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 9 annotations for this variant. Register or sign in to see them.
There are 5 disease-related annotations for this variant. Register or sign in to see them.
VIP Variant in ADRB2
Arg16Gly is encoded by a common non-synonymous polymorphism in the ADRB2 gene. The estimated frequency of the Arg16 variant is 39.3% in white Americans, 49.2% in blacks Americans, and 51.0% among Chinese [Article:16142389]. In vitro studies using Chinese hamster fibroblasts showed that the Gly16 receptor had an enhanced agonist-promoted downregulation relative to Arg16 [Article:7915137]. Similar findings were reported for human smooth muscle cells [Article:7598936]. Due to the functional significance as well as the prevalence of the Arg16Gly variant, it has been the focus of many clinical studies on asthma and cardiovascular diseases. Three meta-analyses have shown that the Arg16Gly variant is not associated with asthma [Article:15153795, 15867853, 15987731]. However, the allele encoding Gly16 has been associated with nocturnal asthma and with severe asthma [Article:15987731]. Pharmacogenetic studies have observed an association between this polymorphism and response to beta2-agonists. Several studies have shown that homozygotes of Arg16 are more likely to respond (more rapid response and increased forced expiratory volume in one second (FEV1)) to albuterol (a short acting beta2-agonist (SABA)) compared to homozygotes of Gly16 and heterozygotes [Article:9399966, 10340917, 15557128]. One study observed this association only in response to high doses of SABA [Article:18569231]. Other investigations, however, found no association between this SNP and variable drug response [Article:15976384, 16931635, 16596417] while some groups reported contradictory results [Article:10984540, 10934093, 16263254]. Subjects who are homozygous for Arg16 and receiving regular albuterol treatment reported to have decreased response, measured by lower morning peak flow rates (PEFR), compared with those who were not receiving regular albuterol treatment, suggesting that regular albuterol therapy may not be appropriate for Arg16 homozygous asthma patients [Article:15500895].
The Arg16Gly amino acid substitution has been shown to influence agonist-mediated vascular response. The allele encoding the Arg16 receptor was associated with enhanced isoproterenol-mediated vascular desensitization in a study involving 26 healthy volunteers [Article:11586955]. This prospective study suggests that this isoform is an important determinant of the vascular response to stress [Article:11586955]. In addition, effects of common beta2-AR haplotypes on vascular responses to a beta2-agonist have been studied in 35 healthy volunteers [Article:16153394]. In this study, the Arg16 receptor showed higher sensitivity to terbutaline than the Gly16 isoform at baseline. After terbutaline treatment for 2 weeks, the extent of desensitization of venous beta2-AR differs by haplotype; Arg16Gln27Thr164 has the greatest desensitization while Gly16Glu27Thr164 showed the lowest desensitization [Article:16153394]. However, these studies involved a small number of healthy volunteers who may have different physiology from that of patients with cardiovascular disease. In addition, this study did not randomize the treatment sequence to minimize the effects of the time. In another study, the Arg16 isoform was associated with higher peak oxygen consumption (peak VO2) compared to Gly16 in 118 heart failure patients [Article:10785504]. However, in another cohort study of 199 patients with stable congestive heart failure, the Arg16 isoform was not associated with improvement of left ventricular ejection fraction and decrease in heart rate in response to a beta blocker [Article:15861037]. In a cohort study with 171 idiopathic dilated heart failure patients, the Arg16 isoform was associated with lower risk of death or heart transplantation compared with the Gly16 [Article:15464701]. However, these findings have not been replicated. In fact, studies have produced conflicting results regarding an association between beta2-AR haplotypes and death or heart transplantation in stable heart failure. While homozygosity for Arg16Gln27 haplotype was associated with an increased risk of death or heart transplantation in a prospective cohort study involving 227 patients [Article:17223428], no beta2-AR haplotypes were associated with the outcomes in another prospective cohort study of 637 patients [Article:18702968]. The studies evaluating intermediate or clinical outcomes have relatively small sample sizes and have different rates of background medications such as angiotensin-converting enzyme inhibitors and beta blockers for heart failure, which may account in part for the conflicting results.
