GENETIC MARKERS FOR RISK MANAGEMENT OF CARDIAC ARRHYTHMIA

• US 20090325163A1
• Filed: 12/05/2007
• Published: 12/31/2009
• Est. Priority Date: 12/05/2006
• Status: Active Grant

• Current Assignee: Decode Genetics Ehf. (Amgen Inc.)
• Original Assignee: Decode Genetics Ehf. (Amgen Inc.)
• Inventors: Gudbjartsson, Daniel, Helgadottir, Anna
• Granted Patent: US 8,637,244 B2
• Time in Patent Office: Days
• US Class Current: 435/6.16
• CPC Class Codes: C12Q 1/6827 for detection of mutation or polymorphism
• CPC Class Codes: C12Q 1/6837 using probe arrays or probe chips C12Q1/6874 takes precedence
• 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 2600/118 Prognosis of disease development
• 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 2600/172 Haplotypes
• CPC Class Codes: G16B 20/00 ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
• CPC Class Codes: G16B 20/20 Allele or variant detection, e.g. single nucleotide polymorphism [SNP] detection
• CPC Class Codes: G16B 20/40 Population genetics; Linkage disequilibrium

Abstract

The invention relates to procedure and methods of determining a susceptibility to cardiac arrhythmia, including Atrial Fibrillation, Atrial Flutter and Stroke, by assessing the presence or absence of alleles at polymorphic markers found to be associated with Atrial Fibrillation, Atrial Flutter and Stroke. The invention further relates to kits encompassing reagents for assessing such markers, and diagnostic methods, uses and procedures for utilizing such susceptibility markers.

Claims

1. A method of determining a susceptibility to cardiac arrhythmia or stroke in a human individual, the method comprising determining the presence or absence of at least one allele of at least one polymorphic marker in a nucleic acid sample from the individual, wherein the at least one polymorphic marker is selected from the polymorphic markers set forth in Table 5, and markers in linkage disequilibrium therewith,

and wherein determination of the presence or absence of the at least one allele is indicative of a susceptibility to cardiac arrhythmia or stroke in the individual.

3. The method of claim 1, wherein the at least one polymorphic marker is selected from the markers set forth in Table 9, and markers in linkage disequilibrium therewith.

4. The method of claim 1, wherein the at least one polymorphic marker is selected from D4S406 (SEQ ID NO:

45), rs2634073 (SEQ ID NO;

33), rs2200733 (SEQ ID NO;

28), rs2220427 (SEQ ID NO;

1), rs10033464 (SEQ ID NO;

41), and rs13143308 (SEQ ID NO;

51), and markers in linkage disequilibrium therewith.

5. The method of claim 1, wherein the presence of alleles −

2, −

4 and/or −

8 in marker D4S406, allele A of marker rs2634073, allele T of marker rs2200733, allele T of marker rs2220427, allele T of marker rs10033464, and/or allele G of marker rs13143308 is indicative of increased susceptibility of cardiac arrhythmia or stroke in the individual.

6. The method of claim 1, wherein the susceptibility is increased susceptibility characterized by an odds ratio (OR) of at least 1.3.

7. The method of claim 1, wherein the susceptibility is increased susceptibility characterized by an odds ratio (OR) of at least 1.4.

8. The method of claim 1, wherein the susceptibility is increased susceptibility characterized by an odds ratio (OR) of at least 1.5.

9. The method of claim 1, wherein the susceptibility is increased susceptibility characterized by an odds ratio (OR) of at least 1.6.

10. The method of claim 1, wherein the susceptibility is increased susceptibility characterized by an odds ratio (OR) of at least 1.8.

30. The method of claim 1, wherein the cardiac arrhythmia is atrial fibrillation or atrial flutter.

31. The method of claim 30, wherein atrial fibrillation or atrial flutter is further characterized by an age of onset in the individual of less than 80 years.

32. The method of claim 30, wherein atrial fibrillation or atrial flutter is further characterized by an age of onset in the individual of less than 70 years.

