Susceptibility Gene for Myocardial Infarction, Stroke, Paod and Methods of Treatment
First Claim
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1. A method of prophylaxis therapy for myocardial infarction (MI) comprising:
- selecting a human subject susceptible to MI;
administering to the subject a composition comprising a therapeutically effective amount of an MI therapeutic agent that inhibits leukotriene synthesis in vivo, wherein the MI therapeutic agent inhibits leukotriene synthesis by inhibiting the activity of at least one protein selected from 5-Lipoxygenase activating protein (FLAP) and 5-lipoxygenase (5-LO), andmonitoring myeloperoxidase (MPO) level in the human subject before and during the prophylaxis treatment, wherein the MI therapeutic agent is administered in an amount effective to reduce the MPO level in a subject.
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Abstract
Linkage of myocardial infarction (MI) and a locus on chromosome 13q12 is disclosed. In particular, the FLAP gene within this locus is shown by genetic association analysis to be a susceptibility gene for MI and ACS, as well as stroke and PAOD. Pathway targeting for treatment and diagnostic applications in identifying those who are at risk of developing MI, ACS, stroke or PAOD, in particular are described. The invention also provides for compositions comprising a leukotriene synthesis inhibitor and a stating and methods of using these compositions to reduce C-reactive protein in a human subject at risk of MI, ACS, stroke and/or PAOD.
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Citations
95 Claims
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1. A method of prophylaxis therapy for myocardial infarction (MI) comprising:
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selecting a human subject susceptible to MI; administering to the subject a composition comprising a therapeutically effective amount of an MI therapeutic agent that inhibits leukotriene synthesis in vivo, wherein the MI therapeutic agent inhibits leukotriene synthesis by inhibiting the activity of at least one protein selected from 5-Lipoxygenase activating protein (FLAP) and 5-lipoxygenase (5-LO), and monitoring myeloperoxidase (MPO) level in the human subject before and during the prophylaxis treatment, wherein the MI therapeutic agent is administered in an amount effective to reduce the MPO level in a subject. - View Dependent Claims (2, 3, 4, 7, 11, 12, 13, 14, 18, 23, 24, 26, 27, 28, 29, 85, 86, 87)
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5-6. -6. (canceled)
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8-10. -10. (canceled)
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15-17. -17. (canceled)
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19-22. -22. (canceled)
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25. (canceled)
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30. A method of prophylaxis therapy for myocardial infarction (MI) comprising:
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selecting a human subject having a FLAP (SEQ ID NO;
1) haplotype comprising;
SG13S375 (SEQ ID NO;
1, position
164874), allele T;administering to the subject a composition comprising a therapeutically effective amount of an MI therapeutic agent that inhibits leukotriene synthesis in vivo, wherein the MI therapeutic agent inhibits leukotriene synthesis, and monitoring myeloperoxidase (MPO) level in the human subject before and during the prophylaxis treatment, wherein the MI therapeutic agent is administered in an amount effective to reduce the MPO level in a subject. - View Dependent Claims (31, 32, 33, 34, 88, 89, 90)
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35-36. -36. (canceled)
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37. A method of prophylaxis therapy for myocardial infarction (MI) comprising:
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analyzing nucleic acid of a human subject for the presence and absence of a FLAP haplotype, wherein the haplotype is comprised of markers; SG13S375 (SEQ ID NO;
1, position
164874), allele T;SG13S25 (SEQ ID NO;
1, position
165553), allele G;SG13S32 (SEQ ID NO;
1, position
176579), allele A; andSG13S106 (SEQ ID NO;
1, position
198547206117), allele G or A,selecting for treatment a human subject having nucleic acid with the presence of the FLAP haplotype, administering to the subject a composition comprising a therapeutically effective amount of an MI therapeutic agent that inhibits leukotriene synthesis in vivo, wherein the MI therapeutic agent inhibits leukotriene synthesis. - View Dependent Claims (38, 43, 45)
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39-42. -42. (canceled)
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44. (canceled)
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46. A method of prophylaxis for myocardial infarction (MI) comprising:
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administering to a subject in need of prophylaxis for myocardial infarction a composition comprising a therapeutically effective amount of an MI therapeutic agent that inhibits leukotriene synthesis in vivo, and monitoring myeloperoxidase (MPO) level in the human subject before and during the prophylaxis treatment, wherein the MI therapeutic agent is administered in an amount effective to reduce the MPO level in a subject.
