then detaches from the adrenergic receptor and attaches to adenylyl cyclase. Subsequently, cyclic adenosine monophosphate (cAMP) is produced, increasing intracellular levels. In this signalling cascade, the cAMP second messenger then activates protein kinase A or PKA that leads to protein phosphorylation implicated in cardiomyocyte function. In the Gi pathway, β2- adrenergic receptors are coupled to a Gi protein, and ligand binding results in GDP being exchanged for GTP instead. The Gi-GDP unit then inhibits the activation of adenylyl cyclase thereby inhibiting cAMP production (Ho, Iwatsubo, Vatner, 2010).
Polymorphism refers to the variability that takes place in the sequence of the deoxyribonucleic acid (DNA) affecting less that 1% of the population. Polymorphism is different from mutation in that mutations are very rare variants and may be the only cause of some of the inherited diseases such as cystic fibrosis. These mutations are very necessary in the manifestation of the disease (Mamotte, 2006). Most incidents of polymorphisms that have been reported take place in promoter, 5’UTR (untranslated region), introns, and 3’ UTR. Polymorphisms in these areas are more common than the coding polymorphisms. Out of the nine adrenergic genes, seven of them are known to have noncoding or non-synonymous polymorphism (Figure 1) (Small, McGraw, & Liggett, 2003).
Figure 1: The localization of polymorphisms that are non-synonymous in human adrenergic receptors (Small, McGraw, & Liggett, 2003)
For the β-adrenergic receptors, the polymorphism of the β1 receptors has a crucial role especially in patients with heart attack, as well as those who have a low response to β-blockers (Biaggioni & Garland, 2001). The gene that encode for the β1-adrenergic receptors has no introns and is located on the chromosome 10q24-26. Eight coding SNSPs have been identified as being non-synonymous and lead to a substitution of an amino acid. 145A>G and 1165C>G coding SNPs appear most frequently and cause alterations in the amino acid residues Serine49Glycine and Arginine389Glycine located in the amino and carboxyl terminal respectively (Baumann, Bramlage, Lutheri et al., 2000).
The Arg-389 receptor has been associated with greater agonist affinity, increased coupling to Gs and slightly greater basal levels of adenylyl cyclase activities than the Gly-389 receptor (Green, Mason, & Moor, 1999). The Arg389Gly substitution rests within a possible binding domain of the G-protein and is, therefore, most likely to be essential in the receptor G-protein coupling function. This effect of the Arg389Gly polymorphism has been shown in rodent studies. The resulting hyperactive signalling events lead to ventricular dysfunction and altered therapeutic response to β-blockade (Perez, et al., 2003). In other studies utilising a preparation of the human right-atrial, the cAMP and ionotropic responses to noradrenaline stimuli were recorded to be higher in subjects with Arg389 receptor when compared to the Gly389 variant also (Green, Mason, & Moor, 1999).
On the other hand, the gene that encodes for the β2-adrenergic receptor is located on chromosome 5q31-32 but is also intronless. Five coding SNPs that are synonymous and four coding SNPs that are non-synonymous have been identified. The coding SNPs that are non-synonymous are located at nucleotides 79(C>G), 46(A>G), and 491(C>T) and result in polymorphism of amino acid residues Glutamine27Glutamic acid and Arginine16Glycine on the N-terminus and Threonine164Isoleucine in the 4th intracellular loop (Brodde & Leineweber, 2005). The occurrence of the SNP located at position 100 (Val34Met) is very rare and has no functional effect that it causes (Liggett, 1999). In addition to these SNPs, other eight SNPs occur within the 5' flanking sequence (Scott, Swan, Wheatley, & Hall, 1999). There are reports showing the effects of this kind of polymorphism on the receptor coupling with the Ser49 variant having less activity than the Gly49 variant (Levin, Marullo, Muntaner, Andersson, & Magnusson, 2002).
- Clinical significance of polymorphisms of adrenergic receptor signalling pathway of polymorphisms
Heart failure is the most common syndrome results from a number of conditions affecting the heart such as hypertension, ischaemic heart disease, and dilated cardiomyopathy. The mortality rate for heart failure is currently high, with over 50% of patients suffering from severe heart failure dying every year (Cleland, Gemmell, Khand, & Boddy, 1999).
In conditions such as heart failure, β1- and β2-adrenergic receptors and the signalling cascade that accompany them are altered. The β2-AR is known to mediate vasodilation. However, in hypertension, there is an impairment of β2-AR stimulation. Desensitization of β2-AR is usually modulated by β2-AR SNPs, and through this vasodilator responsiveness; the various β2-AR variants may be involved in the development of hypertension or its maintenance. Other studies have reported no influence on hypertension development by the β2-AR variants, Gln27Glu or Arg16Gly (Brodde, 2008). There has been, however, an association that has been reported between hypertension and Ile164-β2-AR variant in women (Biolo, et al., 2008).
Out of the three β-adrenergic receptors that have been identified, β1, β2 and β3, the first two have been associated with an increased contractility, as well as heart rate (Gerhardstein, Puri, Chien, & Hosey, 1999). The β-adrenergic receptors signalling has a very crucial role that it plays in heart failure since the level of synthetic activity increases inversely in correlation with survival (Muthumala, Drenos, Elliott, & Humphries, 2008). Some of the destructive effects that may result from the β1AR signalling are myocyte growth, apoptosis, myopathy, fibroblast hyperplasia, proarrhythmia and fetal gene induction (Communal, Singh, Sawyer, & Colucci, 1999; Engelhardt, Hein, Wiesmann, & Lohse, 1999). In the heart failure conditions, the cardiac βARs are less responsive and may either cause down regulation or uncouple themselves from the Gs protein-adenylyl cyclase pathway (Bristow, et al., 1982).
