MATERNAL SERUM BIOMARKERS FOR DETECTION OF PRE-ECLAMPSIA
The present invention concerns the identification and detection of maternal serum biomarkers of pre-eclampsia and associated complications, gestational hypertension and placental insufficiency using global proteomic approaches. The invention further concerns the identification of maternal serum biomarkers for detection of pre-eclampsia and associated complications, gestational hypertension and placental insufficiency during early gestation.
1 . A method for the diagnosis of active pre-eclampsia in a pregnant female mammalian subject comprising:
(a) testing in a maternal serum sample obtained from said subject the level of two or more proteins selected from the group consisting of apolipoprotein C-III (P02656), choriogonadotropin subunit beta (P1233), cystatin-C (P01034), endoglin (P17813), fibronectin (Q8IVI8), matrix metalloproteinase-9 (P14780), and pappalysin-2 (Q9BXP8), relative to the level in normal maternal serum or maternal serum known to be indicative of pre-eclampsia; and
(b) diagnosing said subject with pre-eclampsia if said level is determined to show a statistically significant difference relative to the level in said normal maternal serum, or is determined not to show a statistically significant difference relative to the level in said maternal serum known to be indicative of pre-eclampsia.
2 . The method of claim 1 wherein the subject is a human patient.
3 . The method of claim 2 , wherein said testing is implemented using an apparatus adapted to determine the level of said proteins.
4 . The method of claim 2 , wherein said testing is performed by using a software program executed by a suitable processor.
5 . The method of claim 4 , wherein the program is embodied in software stored on a tangible medium.
6 . The method of claim 5 wherein the tangible medium is selected from the group consisting of a flash drive, a CD-ROM, a floppy disk, a hard drive, a DVD, and a memory associated with the processor.
7 . The method of any one of claims 2 to 6 , further comprising the step of preparing a report recording the results of said testing or the diagnosis.
8 . The method of claim 7 wherein said report is recorded or stored on a tangible medium.
9 . The method of claim 8 wherein the tangible medium is paper.
10 . The method of claim 8 wherein the tangible medium is selected from the group consisting of a flash drive, a CD-ROM, a floppy disk, a hard drive, a DVD, and a memory associated with the processor.
11 . The method of any one of claims 2 to 6 , further comprising the step of communicating the results of said diagnosis to an interested party.
12 . The method of claim 11 wherein the interested party is the patient or the attending physician.
13 . The method of claim 11 wherein the communication is in writing, by email, or by telephone.
14 . The method of claim 2 comprising testing the abundance of at least three of said proteins.
15 . The method of claim 2 comprising testing the abundance of at least four of said proteins.
16 . The method of claim 2 comprising testing the level of proteins fibronectin (Q8IVI8), choriogonadotropin subunit beta (P1233), matrix metalloproteinase-9 (P14780) and pappalysin-2 (Q9BXP8), and diagnosing said subject with pre-eclampsia, if two or more of said tested proteins shows a statistically significant difference in the maternal serum sample relative to normal maternal serum.
17 . The method of claim 16 comprising diagnosing said subject with pre-eclampsia, if all of said tested proteins show a statistically significant difference in the maternal serum sample relative to normal maternal serum.
18 . The method of claim 2 wherein said level is determined by an immunoassay.
19 . The method of claim 2 wherein said level is determined by mass spectrometry.
20 . The method of claim 2 wherein said level is determined using a protein array.
21 . An immunoassay kit comprising antibodies and reagents for the detection of one or more proteins selected from the group consisting of alpha-1B-glycoprotein (P04217), actin (P62736), apolipoprotein B-100 (Q13787), apolipoprotein C-II (P02655), apolipoprotein C-III (P02656), C4b-binding protein beta chain (P20851), cathepsin D (P07339), choriogonadotropin subunit beta (P1233), cholinesterase (P06276), chorionic somatomammotropin hormone (P01243), cystatin-C (P01034), endoglin (P17813), coagulation factor XI (P03951), coagulation factor VII (P08709), fibronectin (Q8IVI8), filamin-A (P21333), heparin cofactor 2 (P05546), hepatocyte growth factor-like protein (P26927), histidine-rich glycoprotein (P04196), insulin-like growth factor-binding protein 2 (P18065), laminin subunit beta-1 (P07942), lipopolysaccharide-binding protein (P18428), matrix metalloproteinase-9 (P14780), pappalysin-2 (Q9BXP8), plastin-2 (P13796), profiling-1 (P07737), pregnancy-specific bet-1-glycoprotein (P11464), receptor-type tyrosine-protein phosphatase gamma (P23470), pregnancy zone protein (P20742), plasma retinol-binding protein (P02753), SH3 domain-binding glutamic acid-rich-like protein 3 (Q9H299), trangelin-2 (P37802), talin-1 (Q9Y490), tropomyosin alpha-4-chain (P67936), vasorin (Q6EMK4), vascular endothelial growth factor receptor 3 (P35916), vinculin (P18206), von Willebrand factor (P04275).
