Methods for diagnosis, prediction and treatment of heart failure and other cardiac conditions based on beta1-adrenergic receptor polymorphism

• US 20050112632A1
• Filed: 09/13/2004
• Published: 05/26/2005
• Est. Priority Date: 09/12/2003
• Status: Active Grant

• Current Assignee: University of Cincinnati
• Original Assignee: University of Cincinnati
• Inventors: Liggett, Stephen Bryant, Wagoner, Lynne Elizabeth
• Granted Patent: US 7,449,292 B2
• Time in Patent Office: Days
• US Class Current: 435/6
• 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 risk of a subject developing heart failure, comprising:

obtaining a sample from the subject; and

determining from the sample the presence or absence of a polymorphism in a adrenergic receptor, wherein the polymorphism comprises arginine at position 389 and wherein the polymorphism indicates a relatively increased risk of the subject developing heart failure as compared to a subject lacking the polymorphism, thereby predicting relative risk of developing heart failure rate in the subject.

2. The method according to claim 1, wherein the determining step comprises analyzing a nucleic acid comprising the sample.

3. The method according to claim 1, wherein the determining step comprises analyzing a protein comprising the sample.

4. The method according to claim 1, further comprising determining the presence or absence of a polymorphism in an α

_2c-adrenergic receptor.

5. The method according to claim 2, 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.

6. The method according to claim 3, wherein the analyzing comprises contacting the protein with an antibody or fragment thereof, amino acid sequencing, or mass spectroscopy analysis.

7. A method of predicting relative survival rate in a subject with heart failure, comprising:

obtaining a sample from the subject; and

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

₁-adrenergic receptor, wherein the polymorphism comprises arginine at position 389 and wherein the polymorphism indicates a relatively decreased survival rate in the subject as compared to a subject lacking the polymorphism, thereby predicting relative survival rate in the subject with heart failure.

8. The method according to claim 7, wherein the determining step comprises analyzing a nucleic acid comprising the sample.

9. The method according to claim 7, wherein the determining step comprises analyzing a protein comprising the sample.

10. The method according to claim 7, further comprising determining the presence or absence of a polymorphism in an α

_2c-adrenergic receptor.

11. The method according to claim 8, 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, mass spectroscopy analysis, or ligase/polymerase genetic bit analysis.

12. The method according to claim 9, wherein the analyzing comprises contacting the protein with an antibody or fragment thereof, amino acid sequencing, or mass spectroscopy analysis.

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

obtaining a sample from the subject; and

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

₁-adrenergic receptor, wherein the polymorphism comprises arginine at position 389 and wherein the polymorphism is indicates a relatively greater efficacy of a beta blocker therapy in the subject as compared to a subject lacking the polymorphism, thereby predicting relative efficacy of the beta blocker therapy.

14. The method according to claim 13, wherein the subject is diagnosed with a cardiovascular disease.

15. The method according to claim 14, wherein the cardiovascular disease is heart failure.

16. The method according to claim 13, wherein the beta blocker therapy comprises administering a drug selected from the group consisting of carvedilol, metoprolol, bisoprol and propranolol.

17. The method according to claim 13, wherein the determining step comprises analyzing a nucleic acid comprising the sample.

18. The method according to claim 13, wherein the determining step comprises analyzing a protein comprising the sample.

19. The method according to claim 13, further comprising determining the presence or absence of a polymorphism in an α

_2c-adrenergic receptor.

20. The method according to claim 17, 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.

21. The method according to claim 18, wherein the analyzing comprises contacting the protein with an antibody or fragment thereof, amino acid sequencing, or mass spectroscopy analysis.

22. A transgenic animal whose genome comprises at least one transgene comprising a nucleic acid sequence encoding a polymorphism of a β

₁-adrenergic receptor.

23. The transgenic animal of claim 22, wherein the animal is a mouse.

24. The transgenic animal of claim 22, wherein polymorphism is a C at position 1165 of the nucleic acid sequence encoding the β

₁-adrenergic receptor.

25. A method for testing a compound suspected of ameliorating cardiovascular disease, the method comprising:

providing a mammalian cell;

administering to the cell the compound; and

monitoring phenotype of the cell.

26. The method of claim 25, wherein the cardiovascular disease is heart failure.

27. The method of claim 25, wherein the mammalian cell is a transgenic cell.

28. The method of claim 27, wherein the transgenic cell comprising a nucleic acid sequence encoding a polymorphism of β

₁-adrenergic receptor.

29. A transgenic cell comprising a nucleic acid sequence encoding a polymorphism of β

₁-adrenergic receptor operably linked with a nucleotide regulatory element that controls expression of the nucleic acid sequence in the cell.

30. The transgenic cell of claim 29, wherein the cell is eukaryotic.

31. The transgenic cell of claim 29, wherein the cell is mammalian.

32. The transgenic cell of claim 29, wherein the nucleic acid sequence encoding the β

₁-adrenergic receptor has a C at position 1165.