Important Variant Information for ADRB1
Submitted by: Michael A. Pacanowski and Julie A. Johnson (PEAR)
Reviewed by: Scott T. Weiss (PHAT)
Submitted date: February 25, 2006
Revised: February 12, 2007
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There are Two Important Variants for ADRB1.
| Gene HGNC Name: | ADRB1 |
|---|---|
| Variant Summary: | The Ser49Gly polymorphism is located in the extracellular portion of the protein near the amino-terminus [PMID: 10093986, 10477438]. In vitro studies are not consistent with regard to the effect of this variant on adenylyl cyclase activity or cAMP accumulation in the presence of agonists or antagonists. However, greater agonist-promoted down-regulation in cells expressing the Gly49 allele is well characterized, and is potentially a result of altered N-glycosylation. Additionally, the sensitivity to inhibition by metoprolol may be greater in cells expressing the Gly49 allele [PMID: 12034720, 11791000, 15247626]. Cardiac inotropy and lusitropy, however, did not differ by codon 49 genotype in atrial isolates treated with norepinephrine ex vivo, with or without consideration given to previous beta-blocker use by the donor patient [PMID: 12383575]. The estimated minor allele frequencies/ heterozygosity of Ser49Gly (A145G) among different racial/ ethnic groups based on the literature to date are as follows: white 12-16%/ 21-28%, black 23-28%/ 36%, Hispanic 20-21%/ 33%, and Asian 14%/ 23%. This variant is commonly referred to as 145 A>G on the mRNA sequence. This positional numbering is relative to the start of the coding sequence. HYPERTENSION: The Ser49Gly polymorphism does not appear to be associated with hypertension, although the Gly49 genotype was associated with lower resting heart rate in hypertensive patients, independent of beta-blocker therapy [PMID: 11447084, 11854867, 16402084, 16907703]. In two studies, Ser49 homozygotes experienced a significantly greater blood pressure reduction than Gly carriers after treatment with metoprolol [PMID:12844134, 16815314]. Haplotype analysis of the variants at codons 49 and 389 revealed that those with the Gly49Arg389/Ser49Gly389 diplotype were virtually unresponsive to metoprolol, whereas the greatest response was observed in subjects with the Ser49Arg389/Ser49Arg389 diplotype (other diplotypes were intermediate) [PMID: 12844134, 16815314]. The negative chronotropic response to metoprolol was not influenced by the Gly49 variant in untreated hypertensive patients after adjustment for plasma S-metoprolol concentrations [PMID: 16402084]. CORONARY ARTERY DISEASE:The Gly49 allele was nonsignificantly associated with lower resting heart rate in patients undergoing cardiac stress testing, but did not influence exercise-induced changes in hemodynamic parameters [PMID: 16210433]. Aerobic performance (oxygen uptake) was greater in patients with haplotypes containing the Gly49 allele, although the response to physical training was not significantly different [PMID: 16421173]. The Ser49Gly polymorphism did not alter the risk of mortality among patients treated with beta-blockers who were followed for three years after myocardial infarction [PMID: 16189366]. HEART FAILURE: The codon 49 polymorphism does not appear to be a risk factor for developing heart failure, but may be associated with drug response and outcomes [PMID: 16188498]. The Ser49 allele was associated with a relatively greater need for adjustment of concomitant heart failure medications during the initial titration phase of metoprolol succinate, but variation at this locus did not influence drug tolerability, the dose of metoprolol achieved, changes in the 6-minute walk, or quality of life [PMID: 15735607]. Left ventricular end diastolic diameter reduction was significantly greater in Gly49 carriers despite acheiving similar heart rates and doses of metoprolol as Ser49 homozygotes. However, the polymorphism did not influence the change in