22 . An immunoassay kit comprising antibodies and reagents for the detection of one or more proteins selected from the group consisting of cystatin-C (P01034), endoglin (P17813), fibronectin (Q8IVI8), apolipoprotein C-III (P02656), choriogonadotropin subunit beta (P1233) and pappalysin-2 (Q9BXP8).
23 . The immunoassay kit of claim 22 comprising antibodies and reagents for the detection of all of said proteins.
24 . An immunoassay kit comprising antibodies and reagents for the detection of one or more proteins selected from the group consisting of cystatin-C (P01034), endoglin (P17813), fibronectin (Q8IVI8), apolipoprotein C-III (P02656), and pappalysin-2 (Q9BXP8).
25 . The immunoassay kit of claim 24 comprising antibodies and reagents for the detection of all of said proteins.
26 . An immunoassay kit comprising antibodies and reagents for the detection of one or more proteins selected from the group consisting of fibronectin (Q8IVI8), pappalysin-2 (Q9BXP8), and matrix metalloproteinase-9 (P14780).
27 . The immunoassay kit of claim 26 comprising antibodies and reagents for the detection of all of said proteins.
28 . A report comprising the results of and/or diagnosis based on a test comprising
(a) testing in a maternal serum sample obtained from said subject the level of two or more proteins selected from the group consisting of apolipoprotein C-III (P02656), choriogonadotropin subunit beta (P1233), cystatin-C (P01034), endoglin (P17813), fibronectin (Q8IVI8), matrix metalloproteinase-9 (P14780), and pappalysin-2 (Q9BXP8), relative to the level in normal maternal serum or maternal serum known to be indicative of pre-eclampsia; and
(b) diagnosing said subject with pre-eclampsia if said level is determined to show a statistically significant difference relative to the level in said normal maternal serum, or is determined not to show a statistically significant difference relative to the level in said maternal serum known to be indicative of pre-eclampsia.
29 . A tangible medium storing the results of and/or diagnosis based on a test comprising
(a) testing in a maternal serum sample obtained from said subject the level of two or more proteins selected from the group consisting of apolipoprotein C-III (P02656), choriogonadotropin subunit beta (P1233), cystatin-C (P01034), endoglin (P17813), fibronectin (Q8IVI8), matrix metalloproteinase-9 (P14780), and pappalysin-2 (Q9BXP8), relative to the level in normal maternal serum or maternal serum known to be indicative of pre-eclampsia; and
(b) diagnosing said subject with pre-eclampsia if said level is determined to show a statistically significant difference relative to the level in said normal maternal serum, or is determined not to show a statistically significant difference relative to the level in said maternal serum known to be indicative of pre-eclampsia.
