GENETIC SUSCEPTIBILITY VARIANTS ASSOCIATED WITH CARDIOVASCULAR DISEASE

• US 20100068705A1
• Filed: 02/21/2008
• Published: 03/18/2010
• Est. Priority Date: 02/21/2007
• Status: Active Grant

• Current Assignee: Decode Genetics Ehf. (Amgen Inc.)
• Original Assignee: Decode Genetics Ehf. (Amgen Inc.)
• Inventors: Manolescu, Andrei, Helgadottir, Anna, Thorleifsson, Gudmar
• Granted Patent: US 9,617,597 B2
• 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: 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 2600/172 Haplotypes
• CPC Class Codes: Y02A 90/10 Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation

Abstract

The invention relates to methods of diagnosing susceptibility to cardiovascular disease, including coronary artery disease. MI, abdominal aorta aneurysm, intracranial aneurysm restenosis and peripheral arterial disease, by assessing the presence or absence of alleles of certain polymorphic markers found to be associates with cardiovascular disease. The invention further relates to kits encompassing reagents for assessing such markers, and methods for assessing the probability of response to therapeutic agents and methods using such markers.

Claims

1. A method for determining a susceptibility to cardiovascular disease in a human individual, comprising determining the presence or absence of at least one allele of at least one polymorphic marker in a nucleic acid sample obtained from the individual or in a genotype dataset derived from the individual, wherein the at least one polymorphic marker is selected from the polymorphic markers set forth in Table 10, and markers in linkage disequilibrium therewith, and wherein the presence of the at least one allele is indicative of a susceptibility to cardiovascular disease.

2. The method according to claim 1, wherein the at least one polymorphic marker is located within the genomic segment with the sequence as set forth in SEQ ID NO:

94.

3. The method according to claim 1, wherein the at least one polymorphic marker is in linkage disequilibrium with the CDKN2A and/or CDKN2B genes.

4. The method according to claim 1, wherein the at least one polymorphic marker is selected from the markers set forth in Table 3 and Table 21.

5. The method according to claim 1, wherein the at least one polymorphic marker is selected from rs10811650, rs10116277, rs1333040, rs10738607, rs4977574, rs6475608, D9S1870, rs2383207, rs1333045, rs1333046, rs10757278 and rs1333048.

6. The method according to claim 1, wherein the at least one polymorphic marker is selected from the group consisting of rs1333040, rs10116277, rs2383207 and rs10757278.

7. The method according to claim 1, wherein the at least one polymorphic marker is rs10757278.

8. The method according to claim 1, further comprising assessing the frequency of at least one haplotype in the individual.

9. The method of claim 1, wherein the susceptibility conferred by the presence of the at least one allele or haplotype is increased susceptibility.

10. The method according to claim 9, wherein the presence of allele T in rs1333040, allele T in rs10116277, allele G in rs2383207, allele G in rs10757278, allele X in DG9S1870 or allele 0 in D9S1814 is indicative of increased susceptibility to cardiovascular disease.

11. The method according to claim 9, wherein the presence of the at least one allele or haplotype is indicative of increased susceptibility with a relative risk (RR) or odds ratio (OR) of at least 1.2.

12. The method according to claim 9, wherein the presence of the at least one allele or haplotype is indicative of increased susceptibility with a relative risk (RR) or odds ratio (OR) of at least 1.3.

13. The method according to claim 1, wherein the susceptibility conferred by the presence of the at least one allele or haplotype is decreased susceptibility.

14. The method according to claim 1, wherein the presence of the marker or haplotype is indicative of a different response rate of the subject to a particular treatment modality for a Cardiovascular disease.

15. The method according to claim 14, wherein the treatment modality is a coronary stenosis method selected from balloon angioplasty, stenting, cutting balloon angioplasty, percutaneous transluminal coronary angioplasty (PTCA), directional coronary atherectomy, rotational coronary, atherectomy, brachytherapy, drug-eluting stent (DES) insertion, metal stent insertion, and coronary artery surgery.

