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.
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There are 3 disease-related annotations for this variant. Register or sign in to see them.
VIP Variant in ADRB2
Gln27Glu is encoded by a common non-synonymous polymorphism (rs1042714) in the ADRB2 gene. The estimated frequency of the Glu isoform is 24.6% among Caucasians. 18.7% among Blacks and 9% among Chinese [Article:16142389]. Previous studies have suggested that the Glu27 isoform do not down-regulate of the expression of the beta2-AR [Article:7915137, 7598936]. Individuals who were homozygous for Glu27 had higher maximal venodilatation in response to isoproterenol than those who were homozygous for Gln27, suggesting that the Gln to Glu change is associated with increased agonist-mediated responsiveness [Article:11586955]. Impact of the ADRB2 polymorphisms on vascular responses to isoproterenol were studied with internal mammary arteries obtained from 96 patients undergoing coronary bypass surgery. The arteries from patients homozygous for Gly16 displayed reduced sensitivity to isoproterenol compared with those from patients carrying Arg16. Among the arteries from the Gly16 homozygotes, those from the patients homozygous for Glu27 showed isoproterenol sensitivity similar to the arteries from the Arg16 carriers [Article:17885618]. Thus, overall data suggest that the ADRB2 polymorphisms may influence vascular responses to a beta2-agonist. In addition, the Gln27 receptor has been associated with increases in systolic blood pressure [Article:15931235].
Several studies found that the beta2-AR mediated increases in heart rate and contractibility are not dependent on the amino acid changes at codons 16 and 27 [Article:19422376]. The polymorphism encoding the Gln27Glu change was not associated with the increased risk of sudden cardiac death and ventricular arrhythmias in patients with coronary artery disease [Article:18534365], nor is it associated with the risk of MI or ischemic stroke in patients who were pharmacologically treated for hypertension [Article:18219297]. The polymorphism has also been studied in heart failure. In a prospective cohort study with 80 patients with heart failure, those homozygous for Gln27 were less likely to have improved left ventricular ejection fraction after carvedilol treatment compared to Glu27 carriers [Article:12835612]. However, in another prospective cohort study with 199 heart failure patients, the this variant was not associated with the improvement of left ventricular ejection fraction or decrease in heart rate in response to a beta blocker [Article:15861037]. Nevertheless, the Gln27 isoform was associated with a lower risk of death or heart transplantation in idiopathic dilated heart failure [Article:15464701]. In addition, the Gln17 isoform, in the presence of the Gly16 and Ile164 variants were associated with decreased risk of MI [Article:15931235]. Thus, data on the role of this polymorphism in heart failure are conflicting. In a prospective cohort study involving 735 patients who were prescribed a beta-blocker after an acute coronary syndrome, patients homozygous for Gln27 had higher mortality rate (16%) compared to those heterozygous and homozygous for Glu27 (11% and 6%, respectively). In addition, those homozygous for both Arg16 and Gln27 were at higher risk for death in 3 years (3-year mortality rate 20%) compared to the other diplotypes (3-year mortality rate 6-11%) [Article:16189366]. Although these findings have not been replicated, the Arg16Gln27 diplotype is associated with higher mortality in patients who receive a beta blocker after acute coronary syndrome.
