Diagnostics and therapeutics for cardiovascular disease

• US 20030175764A1
• Filed: 12/13/2002
• Published: 09/18/2003
• Est. Priority Date: 03/10/1997
• Status: Abandoned Application

• Current Assignee: Interleukin Genetics Incorporated (Orig3n, Inc.)
• Original Assignee: Interleukin Genetics Incorporated (Orig3n, Inc.)
• Inventors: Kornman, Kenneth S., Duff, Gordon W., Crossman, David C., Francis, Sheila E., Stephenson, Katherine
• Application Number:
  US10/320,360
• Publication Number:
  US 20030175764A1
• Time in Patent Office: Days
• US Class Current: 435/6
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 14/54 Interleukins [IL]
• CPC Class Codes: C07K 14/545 IL-1
• CPC Class Codes: C12Q 1/683 involving restriction enzymes, e.g. restriction fragment length polymorphism [RFLP]
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers
• CPC Class Codes: G01N 2800/32 Cardiovascular disorders
• CPC Class Codes: G01N 2800/323 Arteriosclerosis, Stenosis
• CPC Class Codes: G01N 2800/324 Coronary artery diseases, e.g. angina pectoris, myocardial infarction
• CPC Class Codes: G01N 33/6893 related to diseases not provided for elsewhere
• CPC Class Codes: Y10S 435/912 Absidia

Abstract

The kits and methods of the present invention relate to the diagnosis of cardiovascular disorders. In one aspect, the invention discloses a method and a kit for determining whether a subject has a fragile plaque disorder. In one aspect, the invention discloses a method and a kit for determining whether the subject has an occlusive disorder. In one aspect, the invention discloses a method and a kit for determining whether the subject has a restenosis disorder. Other methods of the present invention relate to the selection of therapeutics for a patient with a cardiovascular disease.

Claims

1. A method for determining whether a patient has a cardiovascular disorder, comprising:

detecting a first cardiovascular disorder associated allele in a nucleic acid sample from the patient, wherein detection of the first cardiovascular disorder associated allele indicates that the patient has the cardiovascular disorder.

2. The method of claim 1, wherein the first cardiovascular disorder associated allele is selected from the group consisting of allele 2 of IL-1A (+4845), allele 2 of IL-1B (+3954), allele 1 of IL-1B (−

511), allele 1 of IL-1RN (+2018), and an allele in linkage disequilibrium with an aforementioned allele.

3. The method of claim 1, wherein the first cardiovascular disorder associated allele is selected from the group consisting of allele 1 of IL-1A (+4845), allele 1 of IL-1B (+3954), allele 2 of IL-1B (−

511), allele 2 of IL-1RN (+2018), and an allele in linkage disequilibrium with an aforementioned allele.

4. The method of claim 1, wherein the first cardiovascular disorder associated allele is selected from the group consisting of allele 1 of IL-1A (+4845), allele 1 of IL-1B (+3954), allele 1 of IL-1B (−

511), allele 1 of IL-1RN (+2018), and an allele in linkage disequilibrium with an aforementioned allele.

5. The method of claim 1, further comprising

detecting a second cardiovascular disorder associated allele in the nucleic acid sample, wherein detection of the second cardiovascular disorder associated allele indicates that the patient has the cardiovascular disorder.

6. The method of claim 5,

wherein the first cardiovascular disorder associated allele is selected from the group consisting of allele 2 of IL-1A (+4845), allele 2 of IL-1B (+3954), an allele in linkage disequilibrium with allele 2 of IL-1A (+4845), and an allele in linkage disequilibrium with allele 2 of IL-1B (+3954), and

wherein the second cardiovascular disorder associated allele is selected from the group consisting of allele 1 of IL-1B (−

511), allele 1 of IL-1RN (+2018), an allele in linkage disequilibrium with allele 1 of IL-1B (−

511), and an allele in linkage disequilibrium with allele 1 of IL-1RN (+2018).

7. The method of claim 5,

wherein the first cardiovascular disorder associated allele is selected from the group consisting of allele 1 of IL-1A (+4845), allele 1 of IL-1B (+3954), an allele in linkage disequilibrium with allele 1 of IL-1A (+4845), and an allele in linkage disequilibrium with allele 1 of IL-1B (+3954), and

wherein the second cardiovascular disorder associated allele is selected from the group consisting of allele 2 of IL-1B (−

511), allele 2 of IL-1RN (+2018), an allele in linkage disequilibrium with allele 2 of IL-1B (−

511), and an allele in linkage disequilibrium with allele 2 of IL-1RN (+2018).

8. The method of claim 5,

wherein the first cardiovascular disorder associated allele is selected from the group consisting of allele 1 of IL-1A (+4845), allele 1 of IL-1B (+3954), an allele in linkage disequilibrium with allele 1 of IL-1A (+4845), and an allele in linkage disequilibrium with allele 1 of IL-1B (+3954), and

wherein the second cardiovascular disorder associated allele is selected from the group consisting of allele 1 of IL-1B (−

511), allele 1 of IL-1RN (+2018), an allele in linkage disequilibrium with allele 1 of IL-1B (−

511), and an allele in linkage disequilibrium with allele 1 of IL-1RN (+2018).

