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 1 annotations for this variant. Register or sign in to see them.
VIP Variant in ADRB2
As mentioned in an earlier section, the Thr164Ile variant is less common than the Arg16Gly and Gln27Glu amino acid changes. The estimated frequency of the allele encoding the Ile164 isoform is 1% in Caucasians, less than 2% in Africans, and nonpolymorphic in Chinese [Article:16142389]. Receptors containing the Ile164 variant showed a substantial decrease in basal and epinephrine-stimulated adenylyl cyclase activities due to defective coupling of the receptor to the stimulatory G protein, Gs, and impaired agonist-promoted sequestration. Ile164 also displayed a lower binding affinity for epinephrine as compared with the wild-type beta2-AR [Article:7901205]. Consequently, this amino acid change has been associated with reduced response to the long-acting beta2-agonist salmeterol [Article:7901205, 11516429].
In vivo studies found that an increase in heart rate and contractibility mediated by beta2-AR in response to terbutaline is blunted in subjects heterozygous for Ile164 compared with those homozygous for Thr164 [Article:11222464]. A potential association between the Ile164 variant and hypertension was found only in women in a large cross sectional study with 9185 subjects [Article:16041242]. The impact of the Thr to Ile change at codon 164 on death or heart transplantation in heart failure is not clear at this time due to conflicting results. A prospective cohort study of 257 patients found that those with the Ile164 variant were at higher risk for death or heart transplantation in 1 year (event rate 76%) compared to patients homozygous for Thr164 [Article:9788966]. However, the Ile164 variant was not associated with these outcomes, but may interact with beta blocker treatment in a recent prospective cohort study with 443 heart failure patients [Article:18068431]. The low frequency of the Ile164 isoform and unmeasured confounders may have contributed to the conflicting results. Impact of the Thr164Ile substitution on the outcomes in patients who received percutaneous coronary intervention has also been studied. In a prospective cohort study with 330 patients, those carrying the Ile164 variant were 3.7 times more likely to have cardiac death and 4.1 times more likely to have a major cardiac adverse event than patients homozygous for Thr164 after percutaneous coronary intervention [Article:18940527]. The higher incidences of acute myocardial infarction and a major cardiac adverse event have been replicated in a separate cohort of 150 patients with peripheral arterial disease 28. Overall, the roles of the Thr164Ile variant in cardiovascular outcomes have not been well defined. Because of the low allele frequency, studies with larger sample sizes would help define the effect of this amino acid substitution on the clinical outcomes of cardiovascular diseases.
| Key Publications: | |
|---|---|
| Diseases | Heart Failure 1 |
Appendix
| Genomic Variant & GenBank ID: | 9,369,821 C>T on NT_029289 |
|---|---|
| mRNA Variant & GenBank ID: | 730 C>T on NM_000024.4 |
| Protein Variant & GenBank ID: | 164 Thr>Ile on NP_000015 |
| GoldenPath Position: | chr5:148,187,078 (hg18) |
Connected Drug Classes
| Evidence | Drug Class |
|---|---|
| Variant Annotation | Beta Blocking Agents |
Publications related to rs1800888 at chr5:148206885: 6
Cross-References
- UCSC Golden Path:
- chr5:148206885
- dbSNP:
- rs1800888
- ALFRED:
- SI000367Q
- HapMap:
- rs1800888
Platform Availability
- Illumina