30 . A method for the diagnosis of pre-eclampsia in a female mammalian subject in early gestation comprising:
(a) testing in a maternal serum sample obtained from said subject the level of two or more proteins selected from the group consisting of alpha-2-antiplasmin (P08697), actin (P60709), afamin (P43652), antithrombin-III (P01008), apolipoprotein-A-II (P02652), attractin (Q9NTQ4), beta-2-microglobulin (P61769), transforming growth factor-beta-induced protein ig-h3 (Q15582), C4b-binding protein alpha chain (P04003), cathepsin D (P07339), carboxypeptidase B2 (Q961Y4), complement factor D (P00746), cartilage acidic protein 1 (Q9NQ79), dopamine beta-hydroxylase (P09172), coagulation factor XIII B chain (P05160), fibrinogen alpha chain (P02671), fibronectin (Q8IVI8), filamin A (P21333), Rho GDP-dissociation inhibitor 2 (P52566), platelet glycoprotein-1b alpha chain (P07359), haptoglobin-related protein (P00739), lipopolysaccharide-binding protein (P18418), plasma retinol-binding protein (P02753), platelet basic protein (P02775), transgelin-2 (P37802), tubulin beta-1 chain (Q9H4B7), talin-1 (Q9Y490), thymosin beta-4 (P62328), vasorin (Q6EMK4), vascular cell adhesion protein-1 (P19320), von Willebrand factor (P04275), zinc-alpha-2-glycoprotein (P25311), alpha-2-macroglobulin (P01023), apolipoprotein B-100 (Q13787), apolipoprotein C-III (P02656), choriogonadotropin subunit beta (P01233), chorionic somatomammotropin hormone (P01243), cystatin-C (P01034), endoglin (P17813), matrix metalloproteinase-9 (P14780), pappalysin-1 (Q13219), pregnancy-specific beta-1-glycoprotein 1 (Q9P1W5), vascular endothelial growth factor receptor 3 (P35916), C-reactive protein (P02741), serum amyloid P-component (P02743), membrane copper amine oxidase (Q16853), and catalase (P04040), relative to the level in normal maternal serum or maternal serum known to be indicative of pre-eclampsia; and
(b) diagnosing said subject with pre-eclampsia if said level shows a statistically significant difference relative to the level in said normal maternal serum, or does not show a statistically significant difference relative to the level in said maternal serum known to be indicative of pre-eclampsia.
31 . The method of claim 30 wherein the subject is a human patient.
32 . The method of claim 31 , wherein said testing is implemented using an apparatus adapted to determine the level of said proteins.
33 . The method of claim 31 , wherein said testing is performed by using a software program executed by a suitable processor.
34 . The method of claim 33 , wherein the program is embodied in software stored on a tangible medium.
35 . The method of claim 34 wherein the tangible medium is selected from the group consisting of a flash drive, a CD-ROM, a floppy disk, a hard drive, a DVD, and a memory associated with the processor.
36 . The method of any one of claims 31 to 35 , further comprising the step of preparing a report recording the results of said testing or the diagnosis.
37 . The method of claim 36 wherein said report is recorded or stored on a tangible medium.
38 . The method of claim 37 wherein the tangible medium is paper.
39 . The method of claim 37 wherein the tangible medium is selected from the group consisting of a flash drive, a CD-ROM, a floppy disk, a hard drive, a DVD, and a memory associated with the processor.
40 . The method of any one of claims 31 to 35 , further comprising the step of communicating the results of said diagnosis to an interested party.
41 . The method of claim 40 wherein the interested party is the patient or the attending physician.
42 . The method of claim 40 wherein the communication is in writing, by email, or by telephone.
43 . The method of claim 30 wherein the subject is about 9 to about 11 weeks gestation.
44 . The method of claim 30 wherein the subject is about 10 to about 14 weeks gestation.
45 . The method of claim 30 wherein the pre-eclampsia is severe pre-eclampsia.
46 . The method of any one of claims 43 - 45 comprising testing the level of at least three of said proteins.
47 . The method of any one of claims 43 - 45 comprising testing the level of at least four of said proteins.
48 . The method of any one of claims 43 - 45 comprising testing the level of at least five of said proteins.
49 . The method of claim 43 comprising testing the level of at least six of said proteins.
50 . The method of claim 43 comprising testing the level of proteins complement factor D (P00746), vascular cell adhesion protein-1 (P19320), pappalysin-1 (Q13219), endoglin (P17813), plasma retinol-binding protein (P02753), and choriogonadotropin subunit beta (P01233).
51 . The method of claim 44 comprising testing the level of proteins membrane copper amine oxidase (Q16853), C-reactive protein (P02741), Serum amyloid P-component (P02743), catalase, tubulin beta, plasma retinol binding protein, lipopolysaccharide binding protein, and chorionic somatomammotropin.
52 . The method of claim 44 comprising testing the level of proteins pappalysin-1 (SEQ ID NO: 63), vascular cell adhesion protein 1 (SEQ ID NO: 60), beta-2-microglobulin (SEQ ID NO: 45), and cystatin C (SEQ ID NO: 11).
53 . The method of claim 45 comprising testing the level of proteins C-reactive protein (P02741), vascular cell adhesion protein-1 (P19320), pappalysin-1 (Q13219), beta-2-microglobulin (P61769), and plasma retinol-binding protein (P02753).
