Diagnostics and therapeutics for cardiovascular disease

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.

What is claimed is:  
     
         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.