Biomarkers for the diagnosis of lacunar stroke

Abstract

This invention provides gene expression profiles useful for diagnosing lacunar stroke and for distinguishing lacunar stroke from non-lacunar stroke.

1 . A method for diagnosing the occurrence of lacunar stroke or a predisposition for experiencing lacunar stroke, the method comprising:
 a) determining a level of expression of a plurality of lacunar stroke-associated biomarkers in a biological sample from a patient, wherein the biomarkers are selected from Table 3; and   b) comparing the level of expression of the lacunar stroke-associated biomarkers to the expression level of a plurality of stably expressed endogenous reference biomarkers;   wherein an increase of the expression level of one or more biomarkers selected from the group consisting of RASEF, CALM1, TTC12, CCL3, CCL3L1, CCL3L3, CCDC78, PRSS23, LAIR2, C18orf49, UTS2, LGR6, PROCR, LAG3, OASL, LOC100132181, HLA-DRB4, CCL2, ALS2CR11, SCAND2, GBP4, RUNX3, TSEN54, UBA7, FAM179A, TGFBR3, CCDC114, AKAP9, BNC2, BZRAP1, CCL4, CHST2, CSF1, ERBB2, GBR56, GRAMD3, GRHL2, GRK4, ITIH4, KIAA1618, LOC147646, LOC150622, LOC161527, PLEKHF1, PRKD2, RGNEF, SESN2, SLAMF7, SPON2, STAT1, SYNGR1, TRX21, TMEM67, TUBE1, and ZNF827, and/or a decrease of the expression level of one or more biomarkers selected from the group consisting of HLA-DQA1, FLJ13773, QKI, MPZL3, FAM70B, LOC254128, IL8, CHML, STX7, VAPA, UGCG, PDXDC1, LRRC8B, STK4, GTF2H2, AGFG1, BTG1, CFDP1, CNPY2, FAM105A, GATM, GTF2H2B, IGHG1, IL18RAP, N4BP2, PHACTR1, RTKN2, SLC16A1, SOCS1, SPAG17, ST6GALNAC1, STK17B, STT3B, STX16, TBC1D12, TRIM4, UACA, and WHAMML2 compared to the expression level of the plurality of endogenous reference biomarkers indicates that the patient suffers from or is at risk of experiencing lacunar stroke, thereby diagnosing the occurrence of lacunar stroke or the predisposition for experiencing lacunar stroke.   
     
     
         2 . The method of  claim 1 , wherein an increase of the expression level of one or more biomarkers selected from the group consisting of RASEF, CALM1, TTC12, CCL3, CCL3L1, CCL3L3, CCDC78, PRSS23, LAIR2, C18orf49, UTS2, LGR6, PROCR, LAG3, OASL, LOC100132181, HLA-DRB4, CCL2, ALS2CR11, SCAND2, GBP4, RUNX3, TSEN54, UBA7, FAM179A, TGFBR3, and CCDC114, and/or a decrease of the expression level of one or more biomarkers selected from the group consisting of HLA-DQA1, FLJ13773, QKI, MPZL3, FAM70B, LOC254128, IL8, CHML, STX7, VAPA, UGCG, PDXDC1, LRRC8B, STK4, and GTF2H2, compared to the expression level of the plurality of endogenous reference biomarkers indicates that the patient suffers from or is at risk of experiencing lacunar stroke. 
     
     
         3 . The method of  claim 1 , wherein the expression levels of the biomarkers are concurrently or sequentially determined. 
     
     
         4 . The method of  claim 1 , further comprising the step of obtaining a biological sample from the patient. 
     
     
         5 . The method of  claim 4 , wherein the biological sample is blood, serum or plasma. 
     
     
         6 . The method of  claim 1 , wherein the plurality of stably expressed endogenous reference biomarkers are selected from USP7, MAPRE2, CSNK1G2, SAFB2, PRKAR2A, PI4KB, CRTC1, HADHA, MAP1LC3B, KAT5, GTSE1, CDC2L1///CDC2L2, TCF25, CHP, LRRC40, hCG — 2003956///LYPLA2///LYPLA2P1, DAXX, UBE2NL, EIF1, KCMF1, PRKRIP1, CHMP4A, TMEM184C, TINF2, PODNL1, FBXO42, LOC441258, RRP1, C10orf104, ZDHHC5, C9orf23, LRRC45, NACC1, LOC100133445///LOC115110 and PEX16. 
     
     
         7 . The method of  claim 1 , wherein the level of expression of 15 to 85 lacunar stroke-associated biomarkers is determined. 
     
     
         8 . The method of  claim 1 , wherein the determining step is performed within 72 hours after a suspected ischemic event. 
     
     
         9 . The method of  claim 1 , wherein the patient has at least one vascular risk factor. 
     
     
         10 . The method of  claim 1 , wherein the patient shows evidence of microhemorrhage. 
     
     
         11 . The method of  claim 1 , wherein the patient is non-Caucasian. 
     
     
         12 . The method of  claim 1 , wherein the patient does not have arterial disease ipsilateral to the stroke. 
     
