Clinical Annotations
To see the clinical annotation for this variant please register or sign in.
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 8 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 Ser49Gly polymorphism is located in the extracellular portion of the protein near the amino-terminus [Articles: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 [Articles: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 [Article: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 [Articles:11447084, 11854867, 16402084, 16907703]. In two studies, Ser49 homozygotes experienced a significantly greater blood pressure reduction than Gly carriers after treatment with metoprolol [Articles: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) [Articles: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 [Article: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 [Article: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 [Article: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 [Article: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 [Article: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 [Article: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) [Articles: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 [Article: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 [Article:16153393].
METABOLIC: The Gly49 allele was associated with greater increases in body mass in women 15 years post-partum [Article:15685248]. Conversely, the variant at codon 49 was not associated with body mass index, obesity, waist-to-hip ratio, or waist circumference [Article: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 [Article:11942593]. Variation at codon 49 was associated with low extraversion [Article:15312808].
The Ser49Gly variant has been shown to correlate (or not) with the phenotypes of hypertension, myocardial infarction, and beta-blocker responses to these conditions.
[Articles:12844134, 16189366, 15735607, 15864115, 15861037, 11052857, 16153393, 16402084, 16907703, 16815314, 15247626, 16421173]
| Key Publications: | |
|---|---|
| Drugs / Other Molecules |
Drug (5)
|
| Diseases | Acquired Long QT Syndrome (aLQTS) 18 Angina, Unstable 19 20 21 Cardiomyopathy, Dilated 22 23 Coronary Artery Disease Essential hypertension 24 25 26 27 Heart Failure Heart Failure 28 29 30 31 32 33 34 35 Hypertension Ischemia Myocardial Infarction Myocardial Ischemia Obesity 36 37 |
| 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
1. ADRB1:49 Ser>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 | |
| carvedilol | |
| diltiazem | |
| metoprolol | |
| verapamil |
Connected Drug Classes
Connected Diseases
Publications related to rs1801252 at chr10:115804036: 17
Cross-References
- UCSC Golden Path:
- chr10:115804036
- dbSNP:
- rs1801252
- HapMap:
- rs1801252
- JSNP:
- IMS-JST091025
- Seattle SNP:
- ADRB1-007862