Association studies of the Arg16Gly substitution with type 2 diabetes mellitus [Article:12077726] and risk factors such as obesity, hypertension and insulin resistance have also reported conflicting results. A nominal association with the Arg16 variant in type 2 diabetes was found in a case-control study of 7,808 unrelated, middle-aged Caucasians [Article:17221209]. In another study of 130 Taiwanese patients with type 2 diabetes matched 1:1 for gender, age, and body mass index (BMI), two copies of the Arg16 isoform was an independent risk factor for development of type 2 diabetes and was associated with earlier disease onset [Article:12390345]. However, there are other studies reporting Gly16 as the risk variant. The affect of this polymorphism on insulin secretion was studied in a cohort of 47 Japanese type 2 diabetic patients. Gly16 homozygotes had significantly higher levels of fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR) compared with the Arg16 homozygotes [Article:14693408]. These findings are in agreement with similar studies where the Gly16 isoform was associated with higher insulin resistance in non-obese, normotensive Japanese individuals [Article:16054001]. Likewise, conflicting associations have been reported for hypertension risk among type 2 diabetic patients, with some groups reporting increased risk of hypertension associated with Arg16 [Article:11358945] and others reporting associations with the Gly16 isoform [Article:12900437]. Finally, several studies have reported increased BMI correlated with the Arg16 isoform [Article:10027586, 10027586, 11016907, 11016907, 12900437], while other studies found a protective effect of the same allele [Article:11358945, 12390345]. A meta-analysis of 11 populations from previous studies reported no association between the polymorphism encoding Arg16 and obesity [Article:19186333].
Previous studies have suggested that the Arg16Gly variant may be associated with cholesterol metabolism in certain populations. A study of 100 hypertriglyceridemia cases and 241 healthy controls, from a population of Chinese Han demonstrated that controls who were homozygous for the Arg16 isoform had higher serum triglycerides. In hypertriglyceridemia patients, Arg16 homozygotes had higher serum total cholesterol and low-density lipoprotein cholesterol levels (207.27 +/-28.62 mg/dL vs. 184.46 +/-41.38 mg/dL,P<0.05; 117.17 +/-27.07 mg/dL vs. 92.03 +/-42.54 mg/dL,P<0.05) [Article:18247304].
The impact of the Arg16Gly amino acid substitution on other cardiovascular outcomes such as sudden cardiac death, ventricular arrhythmias, myocardial infarction and stroke has also been studied. Case-control studies reported no association between this polymorphism and the above mentioned phenotypic outcomes [Article:18219297, 18534365]. Although these case control studies have relatively large sample sizes (495-5393), they may have been confounded by unmeasured factors. Overall, data on the association of the Arg16Gly isoform with clinical outcomes in cardiovascular diseases are not consistent. Therefore, more studies involving larger sample sizes and a better design are needed to define the roles of this polymorphism in cardiovascular diseases.
| Key Publications: | |
|---|---|
| Drugs / Other Molecules |
Drug (4)
|
| Diseases | Asthma 5 6 7 Heart Failure 8 9 |
| Phenotype | |
| Phenotype Datasets | Bronchodilator response to beta agonist in asthmatics |
Appendix
| Genomic Variant & GenBank ID: | 9,369,376 A>G on NT_029289 |
|---|---|
| mRNA Variant & GenBank ID: | 285 A>G on NM_000024.4 |
| Protein Variant & GenBank ID: | 16 Arg>Gly on NP_000015 |
| GoldenPath Position: | chr5:148,186,633 (hg18) |
Connected Drugs
| Evidence | Drug |
|---|---|
| atenolol | |
| budesonide | |
| formoterol | |
| indacaterol | |
| isoproterenol | |
| losartan | |
| risperidone | |
| salbutamol | |
| salmeterol | |
| terbutaline |
Connected Drug Classes
| Evidence | Drug Class |
|---|---|
| Variant Annotation, VIP Annotation | Beta Blocking Agents |
| Variant Annotation | corticosteroids |
Connected Diseases
| Evidence | Disease |
|---|---|
| Asthma | |
| Heart Failure | |
| Pulmonary Disease, Chronic Obstructive | |
| Schizophrenia |
Publications related to rs1042713 at chr5:148206440: 18
Cross-References
- UCSC Golden Path:
- chr5:148206440
- dbSNP:
- rs1042713
- ALFRED:
- SI000366P
- HapMap:
- rs1042713
- Seattle SNP:
- ADRB2-004265
Platform Availability
- Illumina