16. The method of claim 14, wherein the treatment modality is administration of a therapeutic agent for preventing and/or ameliorating symptoms associated with the Cardiovascular disease.

34. The method of claim 1, further comprising assessing at least one biomarker in a sample from the individual.

35. The method of claim 34, wherein the biomarker is a cardiac marker or an inflammatory marker.

36. The method of claim 34, wherein the at least one biomarker is selected from creatine kinase, troponin, glycogen phosphorylase, C-reactive protein (CRP), serum amyloid A, fibrinogen, interleukin-6, tissue necrosis factor-alpha, soluble vascular cell adhesion molecules (sVCAM), soluble intervascular adhesion molecules (sICAM), E-selectin, matrix metalloprotease type-1, matrix metalloprotease type-2, matrix metalloprotease type-3, matrix metalloprotease type-9, serum sCD40L, leukotrienes, leukotriene metabolites, interleukin-6, tissue necrosis factor-alpha, myeloperoxidase (MPO), and N-tyrosine.

37. The method of claim 36, wherein the leukotriene is selected from LTB4, LTC4, LTD4 and LTE4.

43. The method according to claim 1, wherein linkage disequilibrium is characterized by a particular numeric cutoff value for the linkage disequilibrium measures r² and/or |D′

|.

44. The method according to claim 43, wherein linkage disequilibrium is characterized by a cutoff value for r² of greater than 0.2.

47. The method according to claim 1, wherein the Cardiovascular disease is at least one of Myocardial Infarction, Coronary Artery Disease, Percutaneous Transluminal Coronary Angioplasty (PTCA), Coronary Artery Bypass Surgery (CABG), Restenosis, Peripheral Arterial Disease, Stroke, Abdominal Aorta Aneurysm and Intracranial Aneurysm.

48. The method according to claim 47, wherein the Cardiovascular disease is at least one of Myocardial Infarction, Coronary Artery Disease, Restenosis, Intracranial Aneurysm and Abdominal Aorta Aneurysm.

49. The method according to claim 47, wherein the Stroke is Large Artery Atherosclerotic Stroke or Cardiogenic Stroke.

50. The method according to claim 47, wherein Myocardial Infarction is an early onset Myocardial Infarction.

51. The method according to claim 50, wherein the Cardiovascular Disease is Myocardial Infarction and/or Coronary Artery Disease with an early onset before age 50 for males and 60 for females.

17. A method of identification of a marker for use in assessing susceptibility to cardiovascular disease, the method comprising

a. identifying at least one polymorphic marker in linkage disequilibrium with at least one of the markers within LD Block C09 (SEQ ID NO:

94);

b. determining the genotype status of a sample of individuals diagnosed with, or having a susceptibility to, cardiovascular disease; and

c. determining the genotype status of a sample of control individuals;

wherein a significant difference in frequency of at least one allele in at least one polymorphism in individuals diagnosed with, or having a susceptibility to, cardiovascular disease, as compared with the frequency of the at least one allele in the control sample is indicative of the at least one polymorphism being useful for assessing susceptibility to cardiovascular disease.

19. The method according to claim 17, wherein an increase or a decrease in frequency of the at least one allele in the at least one polymorphism in individuals diagnosed with, or having a susceptibility to, cardiovascular disease, as compared with the frequency of the at least one allele in the control sample is indicative of the at least one polymorphism being useful for assessing increased or decreased susceptibility to, or protection against, cardiovascular disease.

18. (canceled)

20-22. -22. (canceled)

23. A method of genotyping a nucleic acid sample obtained from a human individual at risk for, or diagnosed with, cardiovascular disease, comprising determining the presence or absence of at least one allele of at least one polymorphic marker in the sample, wherein the at least one marker is selected from the group consisting of the markers set forth in Table 3 and Table 21, and markers in linkage disequilibrium therewith, and wherein the presence or absence of the at least one allele of the at least one polymorphic marker is indicative of a susceptibility of cardiovascular disease.

