WO2009108073A1 - Biomarqueurs pour la prédiction d’un éclampsisme et/ou d’une maladie cardiovasculaire - Google Patents

Biomarqueurs pour la prédiction d’un éclampsisme et/ou d’une maladie cardiovasculaire Download PDF

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Publication number
WO2009108073A1
WO2009108073A1 PCT/NZ2009/000026 NZ2009000026W WO2009108073A1 WO 2009108073 A1 WO2009108073 A1 WO 2009108073A1 NZ 2009000026 W NZ2009000026 W NZ 2009000026W WO 2009108073 A1 WO2009108073 A1 WO 2009108073A1
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alpha
risk
isoform
proteins
level
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PCT/NZ2009/000026
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English (en)
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Marion Blumenstein
Robyn North
Mike Mcmaster
Michael Black
Nikola Kirilov Kasabov
Garth James Smith Cooper
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Auckland Uniservices Limited
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Publication of WO2009108073A1 publication Critical patent/WO2009108073A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/92—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving lipids, e.g. cholesterol, lipoproteins, or their receptors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/32—Cardiovascular disorders
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/36—Gynecology or obstetrics
    • G01N2800/368—Pregnancy complicated by disease or abnormalities of pregnancy, e.g. preeclampsia, preterm labour
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/60—Complex ways of combining multiple protein biomarkers for diagnosis

Definitions

  • PE is a disorder that occurs only during pregnancy and affects both the mother and her unborn baby.
  • the rapidly progressing condition is diagnosed when the mother develops hypertension and proteinuria, but may cause seizures, kidney failure, liver dysfunction and severe bleeding.
  • SGA small for gestational age babies
  • AGA appropriate birthweight for gestational age
  • Preeclampsia complicates 4-7% of women in their first pregnancies and it is estimated that over 8 million women are affected each year. Over 70,000 women world-wide die from PE each year. As a third of the babies are premature and there is a 3-10 fold increase in baby death, prediction of PE would be a major healthcare advance for future mothers and their babies.
  • PE pathophysiology
  • the initiating event in PE is thought to be abnormal remodelling of spiral arteries during early placentation resulting in ischemic reperfusion insults to the placenta. These events then trigger a maternal response resulting in abnormal endothelial cell function and vasoconstriction, activated inflammation and coagulation that lead to the clinical manifestations of PE.
  • PE occurs in the third trimester (28-40 weeks' gestation) of pregnancy but in severe cases, the disorder occurs in the 2nd trimester. It is very rare for the condition to occur before 22 weeks' gestation.
  • Obstetricians currently screen pregnant women for PE by serial measurements of blood pressure and protein levels in urine, combined with clinical assessment for other signs and symptoms of the syndrome.
  • CVD cardiovascular disease
  • LDL low density lipoprotein
  • HDL high density lipoprotein
  • CVD cardiovascular disease
  • certain of these proteins and their relative levels of expression may be used as markers for predicting the risk of cardiovascular disease (CVD) in a female subject. .
  • the invention provides a method for predicting the risk of a female subject developing preeclampsia, the method comprising observing the level of one or more proteins, precursors thereof, isoforms thereof, proteolytic peptides thereof, and/or subunits thereof,, and/or nucleic acids encoding the one or more proteins, subunits, proteolytic peptides, precursors and/or isoforms, wherein the one or more proteins is an HDL cargo protein.
