Methods and compositions for diagnosis of ectopic pregnancy
Methods and compositions are provided for diagnosing ectopic pregnancy in a mammalian subject by detecting changes in expression of ISM2, ADAM12, PST1, PSG7, PST11, PSG9, PSG2 and other genes identified therein, including combinations thereof. A selected gene, gene transcript or protein/peptide expression product, or profiles or signatures formed by combinations of same, detected in a biological fluid of a subject, enables comparison of the corresponding genes, proteins or profiles from that of a reference or control having a normal intrauterine pregnancy. Detection of characteristic changes in the gene profile or protein expression signature of the subject is correlated with a diagnosis of ectopic pregnancy. Various compositions for use in such diagnosis include PCR primer-probe sets or ligands, labeled or immobilized, which are capable of detecting the changes in expression or translation of these targets.
1. A diagnostic reagent or kit for use in diagnosing an ectopic pregnancy in a mammalian subject consisting of:
i. a ligand that binds Isthmin2 (ISM2),
ii. a ligand that binds the pro-domain or extracellular (EC) domain of ADAM12,
iii. a ligand that binds pregnancy specific beta-1 glycoprotein isoform 7 (PSG7),
iv. a ligand that binds pregnancy specific beta-1 glycoprotein isoform 11 (PSG11),
v. a ligand that binds pregnancy specific beta-1 glycoprotein isoform 9 (PSG9), and
vi. a ligand that binds pregnancy specific beta-1 glycoprotein isoform 2 (PSG2);
wherein at least one of the ligands is covalently or non-covalently joined with a detectable label or immobilized upon a substrate.
2. A diagnostic reagent or kit for use in diagnosing an ectopic pregnancy in a mammalian subject consisting of:
i. a ligand that binds Isthmin2 (ISM2),
ii. a ligand that binds the pro-domain or extracellular (EC) domain of ADAM12,
iii. a ligand that binds pregnancy specific beta-1 glycoprotein isoform 7 (PSG7),
iv. a ligand that binds pregnancy specific beta-1 glycoprotein isoform 11 (PSG11),
v. a ligand that binds pregnancy specific beta-1 glycoprotein isoform 9 (PSG9), and
vi. a ligand that binds pregnancy specific beta-1 glycoprotein isoform 2 (PSG2); and
a ligand that binds to a protein or peptide fragment selected from the group consisting of:
vii. pregnancy specific beta-1 glycoprotein isoform 1 (PSG1),
viii. choriogonadotropin subunit beta precursor (CGB);
ix. glycoprotein hormones alpha chain precursor (CGA);
x. pappalysin-1 precursor (PAPPA);
xi. chorionic somatomammotropin hormone precursor (CSH1); and
xii. progestagen-associated endometrial protein (PAEP); or
xiii a combination of ligands, each ligand binding a different peptide or protein of (vii) through (xii)
wherein at least one of the ligands is covalently or non-covalently joined with a detectable label or immobilized upon a substrate.
3. The reagent or kit according to claim 1 , wherein each of said ligands is immobilized upon a substrate.
4. The reagent or kit according to claim 1 , wherein said ligands are proteins or peptides.
5. The reagent or kit according to claim 4 , wherein said ligand is an antibody or fragment thereof.
6. The reagent of kit according to claim 1 , wherein each of said ligands is covalently or non-covalently joined with a detectable label.
7. A diagnostic reagent or kit for use in diagnosing an ectopic pregnancy in a mammalian subject consisting of (i) a ligand that that binds to Isthmin2 (ISM2), and (ii) a ligand that binds to the pro-domain or extracellular (EC) domain of ADAM12, wherein at least one of the ligands is covalently or non-covalently joined with a detectable label or immobilized upon a substrate.
8. A diagnostic reagent or kit for use in diagnosing an ectopic pregnancy in a mammalian subject consisting of
(i) a ligand that that binds to Isthmin2 (ISM2),
(ii) a ligand that binds to the pro-domain or extracellular (EC) domain of ADAM12, and one or more ligands selected from:
iii. a ligand that binds to pregnancy specific beta-1 glycoprotein isoform 7 (PSG7),
v. a ligand that binds to pregnancy specific beta-1 glycoprotein isoform 11 (PSG11),
v. a ligand that binds to pregnancy specific beta-1 glycoprotein isoform 9 (PSG9), and
vi. a ligand that binds to pregnancy specific beta-1 glycoprotein isoform 2 (PSG2),
wherein at least one of the ligands is covalently or non-covalently joined with a detectable label or immobilized upon a substrate.