33. The method of claim 30, wherein atrial fibrillation or atrial flutter is further characterized by an age of onset in the individual of less than 60 years.

34. The method of claim 1, wherein the stroke is ischemic stroke.

35. The method of claim 1, wherein linkage disequilibrium is characterized by numerical values for r2 of greater than 0.2.

49. The method of claim 1, further comprising assessing at least one biomarker for atrial fibrillation, atrial flutter and/or stroke in a sample from the individual.

50. The method of claim 1, further comprising analyzing non-genetic information to make risk assessment, diagnosis, or prognosis of the individual.

2. A method of determining a susceptibility to cardiac arrhythmia or stroke in a human individual, comprising determining whether at least one at-risk allele in at least one polymorphic marker is present in a genotype dataset derived from the individual, wherein the at least one polymorphic marker is selected from the markers set forth in Table 5, and markers in linkage disequilibrium therewith, and wherein determination of the presence of the at least one at-risk allele is indicative of increased susceptibility to cardiac arrhythmia or stroke in the individual.

11. A method of assessing a susceptibility to cardiac arrhythmia or stroke in a human individual, comprising screening a nucleic acid from the individual for at least one polymorphic marker allele or haplotype in SEQ ID NO:

50 that correlates with increased occurrence of cardiac arrhythmia or stroke in a human population;

wherein determination of the presence of an at-risk marker allele in the at least one polymorphism or an at-risk haplotype in the nucleic acid identifies the individual as having elevated susceptibility to cardiac arrhythmia and/or stroke, and

wherein the absence of the at least one at-risk marker allele or at-risk haplotype in the nucleic acid identifies the individual as not having the elevated susceptibility.

12-15. -15. (canceled)

16. A method of identification of a marker for use in assessing susceptibility to cardiac arrhythmia and/or stroke in human individuals, the method comprising

a. identifying at least one polymorphic marker within SEQ ID NO:

50, or at least one polymorphic marker in linkage disequilibrium with at least one marker within SEQ ID NO;

50;

b. determining the genotype status of a sample of individuals diagnosed with cardiac arrhythmia and/or stroke; 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 cardiac arrhythmia and/or stroke 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 cardiac arrhythmia and/or stroke.

17. The method of claim 16, wherein an increase or a decrease in frequency of the at least one allele in the at least one polymorphism in individuals diagnosed with cardiac arrhythmia and/or stroke, 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 cardiac arrhythmia and/or stroke.

18-19. -19. (canceled)

20. A method of genotyping a nucleic acid sample obtained from a human individual, comprising determining the presence or absence of at least one allele of at least one polymorphic marker predictive of increased risk of cardiac arrhythmia and/or stroke in the sample, wherein the at least one marker is selected from the markers set forth in Table 5, and markers in linkage disequilibrium therewith, and wherein determination of the presence or absence of the at least one allele of the at least one polymorphic marker is predictive of increased risk of cardiac arrhythmia and/or stroke in the individual.

21-25. -25. (canceled)

26. A method of determining a susceptibility to cardiac arrhythmia or stroke in a human individual, the method comprising determining the identity 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 marker is selected from the group of markers associated with the PITX2 gene, wherein the presence of the at least one allele is indicative of a susceptibility to cardiac arrhythmia or stroke in the individual.

27-29. -29. (canceled)

36. A method of assessing an individual for probability of response to a therapeutic agent for preventing and/or ameliorating symptoms associated with cardiac arrhythmia and/or stroke, 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 Table 9, and markers in linkage disequilibrium therewith, wherein determination of 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 for cardiac arrhythmia and/or stroke.

37. The method according to claim 36, wherein the therapeutic agent is an anticoagulant, an anti-arrhythmic agent, a hear rate control agent, a cardioversion agent, or a heart rhythm control agent.

38. The method according to claim 36, wherein the therapeutic agent is selected from warfarin, heparin, low molecular weight heparins, factor Xa inhibitors, thrombin inhibitors, sodium channel blockers, beta blockers, potassium channel blockers, and calcium channel blockers.