ejection fraction following the initiation of a beta-blocker (metoprolol, carvedilol or bisoprolol) [PMID: 15864115, 15861037]. The Ser49 allele was associated with poorer clinical outcomes in heart failure patients. Hospitalization or death rates at five years were significantly lower for patients carrying the variant allele, particularly those treated with beta-blockers, when compared to patients with the wild-type allele not receiving beta-blockers, who had the least favorable prognosis. Consistent with this, variant carriers that were not treated with beta-blockers had a similar prognosis as Ser49 homozygotes that did receive these drugs [ PMID: 11052857]. Additionally, the variant allele was also associated with improved survival at five years in idiopathic dilated cardiomyopathy patients receiving lower beta-blocker doses. At higher doses the gene effect disappeared, suggesting that patients with the wild-type allele may require higher doses to derive any survival benefit. Ser49 homozygotes also tended to require higher beta-blocker doses than variant carrier to achieve similar heart rates [ PMID: 16153393]. METABOLIC: The Gly49 allele was associated with greater increases in body mass in women 15 years post-partum [PMID: 15685248]. Conversely, the variant at codon 49 was not associated with body mass index, obesity, waist-to-hip ratio, or waist circumference [PMID: 15917856]. MISCELLANEOUS: The codon 49 polymorphism was not associated with acquired long QT syndrome or Torsades de Pointes in patients treated with QT-prolonging drugs [PMID: 11942593]. Variation at codon 49 was associated with low extraversion [PMID: 15312808]. |
| Key PubMed IDs: | 12844134, 16189366, 15735607, 15864115, 15861037, 11052857, 16153393, 16402084, 16907703, 16815314, 15247626, 16421173 |
| Genomic Variant & GenBank ID: | 34,552,562 A>G on NT_030059 |
| mRNA Variant & GenBank ID: | 231 A>G on NM_000684 |
| Protein Variant & GenBank ID: | 49 Ser>Gly on NP_000675 |
| dbSNP rs#: | rs1801252 |
| GoldenPath Position: | chr10:115,794,026 (hg18) |
| Key Drugs/Substrates: | Beta adrenergic antagonists [PMID: 12844134, 16189366, 15735607, 15864115, 15861037, 11052857, 16153393, 16815314, 16402084], Metoprolol [PMID: 12844134, 15735607, 15864115, 16402084, 16815314], Carvedilol [PMID: 15861037], Bisoprolol [PMID: 15861037], Xenobiotics [PMID:11942593] |
| Key Phenotypes/Diseases: | Hypertension, Essential Hypertension [PMID: 16815314, 11447084, 11854867, 16402084], Myocardial Infarction, Coronary Arteriosclerosis, Ischemia, Myocardial Ischemia, Angina, Unstable [PMID: 16189366, 11704005, 16421173], Heart Failure, Heart Failure, Congestive [PMID: 11052857, 15735607, 15864115, 15861037, 16187973, 16188498, 10794544, 16153393], Idiopathic Dilated Cardiomyopathy [PMID: 10794544, 16153393], Acquired Long QT Syndrome (aLQTS) [PMID: 11942593], Obesity [PMID: 15685248, 15917856] |
| Phenotype Data Sets: | "Survival of patients on beta-blockers after ACS, and ADRB1, ADRB2" (PA140715199), "Genetic Epidemiology of Responses to Antihypertensives (GERA)" (PA134686741), "Cold Pressor Test (CPT) measurements of twins" (PA129966516). The Ser49Gly variant has been shown to correlate (or not) with the phenotypes of hypertension, myocardial infarction, and beta-blocker responses to these conditions. PMID: 12844134, 16189366, 15735607, 15864115, 15861037, 11052857, 16153393, 16402084, 16907703, 16815314, 15247626, 16421173 |
| Gene HGNC Name: | ADRB1 |
|---|---|
