Biomarkers for diagnosis of stroke and its causes

Abstract

The present invention provides compositions and methods for the diagnosis of the occurrence and cause of stroke.

1 . A method for diagnosing the occurrence and cause of ischemic stroke or a predisposition for developing ischemic stroke, the method comprising:
 a) determining a level of expression of at least 15 ischemic stroke-associated biomarkers in a biological sample from a patient, wherein the biomarkers comprise a plurality of biomarkers selected from Table 7A, a plurality of biomarkers selected from Table 13A, a plurality of biomarkers selected from Table 14 and a plurality of biomarkers selected from Table 15; and   b) comparing the level of expression of the ischemic stroke-associated biomarkers to the expression level of a plurality of stably expressed endogenous reference biomarkers,   wherein an increase or decrease of the expression level of the plurality of biomarkers selected from Table 7A compared to the expression level of the plurality of endogenous reference biomarkers indicates that the patient suffers from or is at risk of developing ischemic stroke;   wherein an increase or decrease of the expression level of the plurality of biomarkers selected from Table 13A compared to the expression level of the plurality of endogenous reference biomarkers indicates that the patient suffers from or is at risk of developing cardioembolic stroke;   wherein an increase or decrease of the expression level of the plurality of biomarkers selected from Table 14 compared to the expression level of the plurality of endogenous reference biomarkers indicates that the patient suffers from or is at risk of developing carotid stenosis; and   wherein an increase or decrease of the expression level of the plurality of biomarkers selected from Table 15 compared to the expression level of the plurality of endogenous reference biomarkers indicates that the patient suffers from or is at risk of developing atrial fibrillation, thereby diagnosing the occurrence and cause of ischemic stroke or the predisposition for developing ischemic stroke.   
     
     
         2 - 6 . (canceled) 
     
     
         7 . The method  claim 1 , wherein the patient has at least one vascular risk factor and an increased expression level of one or more ischemic stroke-associated biomarkers of Table 7A selected from the group consisting of RNF141, CLEC4E, TIMP2, PHTF1, CKLF, CKLF, RRAGD, CLEC4E, CKLF, FGD4, CPEB2, LOC100290882, UBXN2B, ENTPD1, BST1, LTB4R, F5, IFRD1, KIAA0319, CHMP1B, MCTP1, VNN3, AMN1, LAMP2, FCHO2, ZNF608, REM2, QKI, RBM25, FAR2, ST3GAL6, HNRNPH2, GAB1, UBR5 and VAPA, and/or wherein a decreased expression level of one or more ischemic stroke-associated biomarkers of Table 7A selected from the group consisting of PGM5, CCDCl44C///LOC100134159, LECT2, SHOX, TBX5, SPTLC3, SNIP, RBMS3, P704P, THSD4, FAT3, SNRPN, GLYATL1, GADL1, CXADR, OVOL2, SPIB, BXDC5, UNC5B, ASTN2, F1135934, ANKRD28, CCDCl44A, TIMM8A, ALDOAP2, LDB3, PTPRD, LOC729222///PPFIBP1, CCRL1, HNRNPUL2, FCRL4, ELAVL2, PRTG, DLX6, FOXA2, SCD5, GABRB2, GYPA, LOC283027, LOC344595, RPL22, LOC100129488, RPL22 and SH3GL3 indicates that the patient suffers from or is at risk of developing ischemic stroke. 
     
     
         8 - 11 . (canceled) 
     
     
         12 . The method of  claim 1 , wherein an increased expression level of one or more ischemic stroke-associated biomarkers of Table 13A selected from the group consisting of IRF6, ZNF254, GRM5, EXT2, AP3S2, PIK3C2B, ARHGEF5, COL13A1, PTPN20A///PTPN20B, LHFP, BANK1, HLA-DOA, EBF1, TMEM19, LHFP, FCRL1, OOEP and LRRC37A3, and/or wherein a decreased expression level of one or more ischemic stroke-associated biomarkers of Table 13A selected from the group consisting of LOC284751, CD46, ENPP2, C19orf28, TSKS, CHURC1, ADAMTSL4, FLJ40125, CLEC18A, ARHGEF12, C16orf68, TFDP1 and GSTK1 indicates that the patient has experienced or is at risk for cardioembolic stroke. 
     