54 . The method of claim 30 wherein said level is determined by an immunoassay.
55 . The method of claim 30 wherein said level is determined by mass spectrometry.
56 . The method of claim 30 wherein said level is determined using a protein array.
57 . An immunoassay kit comprising antibodies and reagents for the detection of two or more proteins selected from the group consisting of alpha-2-antiplasmin (P08697), actin (P60709), afamin (P43652), antithrombin-III (P01008), apolipoprotein-A-II (P02652), attractin (Q9NTQ4), beta-2-microglobulin (P61769), transforming growth factor-beta-induced protein ig-h3 (Q15582), C4b-binding protein alpha chain (P04003), cathepsin D (P07339), carboxypeptidase B2 (Q961Y4), complement factor D (P00746), cartilage acidic protein 1 (Q9NQ79), dopamine beta-hydroxylase (P09172), coagulation factor XIII B chain (P05160), fibrinogen alpha chain (P02671), fibronectin (Q8IVI8), filamin A (P21333), Rho GDP-dissociation inhibitor 2 (P52566), platelet glycoprotein-1b alpha chain (P07359), haptoglobin-related protein (P00739), lipopolysaccharide-binding protein (P18418), plasma retinol-binding protein (P02753), platelet basic protein (P02775), transgelin-2 (P37802), tubulin beta-1 chain (Q9H4B7), talin-1 (Q9Y490), thymosin beta-4 (P62328), vasorin (Q6EMK4), vascular cell adhesion protein-1 (P19320), von Willebrand factor (P04275), zinc-alpha-2-glycoprotein (P25311), alpha-2-macroglobulin (P01023), apolipoprotein B-100 (Q13787), apolipoprotein C-III (P02656), choriogonadotropin subunit beta (P01233), chorionic somatomammotropin hormone (P01243), cystatin-C (P01034), endoglin (P17813), matrix metalloproteinase-9 (P14780), pappalysin-1 (Q13219), pregnancy-specific beta-1-glycoprotein 1 (Q9P1W5), vascular endothelial growth factor receptor 3 (P35916), C-reactive protein (P02741), serum amyloid P-component (P02743), membrane copper amine oxidase (Q16853), and catalase (P04040).
58 . An immunoassay kit comprising antibodies and reagents for the detection of two or more proteins selected from the group consisting of complement factor D (P00746), vascular cell adhesion protein-1 (P19320), and pappalysin-1 (Q13219).
59 . The immunoassay kit of claim 58 comprising antibodies and reagents for the detection of all of said proteins.
60 . An immunoassay kit comprising antibodies and reagents for the detection of two or more proteins selected from the group consisting of complement factor D (P00746), vascular cell adhesion protein-1 (P19320), pappalysin-1 (Q13219), endoglin (P17813), choriogonadoropin subunit beta (P01233) and plasma retinol-binding protein (P02753).
61 . The immunoassay kit of claim 60 comprising antibodies and reagents for the detection of all of said proteins.
62 . An immunoassay kit comprising antibodies and reagents for the detection of two or more proteins selected from the group consisting of pappalysin-1 (Q13219), C-reactive protein (P02741), plasma retinol-binding protein (P02753), beta-2-microglobulin (P61769) and vascular cell adhesion protein 1 (P19320).
63 . The immunoassay kit of claim 62 comprising antibodies and reagents for the detection of all of said proteins.