39. The method according to claim 36, wherein the therapeutic agent is selected from warfarin, ximelagatran, heparin, enoxaparin, dalteparin, tinzaparin, ardeparin, nadroparin, reviparin, fondaparinux, idraparinux, lepirudin, bivalirudin, argatroban, danaparoid, disopyramide, moricizine, procainamide, quinidine, lidocaine, mexiletine, tocamide, phenyloin, encainide, flecamide, propafenone, ajmaline, cibenzoline, detajmium, esmolol, propranolol, metoprolol, alprenolol, atenolol, carvedilol, bisoprolol, acebutolol, nadolol, pindololol, labetalol, oxprenotol, penbutolol, timolol, betaxolol, cartelol, sotalol, levobunolol, amiodarone, azimilide, bretylium, dofetilide, tedisamil, ibutilide, sematilide, N-acetyl procainamide, nifekalant hydrochloride, vernakalant, ambasilide, verpamil, mibefradil, diltiazem, digoxin, adenosine, ibutilide, amiodarone, procainamide, profafenone and flecamide.

40. A method of predicting prognosis of an individual diagnosed with, cardiac arrhythmia and/or stroke, 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 Table 9, and markers in linkage disequilibrium therewith, wherein determination of the presence of the at least one allele is indicative of a worse prognosis of the cardiac arrhythmia and/or stroke in the individual.

41. A method of monitoring progress of a treatment of an individual undergoing treatment for cardiac arrhythmia and/or stroke, 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 Table 9, and markers in linkage disequilibrium therewith, wherein determination of the presence of the at least one allele is indicative of the treatment outcome of the individual.

42-48. -48. (canceled)

51-52. -52. (canceled)

53. A kit for assessing susceptibility to cardiac arrhythmia and/or stroke 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 group consisting of the polymorphic markers within the segment whose sequence is set forth in SEQ ID NO:

50, and markers in linkage disequilibrium therewith, and wherein the presence of the at least one allele is indicative of a susceptibility to cardiac arrhythmia and/or stroke.

60. The kit of claim 53, 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.

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

64. The kit of claim 60, wherein the oligonucleotide is 20-30 nucleotides in length.

54-59. -59. (canceled)

61-62. -62. (canceled)

65. (canceled)

66. Use of an oligonucleotide probe in the manufacture of a diagnostic reagent for diagnosing and/or assessing susceptibility to cardiac arrhythmia and/or stroke in a human individual, wherein the probe hybridizes to a segment of a nucleic acid whose nucleotide sequence is given by SEQ ID NO:

50 that comprises at least one polymorphic site, wherein the fragment is 15-500 nucleotides in length.

67-71. -71. (canceled)

72. 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 atrial fibrillation, atrial flutter and/or stroke; 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 5, and polymorphisms in linkage disequilibrium therewith.

73-74. -74. (canceled)

75. An apparatus for determining a genetic indicator for cardiac arrhythmia and/or stroke 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 genotype and/or haplotype data for at least one human individual with respect to at least one polymorphic marker selected from the markers set forth in Table 5, and markers in linkage disequilibrium therewith, and generate an output based on the marker or haplotype data, wherein the output comprises a risk measure of the at least one marker or haplotype as a genetic indicator of cardiac arrhythmia and/or stroke for the human individual.

76. The apparatus of claim 75, wherein the routine further comprises determining an indicator of the frequency of at least one allele of at least one polymorphic marker and/or at least one haplotype in a plurality of individuals diagnosed with cardiac arrhythmia and/or stroke, and an indicator of the frequency of at the least one allele of at least one polymorphic marker or at least one haplotype in a plurality of reference individuals, and calculating a risk measure for the at least one allele and/or haplotype based thereupon;

and wherein a risk measure for the individual is calculated based on a comparison of the at least one marker and/or haplotype status for the individual to the calculated risk for the at least one marker and/or haplotype information for the plurality of individuals diagnosed with atrial fibrillation, atrial flutter and/or stroke.

77-79. -79. (canceled)