| Variant Summary: | The Arg389Gly polymorphism is located in the cytoplasmic tail in the G-protein coupling domain [PMID: 10093986, 10212248, 10336842, 10477438]. In vitro studies of the codon 389 variant indicate that basal and agonist-simulated adenylyl cyclase activity is higher with the Arg389 allele as a result of enhanced coupling to Gs. The higher level of activity relative to the Gly389 allele is maintained even in the face of agonist-promoted desensitization [PMID: 10212248, 12525504, 16844790]. A later, haplotype-based study did not confirm the differential effect of this polymorphism on basal adenylyl cyclase activity, attributing such changes to the codon 49 variant [PMID: 15247626]. Cardiac inotropy and lusitropy also did not differ consistently by codon 389 genotype in atrial isolates treated with norepinephrine ex vivo, with or without consideration given to previous beta-blocker use by the donor patient [PMID: 12383575, 12540530]. However, ventricular explants from Arg389 homozygotes with and without heart failure demonstrated greater contractile force in response to isoproterenol. More importantly, bucindolol acted as an inverse agonist rather than a partial agonist in the Arg389 hearts, suggesting genotype-dependent activity [PMID: 16844790]. The estimated minor allele frequencies/ heterozygosity of Arg389Gly (C1165G) among different racial/ ethnic groups, based on the literature to date, are as follows: white 24-34%/ 35-42%, black 39-46%/ 44-53%, Hispanic 31-33%/ 41-42%, and Asian 20-30%/ 30-39%. HYPERTENSION: The Arg389 allele was associated with hypertension in case-control studies, and it was observed in a discordant sib-pair study that diastolic blood pressures and heart rates were significantly higher among Arg389 homozygotes [PMID: 11447084, 15055253, 16210433, 16907703]. The association with resting heart rate was not reproduced in treated or untreated hypertensives [PMID: 11854867, 16402084]. Four studies demonstrated a significant effect of this polymorphism on the blood pressure response to beta-blockade [PMID: 12844134, 12709726, 14534524, 16815314]; one study did not support such an effect [PMID: 11787477]. Blood pressure responses to metoprolol and atenolol were significantly greater among Arg 389 homozygotes when compared to variant carriers, with a three-fold difference described in one study [PMID: 12844134, 12709726, 14534524, 16815314]. Haplotype analysis of the variants at codons 49 and 389 revealed that virtually no response was apparent in those with the Gly49Arg389/Ser49-Gly389 diplotype, whereas the greatest response was observed in subjects with the Ser49Arg389/Ser49Arg389 diplotype (other diplotypes were intermediate) [PMID: 12844134, 16815314]. The negative chronotropic response to metoprolol was not influenced by the Gly389 variant in untreated hypertensive patients after adjustment for plasma S-metoprolol concentrations [PMID: 16402084]. Additionally, the extent to which beta-blockers blunt exercise-induced changes in hemodynamic parameters may also differ based on genotype [PMID: 14534524, 12709726]. The influence of this polymorphism on the antihypertensive response to hydrochlorothiazide has also been studied with no demonstrable effect [PMID: 15864129, 14553962], but increases in total cholesterol subsequent to administration of hydrochlorothiazide were predicted by heterozygosity at codon 389 (relative to Arg389 homozygotes) [PMID: 16109321]. CORONARY ARTERY DISEASE: Resting heart rate and blood pressure appeared to be higher in Arg389 carriers undergoing stress testing, while the change in systolic blood pressure during exercise was greater for Gly389 carriers [PMID: 11704005, 16210433]. Carriers of the variant were also less likely to have extrasystoles compared to noncarriers during stress testing [PMID: 16210433]. Aerobic performance and response to physical training did not differ by codon 389 genotype [PMID: 16421173]. A case-control study of patients with dyslipidemia did not identify any significant genotype effect for cardiovascular events at five years [PMID: 12090746]. The codon 389 polymorphism did not alter the risk of mortality in patients receiving beta-blockers who were followed for three years after myocardial infarction [PMID: 16189366]. HEART FAILURE: The Arg389 genotype alone was not associated with the risk for heart failure, although when considered in the presence of another