Biomarkers of chronic obstructive pulmonary disease

Abstract

The methods described herein are based on the discovery that the plasma level of a panel of specific proteins differs between two subject populations: 1) subjects at risk for chronic obstructive pulmonary disease (“COPD”) but not manifesting clinical symptoms of COPD; and 2) subjects having very severe COPD. The difference in plasma levels is statistically significant for each protein. The identification of these proteins thus facilitates susceptibility detection, early disease detection, disease severity assessment, disease progression monitoring, and therapy efficacy monitoring.

What is claimed is: 
     
         1 . A method for assessing susceptibility of developing chronic obstructive pulmonary disease (COPD) in a subject at risk for developing COPD, the method comprising detecting the presence of or assessing the level of at least one biomarker from the group comprising Lethal (3) malignant brain tumor-like 3 protein (LMBL3); Cathelicidin antimicrobial peptide (CAMP); Contactin-1 (CNTN1); Vascular cell adhesion protein 1 (VCAM1); Interleukin-1 receptor accessory protein (IL1RAP); Dermcidin (DCD); Vitamin K-dependent protein Z (PROZ); Hepatocyte growth factor-like (HGFL); Cell surface glycoprotein (MUC18); 79 kDa glucose-regulated protein (GRP78); Coagulation factor V (FA5); Scavenger receptor cysteine-rich type 1 protein M130 (C163A); Neural cell adhesion molecule (NCAM1); Proteoglycan 4 (PRG4); Procollagen C-endopeptidase enhancer 1 (PCOC1); Plastin-2 OS Homo sapiens (PLSL); Coagulation factor XIII A chain (F13A); Fetuin-B (FETUB); Protein S100-A6 (S10A); Metalloproteinase inhibitor 2 (TIMP2); Peroxiredoxin-1 (PRDX 1); Macrophage colony-stimulating factor 1 receptor (CSF1R); Probable G protein coupled receptor 25 (GPR25); Putative zinc-alpha-2-glycoprotein-like 1 (ZAGL1); HLA class I histocompatibility antigen, B-15 alpha chain (1B15); Mannosyl-oligosaccharide 1,2-alpha-mannosidase IA (MA1A1); Myelin P2 (MYP2); Metalloproteinase inhibitor 1 (TIMP1); HLA class I histocompatibility antigen, A-1 alpha chain (1A01); Haptoglobin-alpha isoform 2 (HPT2a); and Haptoglobin-alpha isoform 2 having a post-translational modification (HPT2a-PTM) in the sequence CEADDGCPK (SEQ ID No. 32) comprising at least one of carbamidomethylation of C1, methylation of D4, methylation of D5, and acetylation of K9, in a biological fluid sample obtained from the subject, wherein the biological fluid is selected from peripheral whole blood, serum and plasma; and
 wherein if
 a) the presence of one or more of LMBL3, CAMP, CNTN1, VCAM1, IL1RAP, DCD, and PROZ is detected; 
 b) an increased level of one or more of HGFL, MUC18, GRP78, FA5, HPT2a and HPT2a-PTM is assessed, relative to the level of the biomarker in a biological fluid sample from a normal reference; 
 c) a decreased level of one or more of C163A, NCAM1, PRG4, PCOC1, PLSL, F13A, and FETUB is assessed, relative to the level of the biomarker in a biological fluid sample from a normal reference; and/or 
 d) a decreased level of one or more of S10A, TIMP2, PRDX1, CSF1R, GPR25, ZAGL1, 1B15, MA1A1, MYP2, TIMP1, and 1A01 is assessed, relative to the level of the biomarker in a biological fluid sample from a normal reference; 
   then an increased susceptibility of developing COPD is indicated in the at-risk subject.   
     
     
         2 . The method of  claim 1 , wherein the biological fluid is plasma or serum. 
     
     
         3 . The method of  claim 1 , wherein at least two or more biomarkers are detected or assessed. 
     
     
         4 . The method of  claim 3 , wherein at least three or more biomarkers are detected or assessed. 
     
     
         5 . The method of  claim 1 , wherein the at least one biomarker is selected from HPT2a, GRP78, HGFL, and IL1RAP. 
     
     
         6 . The method of  claim 3 , wherein at least one of the at least two biomarkers is selected from HPT2a, GRP78, HGFL, and IL1RAP. 
     
     
         7 . The method of  claim 4 , wherein the biomarkers comprise HPT2a, GRP78, HGFL, and IL1RAP. 
     