64 . A report comprising the results of and/or diagnosis based on a test comprising
(a) testing in a maternal serum sample obtained from said subject the level of two or more proteins selected from the group consisting of alpha-2-antiplasmin (P08697), actin (P60709), afamin (P43652), antithrombin-III (P01008), apolipoprotein-A-II (P02652), attractin (Q9NTQ4), beta-2-microglobulin (P61769), transforming growth factor-beta-induced protein ig-h3 (Q15582), C4b-binding protein alpha chain (P04003), cathepsin D (P07339), carboxypeptidase B2 (Q961Y4), complement factor D (P00746), cartilage acidic protein 1 (Q9NQ79), dopamine beta-hydroxylase (P09172), coagulation factor XIII B chain (P05160), fibrinogen alpha chain (P02671), fibronectin (Q8IVI8), filamin A (P21333), Rho GDP-dissociation inhibitor 2 (P52566), platelet glycoprotein-1b alpha chain (P07359), haptoglobin-related protein (P00739), lipopolysaccharide-binding protein (P18418), plasma retinol-binding protein (P02753), platelet basic protein (P02775), transgelin-2 (P37802), tubulin beta-1 chain (Q9H4B7), talin-1 (Q9Y490), thymosin beta-4 (P62328), vasorin (Q6EMK4), vascular cell adhesion protein-1 (P19320), von Willebrand factor (P04275), zinc-alpha-2-glycoprotein (P25311), alpha-2-macroglobulin (P01023), apolipoprotein B-100 (Q13787), apolipoprotein C-III (P02656), choriogonadotropin subunit beta (P01233), chorionic somatomammotropin hormone (P01243), cystatin-C (P01034), endoglin (P17813), matrix metalloproteinase-9 (P14780), pappalysin-1 (Q13219), pregnancy-specific beta-1-glycoprotein 1 (Q9P1W5), vascular endothelial growth factor receptor 3 (P35916), C-reactive protein (P02741), serum amyloid P-component (P02743), membrane copper amine oxidase (Q16853), and catalase (P04040), relative to the level in normal maternal serum or maternal serum known to be indicative of pre-eclampsia; and
(b) diagnosing said subject with pre-eclampsia if said level shows a statistically significant difference relative to the level in said normal maternal serum, or does not show a statistically significant difference relative to the level in said maternal serum known to be indicative of pre-eclampsia.
65 . A tangible medium storing the results of and/or diagnosis based on a test comprising
(a) testing in a maternal serum sample obtained from said subject the level of two or more proteins selected from the group consisting of alpha-2-antiplasmin (P08697), actin (P60709), afamin (P43652), antithrombin-III (P01008), apolipoprotein-A-II (P02652), attractin (Q9NTQ4), beta-2-microglobulin (P61769), transforming growth factor-beta-induced protein ig-h3 (Q15582), C4b-binding protein alpha chain (P04003), cathepsin D (P07339), carboxypeptidase B2 (Q961Y4), complement factor D (P00746), cartilage acidic protein 1 (Q9NQ79), dopamine beta-hydroxylase (P09172), coagulation factor XIII B chain (P05160), fibrinogen alpha chain (P02671), fibronectin (Q8IVI8), filamin A (P21333), Rho GDP-dissociation inhibitor 2 (P52566), platelet glycoprotein-1b alpha chain (P07359), haptoglobin-related protein (P00739), lipopolysaccharide-binding protein (P18418), plasma retinol-binding protein (P02753), platelet basic protein (P02775), transgelin-2 (P37802), tubulin beta-1 chain (Q9H4B7), talin-1 (Q9Y490), thymosin beta-4 (P62328), vasorin (Q6EMK4), vascular cell adhesion protein-1 (P19320), von Willebrand factor (P04275), zinc-alpha-2-glycoprotein (P25311), alpha-2-macroglobulin (P01023), apolipoprotein B-100 (Q13787), apolipoprotein C-III (P02656), choriogonadotropin subunit beta (P01233), chorionic somatomammotropin hormone (P01243), cystatin-C (P01034), endoglin (P17813), matrix metalloproteinase-9 (P14780), pappalysin-1 (Q13219), pregnancy-specific beta-1-glycoprotein 1 (Q9P1W5), vascular endothelial growth factor receptor 3 (P35916), C-reactive protein (P02741), serum amyloid P-component (P02743), membrane copper amine oxidase (Q16853), and catalase (P04040), relative to the level in normal maternal serum or maternal serum known to be indicative of pre-eclampsia; and
(b) diagnosing said subject with pre-eclampsia if said level shows a statistically significant difference relative to the level in said normal maternal serum, or does not show a statistically significant difference relative to the level in said maternal serum known to be indicative of pre-eclampsia.