polymorphism in the beta2C adrenergic receptor (ADRA2C), a multiplicative association was identified [PMID: 12374873, 15342173, 16188498]. This effect was identified only in black patients due to the limited number of white patients that were polymorphic at both loci [PMID: 12374873]. In patients with heart failure, the Gly389 allele was associated with lower resting systolic blood pressure and diminished exercise capacity [PMID: 12422153]. In one study, the Arg389Gly polymorphism did not influence heart rate, systolic blood pressure response, or improvement in left ventricular ejection fraction in heart failure patients initiated on carvedilol or bisoprolol [PMID: 15861037]. In contrast, other studies demonstrated significantly greater improvements in left ventricular ejection fraction in Arg389 homozygotes treated with carvedilol relative to variant homozygotes [PMID: 14502278]. In addition to favorable changes in ejection fraction, left ventricular end systolic and diastolic diameters improved to a greater extent among Arg389 homozygotes treated with metoprolol succinate as compared to variant carriers, in whom no change or an increase was observed [PMID: 15864115]. The codon 389 genotype did not influence the tolerability of metoprolol succinate during the initial titration phase, though patients with the Arg389 genotype experienced a higher rate of decompensation, as indicated by the need for adjustment of concomitant heart failure medications. Beta-blocker-induced changes in the 6-minute walk, quality of life, or the dose of metoprolol achieved did not differ between genotypes [PMID: 15735607]. The polymorphism at codon 389 did not appear to influence baseline hemodynamic parameters or clinical outcomes (death or hospitalization) in heart failure patients treated with extended-release metoprolol [PMID: 12921807]. However, a significant survival advantage was observed in heart failure patients that were homozygous for Arg389 receiving bucindolol. The mortality and hospitalization rates of these patients were significantly better than Gly389 carriers receiving bucindolol, and all patients receiving placebo [PMID: 16844790]. This polymorphism was not associated with idiopathic dilated cardiomyopathy, disease severity, or the development of heart failure [PMID: 10336842, 10794544, 15464701, 16187973]. The effect of the Arg389 variant on five-year mortality in idiopathic dilated cardiomyopathy patients was not significant. However, a modest but significant increase in mortality risk was observed in Gly389 carriers receiving lower dose beta-blocker therapy [PMID: 16153393]. A lower odds of ventricular tachycardia was also observed in variant carriers with idiopathic dilated cardiomyopathy [PMID: 12197595]. MISCELLANEOUS CARDIOVASCULAR: No difference in cardiovascular response to exercise between codon 389 genotypes in healthy subjects has been described, with or without beta-blocker administration [PMID: 11337935, 11337934, 16402084]. Gly389 homozygotes with renal failure were found to have significantly higher left ventricular mass [PMID: 12455717]. Plasma renin activity, heart rate, and contractility increased in response to dobutamine infusion to a significantly greater extent in Arg389 homozygotes than Gly389 homozygotes. Bisoprolol significantly attenuated these effects in Arg389 homozygotes, while systolic and diastolic blood pressure responses were not significantly different [PMID: 16325050]. Another study demonstrated that the inotropic actions of dobutamine (fractional shortening) were significantly enhanced in healthy individuals not carrying the Gly389 polymorphism, as was the systolic blood pressure response, while no difference in heart rate responses was observed [PMID: 15564877]. The codon 389 polymorphism was not associated with acquired long QT syndrome or Torsades de Pointes in patients treated with QT-prolonging drugs [PMID: 11942593]. In patients with obstructive sleep