     
         13 . (canceled) 
     
     
         14 . The method of  claim 1 , wherein an increased expression level of one or more ischemic stroke-associated biomarkers of Table 14 selected from the group consisting of NT5E, CLASP2, GRM5, PROCR, ARHGEF5, AKR1C3, COL13A1, LHFP, RNF7, CYTH3, EBF1, RANBP10, PRSS35, C12orf42 and LOC100127980, and/or wherein a decreased expression level of one or more ischemic stroke-associated biomarkers of Table 14 selected from the group consisting of FLJ31945, LOC284751, LOC100271832, MTBP, ICAM4, SHOX2, DOPEY2, CMBL, LOC146880, SLC20A1, SLC6A19, ARHGEF12, C16orf68, GIPC2 and LOC100144603 indicates that the patient has experienced or is at risk for carotid stenosis. 
     
     
         15 . (canceled) 
     
     
         16 . The method of  claim 1 , wherein an increased expression level of one or more ischemic stroke-associated biomarkers of Table 15 selected from the group consisting of SMC1A, SNORA68, GRLF1, SDC4, HIPK2, LOC100129034, CMTM1 and TTC7A, and/or wherein a decreased expression level of one or more ischemic stroke-associated biomarkers of Table 15 selected from the group consisting of LRRC43, MIF///SLC2A11, PER3, PPIE, COL13A1, DUSP16, LOC100129034, BRUNOL6, GPR176, C6orf164 and MAP3K71P1 indicates that the patient has experienced or is at risk for atrial fibrillation. 
     
     
         17 - 24 . (canceled) 
     
     
         25 . A method for diagnosing ischemic stroke or a predisposition for developing ischemic stroke, the method comprising: determining a level of expression of a plurality of ischemic stroke-associated biomarkers in a biological sample from a patient, wherein an increase or decrease of the level compared to a control indicates that the patient suffers from or is at risk of developing ischemic stroke, wherein the plurality of ischemic stroke-associated biomarkers is selected from the biomarkers set forth in Table 7A. 
     
     
         26 . (canceled) 
     
     
         28 . The method of  claim 25 , wherein the patient has at least one vascular risk factor and an increased expression level of one or more ischemic stroke-associated biomarkers of Table 7A selected from the group consisting of RNF141, CLEC4E, TIMP2, PHTF1, CKLF, CKLF, RRAGD, CLEC4E, CKLF, FGD4, CPEB2, LOC100290882, UBXN2B, ENTPD1, BST1, LTB4R, F5, IFRD1, KIAA0319, CHMP1B, MCTP1, VNN3, AMN1, LAMP2, FCHO2, ZNF608, REM2, QKI, RBM25, FAR2, ST3GAL6, HNRNPH2, GAB1, UBR5 and VAPA, and/or wherein a decreased expression level of one or more ischemic stroke-associated biomarkers of Table 7A selected from the group consisting of PGM5, CCDCl44C///LOC100134159, LECT2, SHOX, TBX5, SPTLC3, SNIP, RBMS3, P704P, THSD4, FAT3, SNRPN, GLYATL1, GADL1, CXADR, OVOL2, SPIB, BXDC5, UNC5B, ASTN2, F1135934, ANKRD28, CCDCl44A, TIMM8A, ALDOAP2, LDB3, PTPRD, LOC729222///PPFIBP1, CCRL1, HNRNPUL2, FCRL4, ELAVL2, PRTG, DLX6, FOXA2, SCD5, GABRB2, GYPA, LOC283027, LOC344595, RPL22, LOC100129488, RPL22 and SH3GL3 indicates that the patient suffers from or is at risk of developing ischemic stroke. 
     
