Methods of determining whether a pregnant woman is at risk of developing preeclampsia

• US 7,790,463 B2
• Filed: 02/02/2006
• Issued: 09/07/2010
• Est. Priority Date: 02/02/2006
• Status: Active Grant

• Current Assignee: The United States of America As Represented By The Secretary of Agriculture, Yale University
• Original Assignee: United States Department Of Health And Human Services (Government of the United States of America), Yale University
• Inventors: Romero, Roberto, Neale, Donna, Mor, Gil G.
• Primary Examiner(s): Landsman; Robert
• Assistant Examiner(s): Chandra; Gyan
• Application Number:
  US11/346,694
• Publication Number:
  US 20070178605A1
• Time in Patent Office: 1,678 Days
• Field of Search: None
• US Class Current: 436/65
• CPC Class Codes: G01N 2500/00 Screening for compounds of potential therapeutic value
• CPC Class Codes: G01N 2800/368 Pregnancy complicated by disease or abnormalities of pregnancy, e.g. preeclampsia, preterm labour
• CPC Class Codes: G01N 33/689 related to pregnancy or the gonads

Abstract

The present invention provides methods and compositions related to biomarker profiles for each trimester of pregnancy. The present invention also provides methods for identifying patients at risk of developing a complication of pregnancy, such as preeclampsia. In further embodiments, the present invention relates to methods for the diagnosis of patients with preeclampsia.

Claims

1. A method for determining that a pregnant woman is at risk of developing preeclampsia, comprising comparing the expression of one or more biomarkers in a blood sample from the pregnant woman to be assessed for risk of developing preeclampsia to a predetermined standard for each of the one or more biomarkers, wherein one of the biomarkers is RANTES, and wherein a significant increase in expression of RANTES in the sample as compared to a predetermined standard for RANTES indicates that the pregnant woman is at risk of developing preeclampsia, thereby determining that the pregnant woman is at risk of developing preeclampsia.

2. The method of claim 1, wherein there is more than one biomarker, said biomarker in addition to RANTES selected from the group consisting of:

IFNg, I-309, GM-CSF, GDNF, GCP-2, Fraktalkine, Flt-3 Ligand, FGF-7, FGF-6, Eotaxin-3, Eotaxin-2, Eotaxin, EGF, CNTF, CK b 8-1, BMP-6, BMP-4, BLC, BDNF, ANG, MCP-1, LIGHT, Leptin, IL-7, IL-6, IL-5, IL-4, IL-3, IL-2, IL-1ra, IL-1b, IL-1a, IL-16, IL-15, IL-13, IL-10, IGF-1, IGFBP-4, IGFBP-2, IGFBP-1, TNFB, TNFA, TGF-B3, TGF-B1, TARC, SDF-1, SCF, PDGF-BB, PARC, NT-3, NAP-2, MIP-3A, MIP-1D, MIG, MDC, M-CSF, MCP-4, MCP-3, MCP-2, Lymphotactin, I-TAC, IL-8, IL-6R, IL-1 Ra, IL-17, IL-12 P70, IL-12 P40, IL-11, IL-1R1, IL-1 R4/ST2, IGF-1 SR, IGFBP-6, IGFBP-3, ICAM-3, ICAM-1, HGF, HCC-4, GRO-A, GRO, VEGF-D, VEGF, uPAR, TRAIL R4, TRAIL R3, Thrombopoietin, TIMP-2, TIMP-1, TECK, sTNF RI, sTNF RII, SGP130, PIGF, Oncostatin M, Steoprotegin, NT-4, MSP-A, MIP-3B, MIP-1B, MIP-1A, MIF, Fas, and FasL.

3. The method of claim 2, wherein there is more than one biomarker, said biomarker in addition to RANTES selected from the group consisting of:

Ang, Leptin, PDGF, ICAM 1, VEGF, G-CSF, Fas, EGF, IGFBP 1, MCP 1, IL8, and FasL.

4. The method of claim 1, wherein the predetermined standard corresponds to the expression levels of the one or more biomarkers in a pregnant woman who is not at risk of developing preeclampsia.

