Methods for predicting relative efficacy of a beta blocker therapy based on a B1-adrenergic receptor polymorphism

• US 7,449,292 B2
• Filed: 09/13/2004
• Issued: 11/11/2008
• Est. Priority Date: 09/12/2003
• Status: Expired due to Fees

• Current Assignee: University of Cincinnati
• Original Assignee: University of Cincinnati
• Inventors: Liggett, Stephen Bryant, Wagoner, Lynne Elizabeth
• Primary Examiner(s): Myers; Carla
• Application Number:
  US10/941,063
• Publication Number:
  US 20050112632A1
• Time in Patent Office: 1,520 Days
• Field of Search: None
• US Class Current: 435/6.14
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/106 Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
• CPC Class Codes: C12Q 2600/136 Screening for pharmacological compounds
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers
• CPC Class Codes: C12Q 2600/158 Expression markers

Abstract

Methods and compositions for the detection, diagnosis, and prevention of cardiac conditions are provided. Polymorphisms of β₁-adrenergic receptor are provided. The Gly389 β₁-adrenergic receptor variants are not as responsive to treatment β blockers such as carvedilol, metoprolol or bisoprol. Thus, genotyping β₁-adrenergic receptor polymorphisms is useful for predicting relative responsiveness to treatment with beta blockers. The Gly389 polymorphism also may be used, alone or in conjunction with other adrenergic receptor polymorphisms, to predict relative risk of developing cardiovascular diseases such as heart failure or to predict relative survival rate in patients with heart failure or other cardiovascular diseases. Also provided are transgenic mice and transgenic cells expressing the β₁-adrenergic receptor polymorphisms, and their use in identifying therapeutic agents.

Claims

1. A method of predicting relative efficacy of a beta blocker therapy in a subject, the method comprising:

determining from a sample from the subject the presence or absence of a polymorphism in a β

₁-adrenergic receptor in the sample from the subject, wherein the polymorphism comprises arginine at position 389; and

predicting relative efficacy of a beta blocker therapy, wherein the beta blocker therapy comprises administering carvedilol, based on the presence or absence of the polymorphism, the presence of the polymorphism indicating a relatively greater efficacy of the beta blocker therapy in the subject, wherein the subject is heterozygous or homozygous for the polymorphism, as compared to a subject lacking the polymorphism.

2. The method according to claim 1, wherein the subject was diagnosed with a cardiovascular disease before the determining step.

3. The method according to claim 2, wherein the cardiovascular disease is heart failure.

4. The method according to claim 1, wherein the determining step further comprises analyzing a nucleic acid in the sample.

5. The method according to claim 1, wherein the determining step further comprises analyzing a protein in the sample.

6. The method according to claim 4, wherein the analyzing comprises nucleic acid sequencing, restriction digestion, allele-specific polymerase reaction, allele-specific oligonucleotide hybridization, single-stranded conformational polymorphism analysis, genetic bit analysis, temperature gradient gel electrophoresis, ligase chain reaction, or ligase/polymerase genetic bit analysis.

7. The method according to claim 5, wherein the analyzing comprises contacting the protein with an antibody or fragment thereof, amino acid sequencing, or mass spectroscopy analysis.

8. The method according to claim 1 wherein efficacy of a beta blocker therapy comprises a measurable improvement in left ventricular ejection fraction.