apnea, the polymorphism was not associated with any hemodynamic variable at baseline; however, after initiation of continuous positive airway pressure therapy, the heart rate decreased to a significantly greater extent in patients with Arg389 genotype compared with the other genotypes [PMID: 16122377]. METABOLIC: The codon 389 variant was not associated with body mass index (BMI), longitudinal changes in body mass index, obesity, waist-to-hip ratio, or waist circumference [PMID: 15833937, 15685248, 15917856]. An earlier study suggested that this variant might be associated with weight and fat mass [PMID: 12032746]. Polymorphisms in ADRB2 and ADRB3 may interact with the codon 389 variant as described in one study evaluating longitudinal changes in body mass index [PMID: 15833937 ]. No difference in allele frequencies between lean and obese children has been documented [PMID: 15479221]. The codon 389 genotype did not affect dobutamine- stimulated lipolysis [PMID: 11753577]. NEUROLOGIC/ PSYCHIATRIC: Susceptibility to Alzheimer's disease was greater in Arg389 homozygotes that were also variant homozygotes at position 825 of GNB3 [PMID: 15212839]. Variation at codon 389 was not associated with extraverted behavior, unlike the codon 49 variant [PMID: 15312808]. Antidepressant responses in the context of the codon 389 polymorphism suggested less improvement in Gly389 carriers, although this finding was not significant after correction for multiple comparisons [PMID: 12815745]. |
| Key PubMed IDs: | 16109321, 15864129, 14553962, 12844134, 12709726, 14534524, 11787477, 16189366, 15861037, 14502278, 15864115, 15735607, 12921807, 16153393, 12815745, 16402084, 16815314, 16844790, 16421173 |
| Genomic Variant & GenBank ID: | 1165 C>G on AF169007 |
| mRNA Variant & GenBank ID: | 1251 C>G on NM_000684 |
| Protein Variant & GenBank ID: | 389 Arg>Gly on NP_000675 |
| dbSNP rs#: | rs1801253 |
| GoldenPath Position: | chr10:115,795,046 (hg18) |
| Key Drugs/Substrates: | Beta adrenergic antagonists [PMID: 11787477, 12844134, 12709726, 14534524, 16189366, 14502278, 16815314, 16844790, 15864115, 15735607, 12921807, 16153393, 16402084], Atenolol [PMID: 11787477, 12709726], Metoprolol [PMID: 12844134, 15735607, 15864115, 16402084, 14534524, 16815314, 12921807], Hydrochlorothiazide [PMID: 15864129, 14553962, 16109321], Carvedilol [PMID: 15861037], Bisoprolol [PMID: 15861037, 16844790, 16325050], Xenobiotics [PMID: 11942593], Beta adrenergic agonists [PMID: 11753577, 16325050, 15564877], Dobutamine [PMID: 11753577, 16325050, 15564877], Antidepressants [PMID: 12815745] |
| Key Phenotypes/Diseases: | Hypertension, Essential Hypertension [PMID: 11447084, 15055253, 16210433, 11854867, 12709726, 12844134, 14534524, 15864129, 14553962, 16109321, 16402084, 16815314, 11787477], Myocardial Infarction, Coronary Arteriosclerosis, Ischemia, Myocardial Ischemia, Angina, Unstable [PMID: 12090746, 16210433, 16189366, 16421173, 11704005], Heart Failure, Heart Failure, Congestive [PMID: 12374873, 15342173, 15861037, 14502278, 15864115, 15735607, 12921807, 10336842, 10794544, 16153393, 12197595, 16844790, 16187973], Obesity [PMID: 15685248, 15917856, 15833937, 12032746, 15833937, 15479221], Sleep Apnea, Obstructive [PMID: 16122377], Depression [PMID: 12815745], Alzheimer Disease [PMID: 15212839], Acquired Long QT Syndrome (aLQTS) [PMID: 11942593] |
| Phenotype Data Sets: | "Survival of patients on beta-blockers after ACS, and ADRB1, ADRB2" ( PA140715199), "Genetic Epidemiology of Responses to Antihypertensives" (GERA) ( PA134686741), "Cold Pressor Test (CPT) measurements of twins" ( PA129966516). The Arg389Gly variant has been shown to correlate with the phenotypes of hypertension, myocardial infarction, and beta-blocker responses to these conditions. PMID: 12844134, 12709726, 14534524, 11787477, 15864129, 14553962, 16109321, 16189366, 15861037, 14502278, 15864115, 15735607, 12921807, 16153393, 16815314, 16844790, 16402084 |