  • the HDL cargo protein is chosen from the group consisting: phospholipid transfer protein, cholesteryl ester transfer protein, lecithin-cholesterol acyltransferase, apolipoprotein (apo) C-I , apoC-II, apoC-III, apoC-IV, paraoxonase-1 , ⁇ araoxonase-3 , serum amyloid A 4 , serum amyloid A 2 , serum amyloid A 1 , apoA-I, , apoH, apoA-IV, clusterin, apoA-II, apoL-I, apoD, apoE, apoF, apoM, angiotensinogen (AGT), alpha-2-antiplasmin, serpin peptidase inhibitor, alpha-2-HS-glycoprotein, haptoglobin-related protein, alpha- 1 -antitrypsin, bikunin (alphal -microglobulin), kininogen,
  • the invention provides a method for predicting the risk of a female subject developing preeclampsia the method comprising at least the steps of: a) taking a sample from the subject at a time when the subject is pregnant; b) detecting one or more proteins, precursors thereof, isoforms thereof, proteolytic peptides thereof, and/or subunits thereof, and/or nucleic acids encoding the one or more proteins, subunits, precursors, proteolytic peptides, and/or isoforms in the sample; and, c) comparing the level of the one or more proteins, subunits, precursors, isoforms, proteolytic peptides and/or nucleic acids against a standard; wherein a difference in the level of the one or more proteins, subunits, precursors, isoforms, proteolytic peptides and/or nucleic acid in the sample compared to the standard is indicative of the risk of developing preeclampsia, and wherein the one or more
  • C4A Complement factor H-related protein 1
  • Clusterin Clusterin
  • Transthyretin Hemopexin
  • Serum amyloid P Serum amyloid A4
  • the HDL cargo protein is chosen from the group of HDL cargo proteins described herein before.
  • the precursors, isoforms, proteolytic fragments and/or subunits include: Fibrinogen alpha chain Fibrinogen beta chain Fibrinogen gamma chain
  • a fibrinogen fragment with an approximate molecular weight of 25kDa is A fibrinogen fragment with an approximate molecular weight of 25kDa
  • HKa (a fragment of HK)
  • Apolipoprotein A-I fragment with an approximately molecular weright of 17kDa Apolipoprotein A-I fragment with an approximately molecular weright of 21 kDa
  • Serum amyloid P fragment with an approximate molecular weight of 27kDa Serum amyloid P fragment with an approximate molecular weight of 27kDa
  • a higher or increased level of one or more of the following compared to a standard, is indicative of risk of developing preeclampsia:
  • Fibrinogen and/or the alpha chain, beta chain and/or gamma chain
  • Apolipoprotein A-I and/or fragments thereof with approximate molecular weights of 17,
  • Clusterin (and/or clusterin isoform I)
  • Vitronectin approximately 75 kDa
  • Angiotensinogen alpha2-HS-Glycoprotein zinc-alpha2-Glycoprotein zinc-alpha2-Glycoprotein
  • a lower or decreased level of one or more of the following compared to a standard is indicative of risk of developing preeclampsia:
  • Vitronectin approximately 65 kDa Vitronectin, approximately 75 kDa alphal -Microglobulin (bikunin)
  • a PEDF isoform with an approximate pi at 6.1 Preferably there is at least an approximately 1.3 fold increase or decrease in the level of a particular protein, precursor, isoform, proteolytic peptide, isoform and/or nucleic acid compared to the standard, more preferably at least an approximately 1.5 fold increase or decrease.
  • the invention provides a method for predicting the risk of a female subject developing preeclampsia with a small for gestational age baby (PE-SGA), the method comprising at least the steps of: a) taking a sample from the subject at a time when the subject is pregnant; b) detecting one or more proteins, precursors thereof, isoforms thereof, proteolytic peptides thereof, and/or subunits thereof, and/or nucleic acid encoding the one or more proteins, subunits, precursors, proteolytic peptides and/or isoforms thereof in the sample; and, c) comparing the level of the one or more proteins, subunits, precursors, proteolytic peptides, isoforms and/or nucleic acids against a standard; wherein a difference in the level of the one or more proteins, subunits, precursors, isoforms, proteolytic peptides and/or nucleic acids in the sample compared to the standard is indicative of the risk of
  • the proteins, subunits, precursors, proteolytic peptides and/or isoforms are chosen from the group consisting: alpha- 1-antichymotrypsin; fibrinogen gamma chain; a fibrinogen fragment with an approximate molecular weight of 27 kDa, a fibrinogen fragment with an approximately molecular weight of 25 kDa; high molecular weight kininogen (HK); and, Vitronectin, approximately 65 kDa; Vitronectin, 75 kDa; and Clusterin.