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47. A method of screening a human subject for risk of developing myocardial infarction, comprising:
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contacting a blood sample from the human subject with a calcium ionophore to stimulate production of a leukotriene; and measuring production of a leukotriene in the blood sample after the contacting step, wherein elevated leukotriene production compared to a control correlates with increased risk of developing myocardial infarction (MI). - View Dependent Claims (52)
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48-51. -51. (canceled)
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53. A method of decreasing risk of a subsequent myocardial infarction in an individual who has had at least one myocardial infarction, comprising
administering a therapeutically effective amount of an MI therapeutic agent to the individual, wherein the MI therapeutic agent inhibits leukotriene synthesis by inhibiting the activity of at least one protein selected from 5-Lipoxygenase activating protein (FLAP) and 5-lipoxygenase (5-LO) and monitoring myeloperoxidase (MPO) in the individual before and during the administration of the therapeutic agent, wherein the MI therapeutic agent is administered in an amount effective to reduce the MPO level in a subject.
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54. A method of screening a human subject for susceptibility for MI comprising
analyzing nucleic acid of a human subject for the presence and absence of the FLAP haplotype comprised of markers: -
SG13S377 (SEQ ID NO;
1, position
169965), allele A;SG13S114 (SEQ ID NO;
1, position
178096), allele A;SG13S41 (SEQ ID NO;
1, position
202045), allele A; andSG13S35 (SEQ ID NO;
1, position
206117), allele G,identifying the subject as having a susceptibility to MI, wherein the presence of the FLAP haplotype correlates with an increased risk of myocardial infarction.
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- 55. A composition comprising a leukotriene synthesis inhibitor and a statin.
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56-58. -58. (canceled)
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60-61. -61. (canceled)
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63. (canceled)
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68-73. -73. (canceled)
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77. A method of reducing C reactive protein (CRP) in a human subject, comprising:
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selecting a human subject that receives statin therapy to reduce serum LDL, wherein the statin therapy optionally reduces serum CRP in the human subject; and administering to the human subject a leukotriene synthesis antagonist, in an amount effective to further reduce CRP in the human subject.
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78. A method of reducing C reactive protein (CRP) in a human subject, comprising:
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identifying a human subject in need of treatment to reduce serum CRP; administering to the human subject a composition comprising a statin; administering to the human subject a composition comprising a leukotriene synthesis inhibitor, wherein the statin and the leukotriene synthesis inhibitor are administered in amounts effective to reduce serum CRP in the human subject. - View Dependent Claims (82, 83)
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79-81. -81. (canceled)
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84. (canceled)
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91. A method of assessing susceptibility to myocardial infarction (MI) or stroke in a human individual, the method comprising:
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screening nucleic acid of the individual to determine whether the nucleic acid comprises a 5-lipoxygenase activating protein (FLAP) haplotype that comprises polymorphisms SG13S25, allele G; and
SG13S114, allele T;wherein the presence of the haplotype in the nucleic acid of the individual identifies the individual as having elevated susceptibility to MI, and wherein the absence of the haplotype in the nucleic acid of the individual identifies the individual as not having the elevated susceptibility to MI or stroke. - View Dependent Claims (92, 93)
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94. A method of prophylaxis therapy for myocardial infarction (MI) comprising:
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selecting a human subject having a FLAP (SEQ ID NO;
1) haplotype comprising;
SG13S25 (SEQ ID NO;
1, position
165553), allele G; and
SG13S114 (SEQ ID NO;
1, position 178096, allele T; andadministering to the subject a composition comprising a therapeutically effective amount of an MI therapeutic agent that inhibits leukotriene synthesis in vivo, wherein the MI therapeutic agent inhibits leukotriene synthesis.
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95. The method of claim 95, further comprising monitoring myeloperoxidase (MPO) level in the human subject before and during the prophylaxis treatment, wherein the MI therapeutic agent is administered in an amount effective to reduce the MPO level in a subject.
Specification