5. The method of claim 4, in which the pregnant woman to be assessed for risk of developing preeclampsia is in the first trimester of pregnancy, wherein the predetermined standard corresponds to the expression levels of the one or more biomarkers in the first trimester of pregnancy.

6. The method of claim 4, in which the pregnant woman to be assessed for risk of developing preeclampsia is in the second trimester of pregnancy, wherein the predetermined standard corresponds to the expression levels of said one or more biomarkers in the second trimester of pregnancy.

7. The method of claim 4, in which the pregnant woman to be assessed for risk of developing preeclampsia is in the third trimester of pregnancy, wherein the predetermined standard corresponds to the expression levels of said one or more biomarkers in the third trimester of pregnancy.

8. The method of claim 1, wherein the method comprises comparing the expression of two or more biomarkers and the determination of risk of developing preeclampsia is based on a score-based classification method.

9. The method of claim 1, wherein the method comprises comparing the expression of two or more biomarkers, wherein the determination of risk of developing preeclampsia is made by comparing a profile of the expression of the two or more biomarkers to a predetermined standard profile for the biomarkers, and wherein a difference in the profiles determines that a pregnant woman is at risk of developing preeclampsia.

10. The method of claim 9, wherein the predetermined standard profile corresponds to the expression profile of the two or more biomarkers in a pregnant woman who is not at risk of developing preeclampsia.

11. The method of claim 10, in which the pregnant woman to be assessed for risk of developing preeclampsia is in the first trimester of pregnancy, wherein the predetermined standard profile corresponds to the expression profile of said two or more biomarkers in the first trimester of pregnancy.

12. The method of claim 10, in which the pregnant woman to be assessed for risk of developing preeclampsia is in the second trimester of pregnancy, wherein the predetermined standard profile corresponds to the expression profile of said two or more biomarkers in the second trimester of pregnancy.

13. The method of claim 10, in which the pregnant woman to be assessed for risk of developing preeclampsia is in the third trimester of pregnancy, wherein the predetermined standard profile corresponds to the expression profile of said two or more biomarkers in the third trimester of pregnancy.

14. The method of claim 9, wherein the predetermined standard profile is determined by comparing the expression of the two or more biomarkers in a pregnant woman to be assessed for risk of developing preeclampsia to the expression of the two or more biomarkers in a pregnant woman who is not at risk of developing preeclampsia using a machine learning technique.

15. The method of claim 1, wherein the predetermined standard is determined by comparing the expression of the one or more biomarkers in the pregnant woman to be assessed for risk of developing preeclampsia to the expression of the one or more biomarkers in a pregnant woman that who is not at risk of developing preeclampsia using support vector machines, K-nearest neighbor classifier, or classification tree analysis.

16. The method of claim 1, wherein there is more than one biomarker, and the biomarker in addition to RANTES is selected from the group consisting of:

Ang, Leptin, PDGF, ICAM 1, VEGF, G-CSF, and Fas and an increase in the expression of one or more of the additional biomarkers as compared to the predetermined standard indicates that the pregnant woman is at risk of developing preeclampsia.

17. The method of claim 1, wherein there is more than one biomarker, said biomarker in addition to RANTES selected from the group consisting of:

EGF, IGFBP 1, MCP 1, IL8, and FasL and a decrease in the expression of one or more of the additional biomarkers as compared to the predetermined standard indicates that the pregnant woman is at risk of developing preeclampsia.

18. The method of claim 1, wherein the expression of the one or more biomarkers is detected using a reagent that detects the one or more biomarkers.

19. The method of claim 18, wherein the reagent is an antibody or fragment thereof that binds the biomarker.

20. The method of claim 19, wherein the reagent is directly or indirectly labeled with a detectable substance.

21. The method of claim 18, wherein the expression of the one or more biomarkers is detected using mass spectroscopy.

22. The method of claim 1, wherein the expression of the one or more biomarkers is detected by:

(a) detecting the expression of a polypeptide which is regulated by the one or more biomarker;

(b) detecting the expression of a polypeptide which regulates the biomarker;

or (c) detecting the expression of a metabolite of the biomarker.