9. The method of claim 1, wherein said detecting step is selected from the group consisting of:

a) allele specific oligonucleotide hybridization;

b) size analysis;

c) sequencing;

d) hybridization;

e) 5′

nuclease digestion;

f) single-stranded conformation polymorphism;

g) allele specific hybridization;

h) primer specific extension; and

j) oligonucleotide ligation assay.

10. The method of claim 1, further comprising amplifying the nucleic acid sample.

11. The method of claim 10, wherein amplifying the nucleic acid sample employs a primer pair selected from the group consisting of any of SEQ ID Nos. 1 and 2;

3 and 4;

5 and 6;

7 and 8; and

9 and 10.

12. The method of claim 9, wherein said size analysis is preceded by a restriction enzyme digestion.

13. The method of claim 12, wherein said restriction enzyme digestion uses a restriction enzyme selected from the group consisting of Alu I, Msp I, Nco I, Fnu 4HI, Ava I, Bsu 36 I, and Taq I.

14. A kit for determining a presence of a cardiovascular disorder in a patient, comprising:

a means for detecting an allele of IL-1A(+4845), an allele of IL-1B(+3954), an allele of IL-1B(−

511), an allele of IL-1RN(+2018), and an allele in linkage disequilibrium with aforesaid alleles; and

a first primer oligonucleotide that hybridizes 5′

or 3′

to an allele selected from the group consisting of an allele of IL-1A (+4845), an allele of IL-1B (+3954), an allele of IL-1B(−

511), an allele of IL-1RN(+2018), and an allele in linkage disequilibrium with aforesaid alleles.

15. The kit of claim 14, further comprising a second primer oligonucleotide that hybridizes 5′

or 3′

to an allele selected from the group consisting of an allele of IL-1A (+4845), an allele of IL-1B (+3954), an allele of IL-1B(−

511), an allele of IL-1RN(+2018), and an allele in linkage disequilibrium with aforesaid alleles.

16. The kit of claim 14, which additionally comprises an amplifying primer oligonucleotide that hybridizes either 3′

or 5′

respectively to the allele for amplifying said allele.

17. The kit of claim 16, wherein said first primer, said second primer and said amplifying primer oligonucleotides hybridize to a region in the range of between about 50 and about 1000 base pairs.

18. The kit of claim 16, wherein said first primer, said second primer and said amplifying primer nucleotides are selected from the group consisting of any of SEQ ID Nos. 1-10.

19. The kit of claim 14, wherein the detection means is selected from the group consisting of:

a) allele specific oligonucleotide hybridization;

b) size analysis;

c) sequencing;

d) hybridization;

e) 5′

nuclease digestion;

f) single-stranded conformation polymorphism;

g) allele specific hybridization;

h) primer specific extension; and

j) oligonucleotide ligation assay.

20. The kit of claim 14, further comprising an amplification means.

21. The kit of claim 14, further comprising a control.

22. The method for treating a patient, comprising:

detecting whether the patient has a cardiovascular disorder associated allele,

diagnosing a cardiovascular disorder,

selecting a cardiovascular disorder therapeutic, and

providing the cardiovascular disorder therapeutic to the patient.

23. The method of claim 22, wherein the cardiovascular disorder comprises a fragile plaque disorder.

24. The method of claim 22, wherein the cardiovascular disorder comprises an occlusive disorder.

25. The method of claim 22, wherein the cardiovascular disorder comprises an in-stent restenosis.

26. The method of claim 22, wherein the cardiovascular disorder further comprises a cardiovascular disorder causing mutation that is in linkage disequilibrium with the cardiovascular disorder associated allele.

27. The method of claim 22, further comprising identifying a presence of a risk factor for the cardiovascular disorder, and formulating a treatment plan that reduces an effect of the risk factor on the patient.

28. The method of claim 27, wherein identifying the presence of a risk factor comprises performing a diagnostic test.

29. The method of claim 27, wherein the treatment plan comprises an administration of a therapeutic agent that modifies the risk factor.

30. The method of claim 22, wherein said detecting is performed using a technique selected from the group consisting of:

a) allele specific oligonucleotide hybridization;

b) size analysis;

c) sequencing;

d) hybridization;

e) 5′

nuclease digestion;

f) single-stranded conformation polymorphism;

g) allele specific hybridization;

h) primer specific extension; and

j) oligonucleotide ligation assay.

31. The method of claim 22, wherein the nucleic acid sample is subjected to an amplification step.

32. The method of claim 31, wherein said amplification step employs a primer selected from the group consisting of SEQ ID Nos. 1-10.

33. The method of claim 30, wherein said size analysis is preceded by a restriction enzyme digestion.

34. The method of claim 33, wherein said restriction enzyme digestion uses a restriction enzyme selected from the group consisting of Alu I, Msp I, Nco I, Fnu 4HI, Ava I, Bsu 36 I, and Taq I.

35. The method of claim 22, wherein the cardiovascular disorder therapeutic comprises a modulator of an IL-1 activity.

36. The method of claim 35, wherein the IL-1 activity is IL-1α

.

37. A method of claim 35, wherein the IL-1 activity is IL-1α

.

38. A method of claim 35, wherein the IL-1 activity is IL-1RN.

39. A method of claim 35, wherein the modulator is an IL-1 agonist.

40. A method of claim 35, wherein the modulator is an IL-1 antagonist.