     
         13 . The method of  claim 1 , wherein the level of expression of the biomarker is determined at the transcriptional level. 
     
     
         14 . The method of  claim 13 , wherein the level of expression is determined by detecting hybridization of a lacunar stroke-associated gene probe to gene transcripts of the biomarkers in the biological sample. 
     
     
         15 . The method of  claim 14 , wherein the hybridization step is performed on a nucleic acid array chip. 
     
     
         16 . The method of  claim 14 , wherein the hybridization step is performed in a microfluidics assay plate. 
     
     
         17 . The method of  claim 13 , wherein the level of expression is determined by amplification of gene transcripts of the biomarkers. 
     
     
         18 . The method of  claim 17 , wherein the amplification reaction is a polymerase chain reaction (PCR). 
     
     
         19 . The method of  claim 1 , wherein the level of expression of the biomarker is determined at the protein level. 
     
     
         20 . The method of  claim 1 , further comprising the step of determining the size and/or location of a suspected ischemic event. 
     
     
         21 . The method of  claim 1 , wherein if the patient has experienced or has a predisposition to experience non-lacunar stroke, further comprising the step of determining the cause or risk of ischemic stroke. 
     
     
         22 . The method of  claim 1 , further comprising the step of delivering a treatment or prevention regime appropriate to the determined cause of the stroke. 
     
     
         23 . A method for diagnosing lacunar stroke or a predisposition for developing lacunar stroke, the method comprising: determining a level of expression of a plurality of lacunar stroke-associated biomarkers in a biological sample from a patient, wherein an increase or decrease of the level compared to a control level of expression indicates that the patient suffers from or is at risk of developing lacunar stroke;
 wherein an increase of the expression level of one or more biomarkers selected from the group consisting of RASEF, CALM1, TTC12, CCL3, CCL3L1, CCL3L3, CCDC78, PRSS23, LAIR2, C18orf49, UTS2, LGR6, PROCR, LAG3, OASL, LOC100132181, HLA-DRB4, CCL2, ALS2CR11, SCAND2, GBP4, RUNX3, TSEN54, UBA7, FAM179A, TGFBR3, CCDC114, AKAP9, BNC2, BZRAP1, CCL4, CHST2, CSF1, ERBB2, GBR56, GRAMD3, GRHL2, GRK4, ITIH4, KIAA1618, LOC147646, LOC150622, LOC161527, PLEKHF1, PRKD2, RGNEF, SESN2, SLAMF7, SPON2, STAT1, SYNGR1, TRX21, TMEM67, TUBE1, and ZNF827, and/or a decrease of the expression level of one or more biomarkers selected from the group consisting of HLA-DQA1, FLJ13773, QKI, MPZL3, FAM70B, LOC254128, IL8, CHML, STX7, VAPA, UGCG, PDXDC1, LRRC8B, STK4, GTF2H2, AGFG1, BTG1, CFDP1, CNPY2, FAM105A, GATM, GTF2H2B, IGHG1, IL18RAP, N4BP2, PHACTR1, RTKN2, SLC16A1, SOCS1, SPAG17, ST6GALNAC1, STK17B, STT3B, STX16, TBC1D12, TRIM4, UACA, and WHAMML2, compared to the control level of expression indicates that the patient suffers from or is at risk of experiencing lacunar stroke, thereby diagnosing the occurrence of lacunar stroke or the predisposition for experiencing lacunar stroke.   
     
     
         24 - 45 . (canceled) 
     
     
         46 . A solid support comprising a plurality of nucleic acids that hybridize to a plurality of lacunar stroke-associated genes selected from the group consisting of HLA-DQA1, FLJ13773, RASEF, CALM1, QKI, TTC12, CCL3///CCL3L1///CCL3L3, CCDC78, PRSS23, LAIR2, C18orf49, MPZL3, UTS2, FAM70B, UTS2, LOC254128, LGR6, IL8, CHML, STX7, PROCR, VAPA, LAG3, OASL, LOC100132181, HLA-DRB4, CCL2, UGCG, PDXDC1, ALS2CR11, SCAND2, GBP4, RUNX3, LRRC8B, TSEN54, UBA7, STK4, FAM179A, TGFBR3, CCDC114, GTF2H2, AKAP9, BNC2, BZRAP1, CCL4, CHST2, CSF1, ERBB2, GBR56, GRAMD3, GRHL2, GRK4, ITIH4, KIAA1618, LOC147646, LOC150622, LOC161527, PLEKHF1, PRKD2, RGNEF, SESN2, SLAMF7, SPON2, STAT1, SYNGR1, TRX21, TMEM67, TUBE1, ZNF827, AGFG1, BTG1, CFDP1, CNPY2, FAM105A, GATM, GTF2H2, IGHG1, IL18RAP, N4BP2, PHACTR1, QK1, RTKN2, SLC16A1, SOCS1, SPAG17, ST6GALNAC1, STK17B, STT3B, STX16, TBC1D12, TRIM4, UACA, and WHAMML2. 
     
     
         47 - 52 . (canceled)