     
         29 - 58 . (canceled) 
     
     
         59 . A method for determining the cause of ischemic stroke in a patient in need thereof, the method comprising: determining a level of expression of a plurality of ischemic stroke-associated biomarkers in a biological sample from a patient who has suffered ischemic stroke, wherein an increase or decrease of the level compared to a control indicates that the patient has experienced cardioembolic stroke, wherein the plurality of ischemic stroke-associated biomarkers is selected from the biomarkers set forth in Table 13A. 
     
     
         60 . The method of  claim 59 , wherein an increased expression level of one or more ischemic stroke-associated biomarkers of Table 13A selected from the group consisting of IRF6, ZNF254, GRM5, EXT2, AP3S2, PIK3C2B, ARHGEF5, COL13A1, PTPN20A///PTPN20B, LHFP, BANK1, HLA-DOA, EBF1, TMEM19, LHFP, FCRL1, OOEP and LRRC37A3, and/or wherein a decreased expression level of one or more ischemic stroke-associated biomarkers of Table 13A selected from the group consisting of LOC284751, CD46, ENPP2, C19orf28, TSKS, CHURC1, ADAMTSL4, F1140125, CLEC18A, ARHGEF12, C16orf68, TFDP1 and GSTK1 indicates that the patient has experienced cardioembolic stroke. 
     
     
         61 - 75 . (canceled) 
     
     
         76 . A method for determining the cause of ischemic stroke in a patient in need thereof, the method comprising: determining a level of expression of a plurality of ischemic stroke-associated biomarkers in a biological sample from a patient who has suffered ischemic stroke, wherein an increase or decrease of the level compared to a control indicates that the patient has experienced carotid stenosis, wherein the plurality of ischemic stroke-associated biomarkers is selected from the biomarkers set forth in Table 14. 
     
     
         77 . The method of  claim 76 , wherein an increased expression level of one or more ischemic stroke-associated biomarkers of Table 14 selected from the group consisting of NT5E, CLASP2, GRM5, PROCR, ARHGEF5, AKR1C3, COL13A1, LHFP, RNF7, CYTH3, EBF1, RANBP10, PRSS35, C12orf42 and LOC100127980, and/or wherein a decreased expression level of one or more ischemic stroke-associated biomarkers of Table 14 selected from the group consisting of F1131945, LOC284751, LOC100271832, MTBP, ICAM4, SHOX2, DOPEY2, CMBL, LOC146880, SLC20A1, SLC6A19, ARHGEF12, C16orf68, GIPC2 and LOC100144603 indicates that the patient has experienced carotid stenosis. 
     
     
         78 - 91 . (canceled) 
     
     
         92 . A method for determining the risk or susceptibility of experiencing atrial fibrillation in a patient, the method comprising: determining a level of expression of a plurality of ischemic stroke-associated biomarkers in a biological sample from the patient, wherein an increase or decrease of the level compared to a control indicates that the patient has experienced or is at risk for experiencing atrial fibrillation, wherein the plurality of ischemic stroke-associated biomarkers is selected from the biomarkers set forth in Table 15. 
     
     
         93 . The method of  claim 92 , wherein an increased expression level of one or more ischemic stroke-associated biomarkers of Table 15 selected from the group consisting of SMC1A, SNORA68, GRLF1, SDC4, HIPK2, LOC100129034, CMTM1 and TTC7A, and/or wherein a decreased expression level of one or more ischemic stroke-associated biomarkers of Table 15 selected from the group consisting of LRRC43, MIF///SLC2A11, PER3, PPIE, COL13A1, DUSP16, LOC100129034, BRUNOL6, GPR176, C6orf164 and MAP3K71P1 indicates that the patient has experienced or is at risk for atrial fibrillation. 
     
     
         94 - 108 . (canceled) 
     
     
         109 . A solid support comprising a plurality of nucleic acids that hybridize to a plurality of the genes set forth in Table 7A, a plurality of nucleic acids that hybridize to a plurality of the genes set forth in Table 13A, a plurality of nucleic acids that hybridize to a plurality of the genes set forth in Table 14 and a plurality of nucleic acids that hybridize to a plurality of the genes set forth in Table 15. 
     
     
         110 - 121 . (canceled)