     
         8 . A method for assessing severity of COPD in a subject diagnosed with COPD, the method comprising detecting the presence of or assessing the level of a biomarker from the group comprising Lethal (3) malignant brain tumor-like 3 protein (LMBL3); Cathelicidin antimicrobial peptide (CAMP); Contactin-1 (CNTN1); Vascular cell adhesion protein 1 (VCAM1); Interleukin-1 receptor accessory protein (IL1RAP); Dermcidin (DCD); Vitamin K-dependent protein Z (PROZ); Hepatocyte growth factor-like (HGFL); Cell surface glycoprotein (MUC18); 79 kDa glucose-regulated protein (GRP78); Coagulation factor V (FA5); Scavenger receptor cysteine-rich type 1 protein M130 (C163A); Neural cell adhesion molecule (NCAM1); Proteoglycan 4 (PRG4); Procollagen C-endopeptidase enhancer 1 (PCOC1); Plastin-2 OS Homo sapiens (PLSL); Coagulation factor XIII A chain (F13A); Fetuin-B (FETUB); Protein S100-A6 (S10A); Metalloproteinase inhibitor 2 (TIMP2); Peroxiredoxin-1 (PRDX1); Macrophage colony-stimulating factor 1 receptor (CSF1R); Probable G protein coupled receptor 25 (GPR25); Putative zinc-alpha-2-glycoprotein-like 1 (ZAGL1); HLA class I histocompatibility antigen, B-15 alpha chain (IBIS); Mannosyl-oligosaccharide 1,2-alpha-mannosidase IA (MA1A1); Myelin P2 (MYP2); Metalloproteinase inhibitor 1 (TIMP1); HLA class I histocompatibility antigen, A-1 alpha chain (1A01); Haptoglobin-alpha isoform 2 (HPT2a); and Haptoglobin-alpha isoform 2 having a post-translational modification in the sequence CEADDGCPK (SEQ ID No. 32) comprising at least one of carbamidomethylation of C1, methylation of D4, methylation of D5, and acetylation of K9, in a biological fluid sample obtained from the subject, wherein the biological fluid is selected from peripheral whole blood, serum and plasma; and
 wherein if :
 a) the presence of one or more of LMBL3, CAMP, CNTN1, VCAM1, IL1RAP, DCD and PROZ is detected; 
 b) an increased level of one or more of HGFL, MUC18, GRP78, FA5, HPT2a and HPT2a-PTM is assessed, relative to the level of the biomarker in a biological fluid sample from a normal reference; 
 c) a decreased level of one or more of C163A, NCAM1, PRG4, PCOC1, PLSL, F13A, and FETUB is assessed, relative to the level of the biomarker in a biological fluid sample from a normal reference; and/or 
 d) a decreased level of one or more of S10A, TIMP2, PRDX1, CSF1R, GPR25, ZAGL1, 1B15, MA1A1, MYP2, TIMP1, and 1A01 is assessed, relative to the level of the biomarker in a biological fluid sample from a normal reference; 
   then increased severity of COPD is indicated in the subject diagnosed with COPD.   
     
     
         9 . The method of  claim 8 , wherein the biological fluid is plasma or serum. 
     
     
         10 . The method of  claim 8 , wherein at least two or more biomarkers are detected or assessed. 
     
     
         11 . The method of  claim 10 , wherein at least three or more biomarkers are detected or assessed. 
     
     
         12 . The method of  claim 8 , wherein the at least one biomarker is selected from HPT2a, GRP78, HGFL and IL1RAP. 
     
     
         13 . The method of  claim 10 , wherein at least one of the at least two biomarkers is selected from HPT2a, GRP78, HGFL and IL1RAP. 
     
     
         14 . The method of  claim 11 , wherein the biomarkers comprise HPT2a, GRP78, HGFL and IL1RAP. 
     