  • a higher level of one or more of alpha- 1 -antichymotrypsin, fibrinogen gamma chain, an approximately 25 kDa fragment of fibrinogen, an approximately 27 kDa fragment of fibrinogen, an approximately 65 kDa part of the two-chain vitronectin molecule and/or clusterin in the sample compared to the standard is indicative of risk of developing PE-SGA.
  • a lower level of HK and/or vitronectin single chain with an approximate molecular weight of 75 kDa in a sample compared to the standard is indicative of risk of developing PE-SGA.
  • the invention provides a method for predicting the risk of a female subject developing PE-SGA 5 the method comprising at least the steps of: a) taking a sample from the subject at a time when the subject is pregnant; b) detecting apolipoprotein A-I in combination with one or more of fibrinogen, pregnancy zone protein and/or alpha-2-macroglobulin, clusterin isoform I 5 alphal-antichymotrypsin, and complement factor I and/or nucleic acids encoding said proteins in the sample; and, c) comparing the level of each of the proteins and/or nucleic acids in the sample against a standard; wherein a difference in the level of each of the proteins and/or nucleic acids in the sample compared to the standard is indicative of developing PE-SGA.
  • one or more precursors, isoforms, proteolytic peptides and/or subunits of the proteins, or nucleic acids encoding one or more thereof is detected in addition to or in lieu of detection of a particular protein.
  • the method includes detecting an approximately 17 kDa Apo-AI fragment and/or an approximately 21 kDa Apo-AI fragment and/or nucleic acids encoding same.
  • the method includes detecting fibrinogen beta chain and/or fibrinogen gamma chain, and/or nucleic acids encoding same.
  • the method includes detecting each of Apolipoprotein AI and pregnancy zone protein and/or alpha-2-macroglobulin, and/or nucleic acids encoding same.
  • a combination of a higher level of apolipoprotein A-I and a higher level of pregnancy zone protein and/or alpha-2-macroglobulin is indicative of the risk of PE-SGA.
  • the method includes detecting each of Apolipoprotein AI, pregnancy zone protein and/or alpha-2-macroglobulin, and Fibrinogen beta chain, and/or nucleic acids encoding same.
  • a combination of a higher level of apolipoprotein A-I, a higher level of fibrinogen beta chain and a higher level of pregnancy zone protein and/or alpha-2-macroglobulin is indicative of the risk of PE-SGA.
  • a higher level of apolipoprotein AI, a higher level of pregnancy zone protein and/or alpha-2-macroglobulin, a higher level of fibrinogen beta chain, a higher level of fibrinogen gamma chain, a higher level of clusterin isoform I, a higher level of alpha- 1-antichymotrypsin and a higher level of complement factor I is indicative of the risk of PE-SGA.
  • the invention provides a method for predicting the risk of a female subject developing preeclampsia with PE-SGA, the method comprising at least the steps of: a) taking a sample from the subject at a time when the subject is pregnant; b) detecting each of the proteins apolipoprotein A-I, serum amyloid P, and transthyretin with an approximate molecular weight of 12 kDa, and/or nucleic acids encoding same in the sample; and, c) comparing the level of each of the proteins and/or nucleic acids in the sample against a standard; wherein a difference in the level of each of the proteins and/or nucleic acids in the sample compared to the standard is indicative of developing PE-SGA.
  • the method further includes detecting fibrinogen.
  • one or more precursors, isoforms, proteolytic peptides and/or subunits of each of the proteins, or nucleic acids encoding one or more thereof is detected in addition to or in lieu of detection of a particular protein.
  • the method includes detecting an apolipoprotein A-I fragment with an approximate molecular weight of 27kDa and/or an apolipoprotein fragment with an approximate molecular weight of 17kDa, and/or nucleic acids encoding same.
  • the method includes detecting serum amyloid P with an approximate molecular weight of 27 kDa and/or a nucleic acid encoding same.