66 . A method for the diagnosis of gestational hypertension in a pregnant female mammalian subject comprising:
(a) testing in a maternal serum sample obtained from said subject the level of two or more proteins selected from the group consisting of cystatin-C (SEQ ID NO: 11), alpha-1-acid glycoprotein 1 (SEQ ID NO: 104), beta-2-microglobulin (SEQ ID NO: 45), cathepsin D (SEQ ID NO: 7), laminin subunit beta-1 (SEQ ID NO: 21), fibronectin (SEQ ID NO:15), chorionic somatomammotropin hormone (SEQ ID NO: 10), SH3 domain-binding glutamic acid-rich-like protein 3 (SEQ ID NO: 30), filamin-A (SEQ ID NO: 16), profilin-1 (SEQ ID NO: 25), serum amyloid P-component (SEQ ID NO: 65), fructose-biphosphate aldolase A (SEQ ID NO: 106), transgelin-2 (SEQ ID NO: 31), vinculin (SEQ ID NO: 36), cartilage acidic protein 1 (SEQ ID NO:50), plastin-2 (SEQ ID NO: 24), tropomyosin alpha-4 chain (SEQ ID NO: 33), 14-3-3 protein zeta/delta (SEQ ID NO: 108), alpha-actinin-1 (SEQ ID NO: 112), catalase (SEQ ID NO: 72), phospholipid transfer protein (SEQ ID NO: 94), phosphoglycerate mutase 1 (SEQ ID NO: 113), peroxiredoxin-2 (SEQ ID NO: 77), trem-like transcript 1 protein (SEQ ID NO: 114), choriogonadotropin subunit beta (SEQ ID NO: 8), glutathione S-transferase P (SEQ ID NO:115), leucyl-cystinyl aminopeptidase (SEQ ID NO: 116), vascular endothelial growth factor receptor 3 (SEQ ID NO: 35), adenylyl cyclase-associated protein 1 (SEQ ID NO: 117), matrix metalloproteinase-9 (SEQ ID NO: 23), peptidyl-prolyl cis-trans isomerase A (SEQ ID NO: 118), transketolase (SEQ ID NO: 119), and phosphoglycerate kinase 1 (SEQ ID NO: 120), relative to the level in normal maternal serum or maternal serum known to be indicative of gestational hypertension; and
(b) diagnosing said subject with gestational hypertension if said level shows a statistically significant difference relative to the level in said normal maternal serum, or does not show a statistically significant difference relative to the level in said maternal serum known to be indicative of gestational hypertension.
67 . The method of claim 66 wherein the subject is a human patient.
68 . The method of claim 67 , wherein said testing is implemented using an apparatus adapted to determine the level of said proteins.
69 . The method of claim 67 , wherein said testing is performed by using a software program executed by a suitable processor.
70 . The method of claim 69 , wherein the program is embodied in software stored on a tangible medium.
71 . The method of claim 70 wherein the tangible medium is selected from the group consisting of a flash drive, a CD-ROM, a floppy disk, a hard drive, a DVD, and a memory associated with the processor.
72 . The method of any one of claims 67 to 71 , further comprising the step of preparing a report recording the results of said testing or the diagnosis.
73 . The method of claim 72 wherein said report is recorded or stored on a tangible medium.
74 . The method of claim 73 wherein the tangible medium is paper.
75 . The method of claim 73 wherein the tangible medium is selected from the group consisting of a flash drive, a CD-ROM, a floppy disk, a hard drive, a DVD, and a memory associated with the processor.
76 . The method of any one of claims 67 to 71 , further comprising the step of communicating the results of said diagnosis to an interested party.
77 . The method of claim 76 wherein the interested party is the patient or the attending physician.
78 . The method of claim 76 wherein the communication is in writing, by email, or by telephone.
79 . The method of claim 67 comprising testing the level of at least three of said proteins.
80 . The method of claim 67 comprising testing the level of at least four of said proteins.
81 . The method of claim 67 comprising testing the level of proteins Pappalysin-2 (SEQ ID NO: 38), choriogonadotropin subunit beta (SEQ ID NO: 8), histidine rich glycoprotein (SEQ ID NO: 19), plasma retinol-binding protein (SEQ ID NO: 29), Matrix metalloproteinase-9 (SEQ ID NO: 23), Apolipoprotein B-100 (SEQ ID NO: 3), endoglin (SEQ ID NO: 12), and Vascular endothelial growth factor receptor 1 (SEQ ID NO: 121).
82 . The method of claim 67 wherein said level is determined by an immunoassay.
83 . The method of claim 67 wherein said level is determined by mass spectrometry.
84 . The method of claim 67 wherein said level is determined using a protein array.
