Clinical Annotations
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Variant Annotations
PharmGKB variant annotations provide information about variant-drug pairs based on individual PubMed publications. Each annotation represents information from a single paper and the goal is to report the information that the author states, not an interpretation of the paper. The PMID for supporting PubMed publications is found in the "Evidence" field.
Information presented, including study size, allele frequencies and statistics is taken directly from the publication. However, if the author does not correct p-values in cases of multiple hypotheses, curators may apply a Bonferroni correction. Curators attempt to report study size based on the actual number of participants used for the calculation of the association statistics, so the number may vary slightly from what is reported in the abstract of the paper. OMB Race Category information is derived from the paper and mapped to standardized categories. Category definitions may be found by clicking on the "OMB Race Category" link.
There are 13 annotations for this variant. Register or sign in to see them.
There are 2 disease-related annotations for this variant. Register or sign in to see them.
VIP Variant in ADRB1
The Arg389Gly polymorphism is located in the cytoplasmic tail in the G-protein coupling domain [Articles: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 [Articles: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 [Article: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 [Articles: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 [Article: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 [Articles:11447084, 15055253, 16210433, 16907703]. The association with resting heart rate was not reproduced in treated or untreated hypertensives [Articles:11854867, 16402084]. Four studies demonstrated a significant effect of this polymorphism on the blood pressure response to beta-blockade [Articles:12844134, 12709726, 14534524, 16815314]; one study did not support such an effect [Article: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 [Articles: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) [Articles: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 [Article:16402084]. Additionally, the extent to which beta-blockers blunt exercise-induced changes in hemodynamic parameters may also differ based on genotype [Articles:14534524, 12709726]. The influence of this polymorphism on the antihypertensive response to hydrochlorothiazide has also been studied with no demonstrable effect [Articles:15864129, 14553962], but increases in total cholesterol subsequent to administration of hydrochlorothiazide were predicted by heterozygosity at codon 389 (relative to Arg389 homozygotes) [Article: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 [Articles:11704005, 16210433]. Carriers of the variant were also less likely to have extrasystoles compared to noncarriers during stress testing [Article:16210433]. Aerobic performance and response to physical training did not differ by codon 389 genotype [Article:16421173]. A case-control study of patients with dyslipidemia did not identify any significant genotype effect for cardiovascular events at five years [Article: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 [Article: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 beta{~}2C~ adrenergic receptor (ADRA2C), a multiplicative association was identified [Articles: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 [Article:12374873]. In patients with heart failure, the Gly389 allele was associated with lower resting systolic blood pressure and diminished exercise capacity [Article: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 [Article:15861037]. In contrast, other studies demonstrated significantly greater improvements in left ventricular ejection fraction in Arg389 homozygotes treated with carvedilol relative to variant homozygotes [Article: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 [Article: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 [Article: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 [Article: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 [Article:16844790]. This polymorphism was not associated with idiopathic dilated cardiomyopathy, disease severity, or the development of heart failure [Articles: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 [Article:16153393]. A lower odds of ventricular tachycardia was also observed in variant carriers with idiopathic dilated cardiomyopathy [Article: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 [Articles:11337935, 11337934, 16402084]. Gly389 homozygotes with renal failure were found to have significantly higher left ventricular mass [Article: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 [Article: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 [Article:15564877]. The codon 389 polymorphism was not associated with acquired long QT syndrome or Torsades de Pointes in patients treated with QT-prolonging drugs [Article: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 [Article: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 [Articles:15833937, 15685248, 15917856]. An earlier study suggested that this variant might be associated with weight and fat mass [Article: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 [Article:15833937]. No difference in allele frequencies between lean and obese children has been documented [Article:15479221]. The codon 389 genotype did not affect dobutamine\- stimulated lipolysis [Article:11753577].
NEUROLOGIC/ PSYCHIATRIC: Susceptibility to Alzheimer's disease was greater in Arg389 homozygotes that were also variant homozygotes at position 825 of GNB3 [Article:15212839]. Variation at codon 389 was not associated with extraverted behavior, unlike the codon 49 variant [Article: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 [Article:12815745].
The Arg389Gly variant has been shown to correlate with the phenotypes of hypertension, myocardial infarction, and beta-blocker responses to these conditions.
[Articles:12844134, 12709726, 14534524, 11787477, 15864129, 14553962, 16109321, 16189366, 15861037, 14502278, 15864115, 15735607, 12921807, 16153393, 16815314, 16844790, 16402084]
| Key Publications: | |
|---|---|
| Drugs / Other Molecules | |
| Diseases | Acquired Long QT Syndrome (aLQTS) 38 Alzheimer Disease 39 Angina, Unstable 40 41 42 43 44 Coronary Artery Disease Depression 45 Essential hypertension 46 47 48 49 50 51 52 53 54 55 56 57 58 Heart Failure Heart Failure 59 60 61 62 63 64 65 66 67 68 69 70 71 Hypertension Ischemia Myocardial Infarction Myocardial Ischemia Obesity 72 73 74 75 76 Sleep Apnea, Obstructive 77 |
| Phenotype Datasets |
Cold Pressor Test (CPT) measurements of twins Genetic Epidemiology of Responses to Antihypertensives (GERA) Survival of patients on beta-blockers after ACS, and ADRB1, ADRB2 |
Appendix
2. ADRB1:389Arg>Gly
| 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 |
| GoldenPath Position: | chr10:115,795,046 (hg18) |
Connected Drugs
| Evidence | Drug |
|---|---|
| atenolol | |
| bisoprolol | |
| bucindolol | |
| carvedilol | |
| diltiazem | |
| dobutamine | |
| hydrochlorothiazide | |
| losartan | |
| metoprolol | |
| muraglitazar | |
| verapamil |
Connected Drug Classes
Connected Diseases
Publications related to rs1801253 at chr10:115805056: 23
Cross-References
- UCSC Golden Path:
- chr10:115805056
- dbSNP:
- rs1801253
- HapMap:
- rs1801253
- Seattle SNP:
- ADRB1-008882
Platform Availability
- Illumina