There is credible experimental evidence that shows the role of polymorphism of the β-adrenergic receptors in the pathogenesis of heart failure. Consistent with the fact that βAR plays a role as disease modifier polymorphism of the ADRB may have an impact on the survival of those with heart failure. This is mainly enhanced by the fact that β1AR signalling contributes in a significant manner to the progression of cardiac dysfunction. A positive association has been reported in patients who have severe heart failure and genotyped for all the three β2-adrenergic receptor polymorphism (Liggett, et al., 1998). There is not any significant association that has been demonstrated on the Arg389Gly polymorphism on the hospitalization of survival of individuals with heart failure (Liggett, et al., 2006). However different subpopulations like East Asians with Gly389 homozygote have a higher risk of HF compared to Arg389 carrier while in the white population it states the opposite (Arg389 increases HF), and in the black population there is no trend between Heart failure and Arg389Gly polymorphism (Wang, Lu, Zhang, Chen, et al.,2010)
In a study conducted by Podlowski, patients with heart failure who were genotyped with a polymorphism of ADRB1 Ser49Gly, patients with Gly49 variant were in a greater risk of developing heart failure, as well as death, than patients with Ser49 variants. Ser49Ser homozygote was associated with less risk of heart failure compared to Gly49 carrier. When study were carried out in various racial descents; East Asians with Gly49 were also at higher risk of HF compared to Ser49 while, in White population, Ser49Gly polymorphisms has no association with HF (Podlowski, et al., 2000). Other studies have shown that the LC-Cys19, Gln27and Arg16 alleles were protective against heart failure progression (Perez, et al., 2003).
The polymorphism of the ADRB1 has also been found to predict the capacity of exercise in patients having heart failure. Patients with Arg389 homozygotes have been reported to have peak VO2 that is significantly higher than in patients with Gly389 homozygotes (Wagoner, et al., 2002). The results have been supported by data from a study conducted using patients having severe heart failure and genotyped for ADRB1 SNPs. The study demonstrated a peakVO2 level that was significantly higher in patients who were Arg389 homozygotes than in those who had Gly389 homozygotes (Sandilands, Parameshwar, Large, Brown, & O’Shaughnessy, 2005).
In addition, β1-49 and β1-389 genotypes have an effect on the manifestation of nonsustained ventricular tachycardia or NSVT especially in patients with heart failure. NSVT is one of the major problems that witnessed in clinical cardiology. As shown in Figure 2 below, heart failure patients with β1-389Gly allele have showed a significant effect on the NSVT occurrence. Those patients having homozygous β1-389Gly allele had a stronger effect than those having heterozygous β1-389Gly allele. There is no effect on the prevalence of NSVT that has been reported in patients with β1-Ser49Gly polymorphism (Biolo, et al., 2008).
Figure 2: Association existing between polymorphisms of adrenergic receptor and NSVT (Biolo, et al., 2008).
The heterogeneity of the response to treatment and heart failure phenotype is well recognized. The β-adrenergic receptors are involved in mediating both the cardiac responses to excessive sympathetic activity and exercise in patients with heart failure and thus contributing to cardiac remodelling. Although the functional polymorphism in the β-adrenergic receptors is not a causative factor responsible for heart failure, it is most likely that it has a modulatory capacity. The polymorphism may also influence the capacity to exercise and have an effect on the on arrhythmias. There are evidences suggesting that β2-adrenergic receptor variants are associated with the differences in lung functions, in patients with heart failure (Snyder, Turner, & Johnson, 2006).
In a study conducted to determine how β1-adrenoceptor arg189gly polymorphism impacts on heart-rate responses to either carvedilol or bisoprolol medications in elderly heart failure patients, it was been reported that those patients suffering sinus rhythm have a similar response to carvedilol and bisoprolol. Those patients who were suffering from atrial fibrillation and were homozygous for arg389 showed a reduced response to carvedilol than those had at least one Gly389 allele. The arg389gly polymorphism showed a huge impact on the response of heart-rate to carvedilol in patients having heart failure together with atrial fibrillation when compared to bisoprolol (Figure 3) (Rau, et al., 2012). Gene–dose interaction has also been reported with the patients carrying ADRB1–389 Arg/Arg genotype showing the need to have a higher beta-blockade dose in order to achieve the same response to those carrying ADRB1–389 Arg/Gly (Fiuzat, et al., 2013).
Figure 3: The mean heart rates taken at different clinical visits (a) sinus rhythm patients and (b) atrial fibrillation patients (Rau, et al., 2012).
- Conclusion
Incidents of cardiovascular diseases including heart failure are some of the leading cause of mortality and morbidity in most countries. SNPs in the genes that encode for adrenergic receptors have serious physiological and functional consequences to the body especially those with heart diseases. Through this review, β1-adrenergic receptors (ADRB) have been shown to have a crucial role in the regulation of heart rate, heart contractility and other heart functions. Some of the SNPs polymorphisms that have been identified include twelve of the coding SNPs in the β1-adrenergic receptor gene and nine coding SNPs in the β2-adrenergic receptor gene.
ADRB has been associated with an increased contractility, as well as heart rate. There is also credible experimental evidence that shows the role of polymorphism of the β-adrenergic receptors in the pathogenesis of heart failure. Increased understanding of the signalling pathway of β-adrenergic receptors and the mechanisms that are beneficial in the blockage of the β-adrenergic receptors will provide more information concerning the impact resulting from β-adrenergic receptor polymorphisms. Comparing treatment responses, atrial fibrillation patients with arg389gly polymorphism respond better to carvedilol treatment when compared to bisoprolol treatment.
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