85 . A report comprising the results of and/or diagnosis based on a test comprising
(a) testing in a maternal serum sample obtained from said subject the level of two or more proteins selected from the group consisting of cystatin-C (SEQ ID NO: 11), alpha-1-acid glycoprotein 1 (SEQ ID NO: 104), beta-2-microglobulin (SEQ ID NO: 45), cathepsin D (SEQ ID NO: 7), laminin subunit beta-1 (SEQ ID NO: 21), fibronectin (SEQ ID NO:15), chorionic somatomammotropin hormone (SEQ ID NO: 10), SH3 domain-binding glutamic acid-rich-like protein 3 (SEQ ID NO: 30), filamin-A (SEQ ID NO: 16), profilin-1 (SEQ ID NO: 25), serum amyloid P-component (SEQ ID NO: 65), fructose-biphosphate aldolase A (SEQ ID NO: 106), transgelin-2 (SEQ ID NO: 31), vinculin (SEQ ID NO: 36), cartilage acidic protein 1 (SEQ ID NO:50), plastin-2 (SEQ ID NO: 24), tropomyosin alpha-4 chain (SEQ ID NO: 33), 14-3-3 protein zeta/delta (SEQ ID NO: 108), alpha-actinin-1 (SEQ ID NO: 112), catalase (SEQ ID NO: 72), phospholipid transfer protein (SEQ ID NO: 94), phosphoglycerate mutase 1 (SEQ ID NO: 113), peroxiredoxin-2 (SEQ ID NO: 77), trem-like transcript 1 protein (SEQ ID NO: 114), choriogonadotropin subunit beta (SEQ ID NO: 8), glutathione S-transferase P (SEQ ID NO: 115), leucyl-cystinyl aminopeptidase (SEQ ID NO: 116), vascular endothelial growth factor receptor 3 (SEQ ID NO: 35), adenylyl cyclase-associated protein 1 (SEQ ID NO: 117), matrix metalloproteinase-9 (SEQ ID NO: 23), peptidyl-prolyl cis-trans isomerase A (SEQ ID NO: 118), transketolase (SEQ ID NO: 119), and phosphoglycerate kinase 1 (SEQ ID NO: 120), relative to the level in normal maternal serum or maternal serum known to be indicative of gestational hypertension; and
(b) diagnosing said subject with gestational hypertension if said level shows a statistically significant difference relative to the level in said normal maternal serum, or does not show a statistically significant difference relative to the level in said maternal serum known to be indicative of gestational hypertension.
86 . A tangible medium storing the results of and/or diagnosis based on a test comprising
(a) testing in a maternal serum sample obtained from said subject the level of two or more proteins selected from the group consisting of cystatin-C (SEQ ID NO: 11), alpha-1-acid glycoprotein 1 (SEQ ID NO: 104), beta-2-microglobulin (SEQ ID NO: 45), cathepsin D (SEQ ID NO: 7), laminin subunit beta-1 (SEQ ID NO: 21), fibronectin (SEQ ID NO:15), chorionic somatomammotropin hormone (SEQ ID NO: 10), SH3 domain-binding glutamic acid-rich-like protein 3 (SEQ ID NO: 30), filamin-A (SEQ ID NO: 16), profilin-1 (SEQ ID NO: 25), serum amyloid P-component (SEQ ID NO: 65), fructose-biphosphate aldolase A (SEQ ID NO: 106), transgelin-2 (SEQ ID NO: 31), vinculin (SEQ ID NO: 36), cartilage acidic protein 1 (SEQ ID NO:50), plastin-2 (SEQ ID NO: 24), tropomyosin alpha-4 chain (SEQ ID NO: 33), 14-3-3 protein zeta/delta (SEQ ID NO: 108), alpha-actinin-1 (SEQ ID NO: 112), catalase (SEQ ID NO: 72), phospholipid transfer protein (SEQ ID NO: 94), phosphoglycerate mutase 1 (SEQ ID NO: 113), peroxiredoxin-2 (SEQ ID NO: 77), trem-like transcript 1 protein (SEQ ID NO: 114), choriogonadotropin subunit beta (SEQ ID NO: 8), glutathione S-transferase P (SEQ ID NO: 115), leucyl-cystinyl aminopeptidase (SEQ ID NO: 116), vascular endothelial growth factor receptor 3 (SEQ ID NO: 35), adenylyl cyclase-associated protein 1 (SEQ ID NO: 117), matrix metalloproteinase-9 (SEQ ID NO: 23), peptidyl-prolyl cis-trans isomerase A (SEQ ID NO: 118), transketolase (SEQ ID NO: 119), and phosphoglycerate kinase 1 (SEQ ID NO: 120), relative to the level in normal maternal serum or maternal serum known to be indicative of gestational hypertension; and
(b) diagnosing said subject with gestational hypertension if said level shows a statistically significant difference relative to the level in said normal maternal serum, or does not show a statistically significant difference relative to the level in said maternal serum known to be indicative of gestational hypertension.