Association studies of the Gln27Glu variant and type 2 diabetes mellitus have yielded neutral [Article:12390345, 12077726, 17221209], positive [Article:10027586, 10323412], and contradictory [Article:11380082, 17150099] results in various populations. In a case-control study of 7,808 unrelated, middle-aged Caucasians, no association was found with obesity, hypertension and type 2 diabetes [Article:17221209]. However, in another case-control study of 400 non-obese subjects (body mass index<27kg/m2) and 108 obese subjects (body mass index> or =27kg/m2), the frequency of the Glu27 variant was higher in type 2 diabetics than non-diabetic subjects (0.14 vs 0.07, p=0.001, odds ratio 2.13, 95% confidence interval 1.34-3.41) [Article:10027586]. Conversely, in 342 type 2 diabetic patients and 305 unrelated non-diabetic controls, Glu27 homozygotes had a lower frequency of diabetes when compared to Gln27 carriers (odds ratio 0.56, 95% confidence interval 0.36-0.91) [Article:17150099]. A study in 1054 Swedish subjects with varying degrees of glucose tolerance had different findings. In 219 type 2 diabetic patients, the Gln27 variant was seen more frequently than in 237 matched non-diabetic subjects (59.8% vs 52.3%; OR=1.72, p=0.02). Glu27 homozygous individuals had the lowest prevalence of diabetes [Article:11380082]. In a case-control genetic association study of 161 healthy Caucasians and 74 African Americans, Gln27 homozygotes compared to Glu27 carriers tended toward higher insulin levels and greater insulin resistance as determined by HOMA-IR [Article:17512307]. Similarly, a cohort of 102 black South African women found that the Glu27 isoform was associated with higher insulin resistance among obese individuals [Article:18393130].
Homozygotes of the Gln27 variant in the presence of Arg16 had increased risk of obesity [Article:12900437], whereas the Glu27 was also associated with increased BMI in African Americans and Hispanic Americans [Article:15672110]. Another study reported that the Glu27 receptor was a risk factor for abdominal obesity among males, particularly among those with low HDL cholesterol [Article:12111048]. A meta-analysis of 23 populations reported variable association results across the different populations, with a summary odds ratio showing no association between this polymorphism and obesity [Article:19186333]. However, the prevalence of Glu27 ranged from 6.71% to 78.29% across the populations, so that the polymorphism encoding this isoform is significantly associated with obesity in race groups with low frequency of this allele such as Asians, Pacific Islanders and American Indians, but not European populations, in which this allele is highly prevalent.
A cohort of 1050 Caucasians were evaluated to determine if ADRB2 polymorphisms would predict the occurrence of metabolic abnormalities in hypertensive patients given a beta-blocker (atenolol 50-100mg or metoprolol 100-200mg daily) for 6 months. They found the Glu27 variant was associated with a higher incidence of dyslipidemia [Article:16027735], which has been found by other groups as well [Article:17671401] where heterozygous Gln27Glu hypertensive patients had an increase in triglyceride levels following use of 100mg metoprolol daily for 2months and also after use of propranolol in healthy individuals[Article:16082424]. These data are similar to others with others [Article:10886486, 11718682] who observed the same association of the Glu27 variant and hypertriglyceridemia.
| Key Publications: | |
|---|---|
| Drugs / Other Molecules |
Drug (4)
|
| Diseases | Acute coronary syndrome 6 Asthma 7 8 9 Heart Failure 10 |
| Phenotype | |
| Phenotype Datasets | Bronchodilator response to beta agonist in asthmatics |
Appendix
| Genomic Variant & GenBank ID: | 9,369,409 G>C on NT_029289 |
|---|---|
| mRNA Variant & GenBank ID: | 318 G>C on NM_000024.4 |
| Protein Variant & GenBank ID: | 27 Glu>Gln on NP_000015 |
| GoldenPath Position: | chr5:148,186,666 (hg18) |
Connected Drugs
| Evidence | Drug |
|---|---|
| atenolol | |
| carvedilol | |
| indacaterol | |
| isoproterenol | |
| losartan | |
| salbutamol | |
| terbutaline |
Connected Drug Classes
| Evidence | Drug Class |
|---|---|
| Variant Annotation, VIP Annotation | Beta Blocking Agents |
Connected Diseases
| Evidence | Disease |
|---|---|
| Acute coronary syndrome | |
| Asthma | |
| Heart Failure | |
| Pulmonary Disease, Chronic Obstructive |
Publications related to rs1042714 at chr5:148206473: 16
Cross-References
- UCSC Golden Path:
- chr5:148206473
- dbSNP:
- rs1042714
- ALFRED:
- SI000175N
- HapMap:
- rs1042714
- Seattle SNP:
- ADRB2-004298
Platform Availability
- Illumina