Single nucleotide polymorphisms associated with dose-dependent edema and methods of use thereof

• US 20070009945A1
• Filed: 07/07/2006
• Published: 01/11/2007
• Est. Priority Date: 07/08/2005
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Ranade, Koustubh, Geese, William, Delmonte, Terrye
• Granted Patent: US 7,482,124 B2
• Time in Patent Office: Days
• US Class Current: 435/6
• CPC Class Codes: C07K 14/57536 Endothelin, vasoactive intestinal contractor [VIC]
• CPC Class Codes: C07K 14/70571 for neuromediators, e.g. serotonin receptor, dopamine receptor
• CPC Class Codes: C12N 9/6486 Renin (3.4.23.15)
• 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
• CPC Class Codes: C12Q 2600/178 miRNA, siRNA or ncRNA
• CPC Class Codes: C12Y 304/23015 Renin (3.4.23.15)
• CPC Class Codes: G01N 2333/70567 Nuclear receptors, e.g. retinoic acid receptor [RAR], RXR, nuclear orphan receptors
• CPC Class Codes: G01N 2500/10 involving cells
• CPC Class Codes: G01N 33/5023 on expression patterns

Abstract

The invention provides novel polynucleotides and polypeptides associated with the incidence of PPAR-agonist induced edema. The invention also provides polynucleotide fragments corresponding to the genomic and/or coding regions of these polynucleotides which comprise at least one polymorphic locus per fragment. Allele-specific primers and probes which hybridize to these regions, and/or which comprise at least one polymorphic locus are also provided. The polynucleotides, primers, and probes of the present invention are useful in phenotype correlations, medicine, and genetic analysis. Also provided are vectors, host cells, antibodies, and recombinant and synthetic methods for producing said polynucleotides and/or polypeptides. The invention further relates to diagnostic and therapeutic methods for applying these novel polynucleotides and polypeptides to the diagnosis, treatment, and/or prevention of various diseases and/or disorders, particularly PPAR-agonist induced edema or related indications. The invention further relates to screening methods for identifying agonists of PPAR proteins with decreased risk of inducing periphereal edema in patients.

Claims

1. An isolated nucleic acid molecule comprising a polynuclelotide sequence selected from the group consisting of the polynucleotide sequence provided as SEQ ID NO:

1, 2, 3, 4, 5, and 6.

2. The isolated nucleic acid molecule according to claim 1, wherein said nucleic acid comprises at least one polymorphic locus selected from the group consisting of:

(a) nucleotide position 12586 of SEQ ID NOS;

1;

(b) nucleotide position 12586 of SEQ ID NO;

2;

(c) nucleotide position 10096 of SEQ ID NO;

3;

(d) nucleotide position 10096 of SEQ ID NO;

4;

(e) nucleotide position 13076 of SEQ ID NO;

5; and

(f) nucleotide position 13076 of SEQ ID NO;

6.

3. An isolated nucleic acid molecule comprising the polynucleotide sequence provided as SEQ ID NO:

7.

4. The isolated nucleic acid molecule according to claim 3, wherein said nucleic acid comprises at least one polymorphic locus selected from the group consisting of:

nucleotide position 12586, 10096, and/or 13076 of SEQ ID NO;

7.

5. The isolated nucleic acid molecule according to claim 4 wherein the nucleotide allele at said polymorphic locus is one or more of the following:

the reference nucleotide allele at position 12586;

the variable nucleotide allele at position 12586;

the reference nucleotide allele at position 10096;

the variable nucleotide allele at position 10096;

the reference nucleotide allele at position 13076;

the variable nucleotide allele at position 13076, or any combination thereof.

6. A method of identifying a patient who may be at risk of developing dose-dependent peripheral edema upon administration of a PPAR-agonist comprising the step of determining whether said patient has a reference or variable allele at one or more polymorphic loci of the human renin gene.

7. The method according to claim 6, wherein the presence of a reference allele at the polymorphic locus at position 12586, 10096, or 13076 is indicative of an increased risk of developing dose-dependent peripheral edema in a patient receiving PPAR-agonist therapy, whereas the presence of the variable allele at said polymorphic position is indicative of a decreased risk of developing dose-dependent peripheral edema in a patient receiving PPAR-agonist therapy.

8. An isolated nucleic acid molecule comprising a polynucleotide sequence selected from the group consisting of the polynucleotide sequence provided as SEQ ID NO:

37, and SEQ ID NO;

39, wherein said nucleic acid comprises at least one polymorphic locus, wherein said polymorphic locus is located at nucleotide position 797.