87 . A method for the diagnosis of placental insufficiency in a pregnant female mammalian subject having preeclampsia comprising:
(a) testing in a maternal serum sample obtained from said subject the level of two or more proteins selected from the group consisting of fibronectin (SEQ ID NO:15), vascular endothelial growth factor receptor 3 (SEQ ID NO: 35), chorionic somatomammortrophin (SEQ ID NO: 10), and pregnancy-specific glycoprotein (SEQ ID NO: 26), relative to the level in normal maternal serum or maternal serum known to be indicative of placental insufficiency; and
(b) diagnosing said subject with placental insufficiency if said level shows a statistically significant difference relative to the level in said normal maternal serum, or does not show a statistically significant difference relative to the level in said maternal serum known to be indicative of placental insufficiency.
88 . The method of claim 87 wherein the subject is a human patient.
89 . The method of claim 88 , wherein said testing is implemented using an apparatus adapted to determine the level of said proteins.
90 . The method of claim 88 , wherein said testing is performed by using a software program executed by a suitable processor.
91 . The method of claim 90 , wherein the program is embodied in software stored on a tangible medium.
92 . The method of claim 91 wherein the tangible medium is selected from the group consisting of a flash drive, a CD-ROM, a floppy disk, a hard drive, a DVD, and a memory associated with the processor.
93 . The method of any one of claims 88 to 92 , further comprising the step of preparing a report recording the results of said testing or the diagnosis.
94 . The method of claim 93 wherein said report is recorded or stored on a tangible medium.
95 . The method of claim 94 wherein the tangible medium is paper.
96 . The method of claim 94 wherein the tangible medium is selected from the group consisting of a flash drive, a CD-ROM, a floppy disk, a hard drive, a DVD, and a memory associated with the processor.
97 . The method of any one of claims 88 to 92 , further comprising the step of communicating the results of said diagnosis to an interested party.
98 . The method of claim 97 wherein the interested party is the patient or the attending physician.
99 . The method of claim 97 wherein the communication is in writing, by email, or by telephone.
100 . The method of claim 97 comprising testing the abundance of at least three of said proteins.
101 . The method of claim 87 comprising testing the abundance of at least four of said proteins.
102 . The method of claim 87 wherein said level is determined by an immunoassay.
103 . The method of claim 87 wherein said level is determined by mass spectrometry.
104 . The method of claim 87 wherein said level is determined using a protein array.
105 . A report comprising the results of and/or diagnosis based on a test comprising
(a) testing in a maternal serum sample obtained from said subject the level of two or more proteins selected from the group consisting of fibronectin (SEQ ID NO:15), vascular endothelial growth factor receptor 3 (SEQ ID NO: 35), chorionic somatomammortrophin (SEQ ID NO: 10), and pregnancy-specific glycoprotein (SEQ ID NO: 26), relative to the level in normal maternal serum or maternal serum known to be indicative of placental insufficiency; and
(b) diagnosing said subject with placental insufficiency if said level shows a statistically significant difference relative to the level in said normal maternal serum, or does not show a statistically significant difference relative to the level in said maternal serum known to be indicative of placental insufficiency.
106 . A tangible medium storing the results of and/or diagnosis based on a test comprising
(a) testing in a maternal serum sample obtained from said subject the level of two or more proteins selected from the group consisting of fibronectin (SEQ ID NO:15), vascular endothelial growth factor receptor 3 (SEQ ID NO: 35), chorionic somatomammortrophin (SEQ ID NO: 10), and pregnancy-specific glycoprotein (SEQ ID NO: 26), relative to the level in normal maternal serum or maternal serum known to be indicative of placental insufficiency; and
(b) diagnosing said subject with placental insufficiency if said level shows a statistically significant difference relative to the level in said normal maternal serum, or does not show a statistically significant difference relative to the level in said maternal serum known to be indicative of placental insufficiency.