     
         15 . A method of monitoring susceptibility of developing COPD in a subject at risk of developing COPD, the method comprising:
 i) detecting the presence of or assessing the level of a biomarker from the group comprising Lethal (3) malignant brain tumor-like 3 protein (LMBL3); Cathelicidin antimicrobial peptide (CAMP); Contactin-1 (CNTN1); Vascular cell adhesion protein 1 (VCAM1); Interleukin-1 receptor accessory protein (IL1RAP); Dermcidin (DCD); Vitamin K-dependent protein Z (PROZ); Hepatocyte growth factor-like (HGFL); Cell surface glycoprotein (MUC18); 79 kDa glucose-regulated protein (GRP78); Coagulation factor V (FA5); Scavenger receptor cysteine-rich type 1 protein M130 (C163A); Neural cell adhesion molecule (NCAM1); Proteoglycan 4 (PRG4); Procollagen C-endopeptidase enhancer 1 (PCOC1); Plastin-2 OS Homo sapiens (PLSL); Coagulation factor XIII A chain (F13A); Fetuin-B (FETUB); Protein S100-A6 (S10A); Metalloproteinase inhibitor 2 (TIMP2); Peroxiredoxin-1 (PRDX1); Macrophage colony-stimulating factor 1 receptor (CSF1R); Probable G protein coupled receptor 25 (GPR25); Putative zinc-alpha-2-glycoprotein-like 1 (ZAGL1); HLA class I histocompatibility antigen, B-15 alpha chain (1B15); Mannosyl-oligosaccharide 1,2-alpha-mannosidase IA (MA1A1); Myelin P2 (MYP2); Metalloproteinase inhibitor 1 (TIMP1); HLA class I histocompatibility antigen, A-1 alpha chain (1A01); Haptoglobin-alpha isoform 2 (HPT2a); and Haptoglobin-alpha isoform 2 having a post-translational modification in the sequence CEADDGCPK (SEQ ID No. 32) comprising at least one of carbamidomethylation of C1, methylation of D4, methylation of D5, and acetylation of K9, in a first biological fluid sample from an at-risk subject diagnosed with COPD obtained at a first time point;   ii) detecting the presence of or assessing the level of the biomarker in a second biological fluid sample from the at-risk subject obtained at a second time point;   iii) comparing the level of the biomarker detected or assessed in the first sample to the level of the biomarker detected or assessed in the second sample, wherein if:
 a) the presence of one or more of LMBL3, CAMP, CNTN1, VCAM1, IL1RAP, DCD, and PROZ is detected in the second biological fluid sample; 
 b) an increased level of one or more of HGFL, MUC 18, GRP78, FA5, HPT2a and HPT2a-PTM is assessed in the second biological sample relative to the level in first biological fluid sample; 
 c) a decreased level of one or more of C163A, NCAM1, PRG4, PCOC1, PLSL, F13A, and FETUB is assessed in the second biological sample relative to the level in first biological fluid sample; and/or 
 d) a decreased level of one or more of S10A, TIMP2, PRDX1, CSF1R, GPR25, ZAGL1, 1B15, MA1A1, MYP2, TIMP1, and 1A01 is assessed in the second biological sample relative to the level in first biological fluid sample; 
   then an increase in susceptibility of developing COPD is indicated for the at-risk subject.   
     
     
         16 . The method of  claim 15 , wherein the biological fluid is plasma or serum. 
     
     
         17 . The method of  claim 15 , wherein at least two or more biomarkers are detected or assessed. 
     
     
         18 . The method of  claim 17 , wherein at least three or more biomarkers are detected or assessed. 
     
     
         19 . The method of  claim 15 , wherein the at least one biomarker is selected from HPT2a, GRP78, HGFL, and IL1RAP. 
     
     
         20 . The method of  claim 17 , wherein at least one of the at least two biomarker is selected from HPT2a, GRP78, HGFL, and IL1RAP. 
     
     
         21 . The method of  claim 18 , wherein the biomarkers comprise HPT2a, GRP78, HGFL, and IL1RAP. 
     
     
         22 . A method of monitoring the progression of COPD in a subject diagnosed with COPD, the method comprising:
 i) detecting the presence of or assessing the level of a biomarker from the group comprising Lethal (3) malignant brain tumor-like 3 protein (LMBL3); Cathelicidin antimicrobial peptide (CAMP); Contactin-1 (CNTN1); Vascular cell adhesion protein 1 (VCAM1); Interleukin-1 receptor accessory protein (IL1RAP); Deimcidin (DCD); Vitamin K-dependent protein Z (PROZ); Hepatocyte growth factor-like (HGFL); Cell surface glycoprotein (MUC18); 79 kDa glucose-regulated protein (GRP78); Coagulation factor V (FA5); Scavenger receptor cysteine-rich type 1 protein M130 (C163A); Neural cell adhesion molecule (NCAM1); Proteoglycan 4 (PRG4); Procollagen C-endopeptidase enhancer 1 (PCOC1); Plastin-2 OS Homo sapiens (PLSL); Coagulation factor XIII A chain (F13A); Fetuin-B (FETUB); Protein S100-A6 (S10A); Metalloproteinase inhibitor 2 (TIMP2); Peroxiredoxin-1 (PRDX1); Macrophage colony-stimulating factor 1 receptor (CSF1R); Probable G protein coupled receptor 25 (GPR25); Putative zinc-alpha-2-glycoprotein-like 1 (ZAGL1); HLA class I histocompatibility antigen, B-15 alpha chain (1B15); Mannosyl-oligosaccharide 1,2-alpha-mannosidase IA (MA1A1); Myelin P2 (MYP2); Metalloproteinase inhibitor 1 (TIMP1); HLA class I histocompatibility antigen, A-1 alpha chain (1A01); Haptoglobin-alpha isoform 2 (HPT2a); and Haptoglobin-alpha isoform 2 having a post-translational modification in the sequence CEADDGCPK (SEQ ID No. 32) comprising at least one of carbamidomethylation of C1, methylation of D4, methylation of D5, and acetylation of K9, in a first biological fluid sample from a subject diagnosed with COPD obtained at a first time point;   ii) detecting the presence of or assessing the level of the biomarker in a second biological fluid sample from the subject obtained at a second time point;   iii) comparing the level of the biomarker detected or assessed in the first sample to the level of the biomarker detected or assessed in the second sample, wherein if:
 a) the presence of one or more of LMBL3, CAMP, CNTN1, VCAM1, IL1RAP, DCD, and PROZ is detected in the second biological fluid sample; 
 b) an increased level of one or more of HGFL, MUC18, GRP78, FA5, HPT2a and HPT2a-PTM is assessed in the second biological sample relative to the level in first biological fluid sample; 
 c) a decreased level of one or more of C163A, NCAM1, PRG4, PCOC1, PLSL, F13A, and FETUB is assessed in the second biological sample relative to the level in first biological fluid sample; and/or 
 d) a decreased level of one or more of S10A, TIMP2, PRDX1, CSF1R, GPR25, ZAGL1, 1B15, MA1A1, MYP2, TIMP1, and 1A01 is assessed in the second biological sample relative to the level in first biological fluid sample; 
   then progression of COPD in the subject is indicated.   
     