9. An isolated polypeptide comprising a sequence selected from the group consisting of the polynucleotide sequence provided as SEQ ID NO:

38, and SEQ ID NO;

40, wherein said polypeptide comprises at least one polymorphic locus, wherein said polymorphic locus is located at amino acid position 198.

10. A method of identifying a patient who may be at risk of developing dose-dependent peripheral edema upon administration of a PPAR-agonist comprising the step of determining whether said patient has a referenece or variable allele at one or more polymorphic loci of the human endotheline-1 gene or human endotheline-1 polypeptide.

11. The method according to claim 10, wherein the presence of a reference allele at the polymorphic locus at nucleotide position 797 of SEQ ID NO:

37 or 39, or the presence of a reference allele at the polymorphic locus at amino acid position 198 of SEQ ID NO38 or 40, is indicative of an increased risk of developing dose-dependent peripheral edema in a patient receiving PPAR-agonist therapy, whereas the presence of the variable allele at said nucleoticde or polypeptide polymorphic position is indicative of a decreased risk of developing dose-dependent peripheral edema in a patient receiving PPAR-agonist therapy.

20. A kit comprising the method of claim 6, 7, 10, 11, 14, 15, 16, 17, 18, or 19.

12. An isolated nucleic acid molecule comprising a polynuclelotide sequence selected from the group consisting of the polynucleotide sequence provided as SEQ ID NO:

50, and SEQ ID NO;

52, wherein said nucleic acid comprises at least one polymorphic locus, wherein said polymorphic locus is located at nucleotide position 1251.

13. An isolated polypeptide comprising a sequence selected from the group consisting of the polynucleotide sequence provided as SEQ ID NO:

51, and SEQ ID NO;

53, wherein said polypeptide comprises at least one polymorphic locus, wherein said polymorphic locus is located at amino acid position 389.

14. A method of identifying a patient who may be at risk of developing dose-dependent peripheral edema upon administration of a PPAR-agonist comprising the step of determining whether said patient has a reference or variable allele at one or more polymorphic loci of the human β

1-adrenergic receptor gene or human β

1-adrenergic receptor polypeptide.

15. The method according to claim 14, wherein the presence of a reference allele at the polymorphic locus at nucleotide position 1251 of SEQ ID NO:

50 or 52, or the presence of a reference allele at the polymorphic locus at amino acid position 389 of SEQ ID NO;

51 or 53, is indicative of an increased risk of developing dose-dependent peripheral edema in a patient receiving PPAR-agonist therapy, whereas the presence of the variable allele at said nucleoticde or polypeptide polymorphic position is indicative of a decreased risk of developing dose-dependent peripheral edema in a patient receiving PPAR-agonist therapy.

16. A method of identifying a PPAR-agonist compound having a decreased likelihood of inducing dose-dependent peripheral edema in a patient comprising the step of:

(a) incubating cells capable of endogenously expressing human renin with a test compound; and

(b) measuring the level of expression of human renin in response to said test compound;

wherein a decreased level of induced human renin expression by the test compound relative to a reference compound is indicative of a decreased risk of said compound inducing dose-dependent peripheral edema in a patient.

17. A method of identifying a PPAR-agonist compound having a decreased likelihood of inducing dose-dependent peripheral edema in a patient comprising the step of:

(a) incubating cells capable of endogenously expressing human endothelin-1 with a test compound; and

(b) measuring the level of expression of human endothelin-1 in response to said test compound;

wherein an increased level of induced human endothelin-1 expression by the test compound relative to a reference compound is indicative of a decreased risk of said compound inducing dose-dependent peripheral edema in a patient.

18. A method of identifying a pharmaceutically acceptable amount of a PPAR-agonist for a patient comprising the step of:

(a) incubating cells isolated from the patient that endogenously express human renin with a PPAR-agonist test compound; and

(b) measuring the level of expression of human renin in response to said PPAR-agonist test compound;

wherein an increase in the level of induced human renin expression by said PPAR-agonist test compound is indicative of a pharmaceutically acceptable amount of a PPAR-agonist being administered.

19. A method of identifying a pharmaceutically acceptable amount of a PPAR-agonist for a patient comprising the step of:

(a) incubating cells isolated from the patient that endogenously express human endothelin-1 with a PPAR-agonist test compound; and

(b) measuring the level of expression of human endothelin-1 in response to said PPAR-agonist test compound;

wherein a decrease in the level of human endothelin-1 expression by said PPAR-agonist test compound is indicative of a pharmaceutically acceptable amount of a PPAR-agonist being administered.