9. A diagnostic reagent or kit for use in diagnosing an ectopic pregnancy in a mammalian subject consisting of
(i) a ligand that that binds to Isthmin2 (ISM2),
(ii) a ligand that binds to the pro-domain or extracellular (EC) domain of ADAM12,
one or more ligands selected from:
iii. a ligand that binds to pregnancy specific beta-1 glycoprotein isoform 7 (PSG7),
v. a ligand that binds to pregnancy specific beta-1 glycoprotein isoform 11 (PSG11),
v. a ligand that binds to pregnancy specific beta-1 glycoprotein isoform 9 (PSG9), and
vi. a ligand that binds to pregnancy specific beta-1 glycoprotein isoform 2 (PSG2); and
one or more ligands selected from:
vii. a ligand that binds to pregnancy specific beta-1 glycoprotein isoform 1 (PSG1),
viii. a ligand that binds to choriogonadotropin subunit beta precursor (CGB);
ix. a ligand that binds to glycoprotein hormones alpha chain precursor (CGA);
x. a ligand that binds to pappalysin-1 precursor (PAPPA);
xi. a ligand that binds to chorionic somatomammotropin hormone precursor (CSH1); and
xii. a ligand that binds to progestagen-associated endometrial protein (PAEP),
wherein at least one of the ligands is covalently or non-covalently joined with a detectable label or immobilized upon a substrate.
10. A diagnostic reagent or kit for use in diagnosing an ectopic pregnancy in a mammalian subject consisting of (i) a ligand that that binds to Isthmin2 (ISM2), (ii) a ligand that binds to the pro-domain or extracellular (EC) domain of ADAM12, and one or more ligands selected from:
vii. a ligand that binds to pregnancy specific beta-1 glycoprotein isoform 1 (PSG1) or a fragment thereof,
viii. a ligand that binds to choriogonadotropin subunit beta precursor (CGB) or a fragment thereof;
ix. a ligand that binds to glycoprotein hormones alpha chain precursor (CGA) or a fragment thereof;
x. a ligand that binds to pappalysin-1 precursor (PAPPA) or a fragment thereof;
xi. a ligand that binds to chorionic somatomammotropin hormone precursor (CSH1) or a fragment thereof; and
xii. a ligand that binds to progestagen-associated endometrial protein (PAEP) or a fragment thereof,
wherein at least one of the ligands is covalently or non-covalently joined to a detectable label or immobilized upon a substrate.
11. A diagnostic reagent or kit for use in diagnosing an ectopic pregnancy in a mammalian subject comprising a set of ligands, the ligands consisting of:
i. a ligand that binds Isthmin2 (ISM2),
ii. a ligand that binds the pro-domain or extracellular (EC) domain of ADAM12,
iii. a ligand that binds pregnancy specific beta-1 glycoprotein isoform 7 (PSG7),
iv. a ligand that binds pregnancy specific beta-1 glycoprotein isoform 11 (PSG11),
v. a ligand that binds pregnancy specific beta-1 glycoprotein isoform 9 (PSG9), and
vi. a ligand that binds pregnancy specific beta-1 glycoprotein isoform 2 (PSG2);
wherein at least one of the ligands is covalently or non-covalently joined with a detectable label or immobilized upon a substrate.
12. A diagnostic reagent or kit for use in diagnosing an ectopic pregnancy in a mammalian subject comprising a set of ligands, the set of ligands consisting of:
(i) a ligand that that binds to Isthmin2 (ISM2),
(ii) a ligand that binds to the pro-domain or extracellular (EC) domain of ADAM12, and a ligand that that binds to a peptide or protein selected from:
iii. pregnancy specific beta-1 glycoprotein isoform 7 (PSG7),
v. pregnancy specific beta-1 glycoprotein isoform 11 (PSG11),
v. pregnancy specific beta-1 glycoprotein isoform 9 (PSG9), and
vi. pregnancy specific beta-1 glycoprotein isoform 2 (PSG2),
wherein at least one of the ligands is covalently or non-covalently joined with a detectable label or immobilized upon a substrate.