24-29. -29. (canceled)

30. A method of assessing an individual for probability of response to a therapeutic agent for preventing and/or ameliorating symptoms associated with cardiovascular disease, comprising:

determining the presence or absence of at least one allele of at least one polymorphic marker in a nucleic acid sample obtained from the individual, wherein the at least one polymorphic marker is selected from the group consisting of the polymorphic markers set forth in Table 3 and Table 21, and markers in linkage disequilibrium therewith, wherein the presence of the at least one allele of the at least one marker is indicative of a probability of a positive response to the therapeutic agent.

31. A method of predicting prognosis of an individual diagnosed with cardiovascular disease, then method comprising determining the presence or absence of at least one allele of at least one polymorphic marker in a nucleic acid sample obtained from the individual, wherein the at least one polymorphic marker is selected from the group consisting of the polymorphic markers set forth in Tables 3 and 21, and markers in linkage disequilibrium therewith, wherein the presence of the at least one allele is indicative of a worse prognosis of the cardiovascular disease in the individual.

32. A method of monitoring progress of treatment of an individual undergoing treatment for cardiovascular disease, the method comprising determining the presence or absence of at least one allele of at least one polymorphic marker in a nucleic acid sample obtained from the individual, wherein the at least one polymorphic marker is selected from the markers set forth in Tables 3 and 21, and markers in linkage disequilibrium therewith, wherein the presence of the at least one allele is indicative of the treatment outcome of the individual.

33. (canceled)

38-42. -42. (canceled)

45-46. -46. (canceled)

52. A kit for assessing susceptibility to cardiovascular disease in a human individual, the kit comprising reagents for selectively detecting at least one allele of at least one polymorphic marker in the genome of the individual, wherein the polymorphic marker is selected from the markers set forth in Tables 10, and markers in linkage disequilibrium therewith, and wherein the presence of the at least one allele is indicative of a susceptibility to cardiovascular disease.

60. The kit according to claim 52, wherein the reagents comprise at least one contiguous oligonucleotide that hybridizes to a fragment of the genome of the individual comprising the at least one polymorphic marker, a buffer and a detectable label.

61. The kit according to claim 52, wherein the reagents comprise at least one pair of oligonucleotides that hybridize to opposite strands of a genomic nucleic acid segment obtained from the subject, wherein each oligonucleotide primer pair is designed to selectively amplify a fragment of the genome of the individual that includes one polymorphic marker, and wherein the fragment is at least 30 base pairs in size.

62. The kit according to claim 60, wherein the at least one oligonucleotide is completely complementary to the genome of the individual.

63. The kit according to claim 60, wherein the oligonucleotide is about 18 to about 50 nucleotides in length.

53-59. -59. (canceled)

64-65. -65. (canceled)

66. A method for diagnosing and/or assessing susceptibility to cardiovascular disease in a human individual comprising an oligonucleotide probe, wherein the probe hybridizes to a segment of a nucleic acid whose nucleotide sequence is set forth in SEQ ID NO:

94, wherein the probe is 15-500 nucleotides in length.

67. A computer-readable medium on which is stored:

a. an identifier for at least one polymorphic marker;

b. an indicator of the frequency of at least one allele of said at least one polymorphic marker in a plurality of individuals diagnosed with cardiovascular disease; and

c. an indicator of the frequency of the least one allele of said at least one polymorphic markers in a plurality of reference individuals;

wherein the at least one polymorphic marker is selected from the polymorphic markers set forth in Table 10, and polymorphic markers in linkage disequilibrium therewith.

68-69. -69. (canceled)

70. An apparatus for determining a genetic indicator for cardiovascular disease in a human individual, comprising:

a computer readable memory; and

a routine stored on the computer readable memory;

wherein the routine is adapted to be executed on a processor to analyze marker and/or haplotype information for at least one human individual with respect to at least one polymorphic marker selected from the markers set forth in Table 10, and markers in linkage disequilibrium therewith, and generate an output based on the marker or haplotype information, wherein the output comprises a risk measure of the at least one marker or haplotype as a genetic indicator of cardiovascular disease for the human individual.

71-74. -74. (canceled)