     
         23 . The method of  claim 22 , wherein the biological fluid is plasma or serum. 
     
     
         24 . The method of  claim 22 , wherein at least two or more biomarkers are detected or assessed. 
     
     
         25 . The method of  claim 24 , wherein at least three or more biomarkers are detected or assessed. 
     
     
         26 . The method of  claim 22 , wherein the at least one biomarker is selected from HPT2a, GRP78, HGFL, and IL1RAP. 
     
     
         27 . The method of  claim 24 , wherein at least one of the at least two biomarker is selected from HPT2a, GRP78, HGFL, and IL1RAP. 
     
     
         28 . The method of  claim 25 , wherein biomarkers comprise HPT2a, GRP78, HGFL, and IL1RAP. 
     
     
         29 . A method for assessing risk of COPD characterized by moderate or severe airway obstruction in a subject diagnosed with COPD, the method comprising assessing the level of a biomarker from the group comprising Hepatocyte growth factor-like (HGFL); 79 kDa glucose-regulated protein (GRP78); and Scavenger receptor cysteine-rich type 1 protein M130 (C163A), in a biological fluid sample obtained from the subject, wherein the biological fluid is selected from peripheral whole blood, serum and plasma; and
 wherein if:
 a) an increased level of one or more of HGFL and GRP78 is assessed, relative to the level of the biomarker in a biological fluid sample from a normal reference; and/or 
 b) a decreased level of C163A is assessed, relative to the level of the biomarker in a biological fluid sample from a normal reference; 
   then increased risk of COPD characterized by moderate or severe airway obstruction is indicated in the subject diagnosed with COPD.   
     
     
         30 . The method of  claim 29 , wherein the greater the increased level of HGFL, the increased level of GRP78, and/or the decreased level of C163A, the greater the risk of COPD characterized by moderate or severe airway obstruction in the subject diagnosed with COPD. 
     
     
         31 . The method of  claim 29 , wherein the level of GRP78 and the level of HGFL are assessed. 
     
     
         32 . The method of  claim 29 , wherein the biological fluid is plasma or serum. 
     
     
         33 . A method of monitoring the progression of airway obstruction in a subject diagnosed with COPD, the method comprising:
 i) assessing the level of a biomarker from the group comprising Hepatocyte growth factor-like (HGFL); 79 kDa glucose-regulated protein (GRP78); and Scavenger receptor cysteine-rich type 1 protein M130 (C163A) in a first biological fluid sample from a subject diagnosed with COPD obtained at a first time point, wherein the biological fluid is selected from peripheral whole blood, serum and plasma;   ii) assessing the level of the biomarker in a second biological fluid sample from the subject obtained at a second time point;   iii) comparing the level of the biomarker assessed in the first sample to the level of the biomarker detected or assessed in the second sample, wherein if:
 a) an increased level of one or more of HGFL and GRP78 is assessed in the second biological sample relative to the level in first biological fluid sample; and/or 
 b) a decreased level of C163A is assessed in the second biological sample relative to the level in first biological fluid sample; 
   then progression of airway obstruction in the subject is indicated.   
     
     
         34 . The method of  claim 33 , wherein the greater the increased level of HGFL, the increased level of GRP78, and/or the decreased level of C163A, the greater the progression of airway obstruction in the subject diagnosed with COPD. 
     
     
         35 . The method of  claim 33 , wherein the level of GRP78 and the level of HGFL are assessed. 
     
     
         36 . The method of  claim 33 , wherein the biological fluid is plasma or serum.