ADRB2 T164I - GET-Evidence

Curation:
Currentness:

ADRB2 T164I

(ADRB2 Thr164Ile)


Short summary

This rare variant in β2-Adrenoceptor has only reported heterozygously (in 2-4% of the population) and strongly decreases the protein’s responsiveness to inducing compounds (agonists). Carriers of this variant are less sensitive to induction of increased heart rate, heart contraction, and vasodilation by β-AR agonists. Mixed data suggests that this variant does not have a significant impact on hypertension or heart disease. It may affect responsiveness to beta blocker drugs.

Variant evidence
Computational -1

Polyphen 2 predicts benign effect.

Functional 4

Reduced agonist binding, reduced G-protein coupling and sequestration responses. In vivo human data shows reduced response to agonist effect on heart rate and contraction.

See Green SA et al. 1993 (7901205), Brodde OE 2008 (18353108).

Case/Control

Mixed data means the effect of this variant on disease is unclear.

See Brodde OE 2008 (18353108).

Familial -
 
Clinical importance
Severity

Unknown what effect, if any, this variant has on disease or drug effect.

Treatability

No recommended treatment for this variant.

Penetrance

Unknown what effect, if any, this variant has on disease or drug effect.

 

Impact

Low clinical importance, Uncertain pharmacogenetic

(The "low clinical importance, uncertain" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

unknown

Summary of published research, and additional commentary

 

Allele frequency

  • T @ chr5:148206885: 1.1% (118/10758) in EVS
  • T @ chr5:148187077: 0.8% (1/128) in GET-Evidence
  • Frequency shown in summary reports: 1.1% (118/10758)

Publications
 

Green SA, Cole G, Jacinto M, Innis M, Liggett SB. A polymorphism of the human beta 2-adrenergic receptor within the fourth transmembrane domain alters ligand binding and functional properties of the receptor. J Biol Chem. 1993 Nov 5;268(31):23116-21. PubMed PMID: 7901205.

This variant is reported to have much lower binding affinities to agonists epinephrine, isoproterenol and norepinephrine. In addition, antagonists without aromatic ring polar substituents displayed a decreased affinity. Functional coupling to G-protein and sequestration in response to agonists were also reduced.

Brodde OE. Beta1- and beta2-adrenoceptor polymorphisms and cardiovascular diseases. Fundam Clin Pharmacol. 2008 Apr;22(2):107-25. Review. PubMed PMID: 18353108.

Review article of studies on the effect of this and other variants in the gene. Conflicting results for an effect on hypertension and coronary heart disease leads the author to conclude: “similar to β1-AR, β2-AR polymorphisms do not seem to be disease-causing genes in hypertension or in CHF but they might affect drug responses.” The variant is described as having a significant effect in vitro, and other variants in the gene have been reported to affect responsiveness to beta blockers.

Genomes
 

Other external references
 

    dbSNP
  • rs1800888
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PolyPhen-2
  • Score: 0 (benign)
    Web search results (30 hits -- see all)
  • Haplotype Analysis of the 2 Adrenergic Receptor Gene and Risk ...
    2 adrenergic receptor (ADRB2), in particular G16R, Q27E, and T164I, have ... American men, we evaluated the G16R, Q27E, and T164I polymorphisms among 523 individuals who ...
    www.genetics.org/cgi/reprint/169/3/1583.pdf
  • Haplotype Analysis of the β2 Adrenergic Receptor Gene and ...
    THE β2 adrenergic receptor (ADRB2), a member of the G-protein-coupled receptor ... in ADRB2 have been identified; in particular, G16R, Q27E, and T164I polymorphisms have ...
    www.ncbi.nlm.nih.gov/pmc/articles/PMC1449541
  • Haplotype Analysis of the {beta}2 Adrenergic Receptor Gene ...
    THE ß2 adrenergic receptor (ADRB2), a member of the G-protein-coupled receptor ... in ADRB2 have been identified; in particular, G16R, Q27E, and T164I polymorphisms have ...
    www.genetics.org/cgi/content/full/169/3/1583
  • Neural Control of Heart Rate Is an Arrhythmia Risk Modifier ...
    Still not a subscriber to JACC Imaging or JACC Interventions? ... The ADRB1-S49G, ADRB1-G389R, ADRB2-R19C, ADRB2-R16G, ADRB2-Q27E, ADRB2-T164I, ADRB3-W64R, and ADRA1A-R492C ...
    content.onlinejacc.org/cgi/content/full/51/9/920
  • Influence of β2-adrenergic receptor (<i>ADRB2</i>) haplotypes ...
    Influence of 2-adrenergic receptor (ADRB2) haplotypes on obesity-related traits and ... p.T164I arose on a haplotype that contained the ancestral p.16G and ...
    www.ashg.org/genetics/abstracts/abs06/f1715.htm
  • Combination Allele-Specific Real-Time PCR for Differentiation ...
    Stimulation of ADRB2 by catecholamines or synthetic therapeutic ... A threonine-to-isoleucine (T164I) substitution in the fourth transmembrane domain alters ligand binding and ...
    www.clinchem.org/cgi/content/full/50/4/769
  • SNPs Identified in ADRB2
    T164I. C/T. G362a24. 742. chr5:148235427. Silent. view. R175R. C/A. G362a25 ... and Genotyping > Candidate Gene List > ADRB2 Main Page > SNPs Identified in ADRB2 ...
    cardiogenomics.med.harvard.edu/.../ADRB2_validated_SNPs.html
  • PLoS ONE: Identification of Novel Single Nucleotide ...
    PLoS ONE: an inclusive, peer-reviewed, open-access resource from the PUBLIC LIBRARY OF ... I50V), IL9 (T113M), CCR3 (P39L), ADRB2 (Q27E, and T164I), CTLA4 (318 C>T), NOS2A ...
    plosone.org/article/info:doi/10.1371/journal.pone.0003600
  • Identification of Novel Single Nucleotide Polymorphisms in ...
    Copyright Atik et al. This is an open-access article distributed under the terms of the Creative Commons ... IL9 (T113M), CCR3 (P39L), ADRB2 (Q27E, and T164I), CTLA4 (318 C>T) ...
    www.ncbi.nlm.nih.gov/pmc/articles/PMC2572999
  • errata changed in issue 21
    The sites of the ADRB2 that interact with. the stimulatory G proteins ... ADRB2 expression. and function. In addition, transgenic mice (having the. T164I variant) ...
    www.eh.uc.edu/ceg/pdf/wwinte21.pdf

Other in silico analyses
 

  • NBLOSUM100 score = 3
  • GET-Evidence autoscore = 4

Edit history
 

Gene search

"GENE" or "GENE A123C":

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