  • the invention provides a method for predicting the risk of a female subject developing preeclampsia with an appropriate birthweight for gestational age baby (PE-AGA), the method comprising at least the steps of: a) taking a sample from the subject at a time when the subject is pregnant; b) detecting PEDF, a subunit thereof, a precursor thereof, a proteolytic peptide thereof and/or an isoform thereof, and/or a nucleic acid encoding one or more thereof in the sample; and, c) comparing the level of the PEDF, subunit, precursor, isoform, proteolytic peptide and/or nucleic acid encoding one or more thereof against a standard; wherein a difference in the level of the PEDF, subunit, precursor, isoform, proteolytic peptide and/or nucleic acid encoding one or more thereof in the sample compared to the standard is indicative of the risk of developing PE-AGA.
  • a higher level of PEDF, a subunit thereof, a precursor thereof, an isoform thereof, a proteolytic peptide thereof and/or nucleic acid encoding one or more thereof in the sample compared to the standard is indicative of risk of developing PE-AGA.
  • the isoform of PEDF is an isoform with an approximate pi of 5.4.
  • Figure 1 2D-DIGE experimental design. a Total number of spots detected by
  • DIGE as differentially expressed in 20 week pregnancy plasma from women with subsequent PE-AGA and/or PE-SGA.
  • Top7 depleted plasma B. Differentially expressed protein spots with mass spectrometry identification are annotated by spot ID numbers (see Figure 4 for protein IDs). Circled area in the upper right of panel A depicts fibrinogen which was removed from plasma by Top7 depletion (B).
  • Figure 8 Western Blot analysis of native plasma (20 weeks' gestation) with two candidate markers for the prediction of preeclampsia. Blots were incubated with polyclonal anti-human fibrinogen (left blot) and alpha- 1- antichymotrypsin antibody (right blot). Cross reacting bands were revealed by Qdot nanocrystal technology. A control blot with no primary antibody revealed no unspecific binding (far left).
  • Fibrinogen alpha, beta, and gamma chains were detected along with additional higher and lower molecular weight fibrinogen species. Densitometric analysis showed significantly higher protein expression of gamma fibrinogen in women who developed PE-SGA compared to controls, (p ⁇ 0.05). * Two fibrinogen species at approximately 27 and 25 kDa which were up-regulated in two women with PE-SGA. Western blot analysis for alpha- 1-antichymotrypsin confirmed significant up-regulation in early pregnancy plasma preceding disease, (p ⁇ 0.01).
  • Figure 11 LC-MS/MS identification of protein spots detected by 2-D DIGE as being differentially expressed in plasma at 20 weeks' gestation before the onset of preeclampsia and at the time women present with preeclampsia (36-38 weeks' gestation) compared with healthy controls.
  • Figure 12 Western Blot analysis of plasma preceding and at the time of clinical manifestation of preeclampsia reveals aberrant vitronectin processing.
  • Figure 15 PEDF 2D-DIGE Study. Maternal characteristics and pregnancy outcome in women with an abnormal uterine artery Doppler waveform who subsequently developed preeclampsia or remained healthy with an uncomplicated pregnancy. Results are mean (SD), median (IQ range) or N
  • Figure 18 Maternal Characteristics, Pregnancy Outcome and plasma pigment epithelium derived factor (PEDF) levels.
  • PE-AGA 5 preeclampsia with an appropriate birthweigth for gestational age; PE-SGA 5 preeclampsia with a small for gestational age baby. Results are mean (SD) or N (%). *P ⁇ 0.05 r P ⁇ 0.01 r P ⁇ 0.0001 compared with Controls.
  • Figure 20 Box plots showing standardized abundances of two spots (spot 427 and 579) found to be significantly (p ⁇ 0.05) up-regulated in plasma of women prior to developing preeclampsia (week 20 of gestation) in DIGE experiment III (gel picture not shown). P-value calculated by Limma t-test using false discovery rate correction comparing DIGE standardized spot volumes from women with subsequent preeclampsia versus controls.
  • the risk of developing PE can be determined by measuring specific proteins, subunits, precursors, proteolytic peptides and/or isoforms or combinations thereof in plasma, serum, urine and cervical fluid in early pregnancy, prior to the onset of disease (for example, 24 weeks of gestation or less).
  • HDL cargo proteins A significant proportion of the proteins (including particular isoforms, subunits, precursors, and/or proteolytic fragments) identified to be differentially expressed prior to preeclampsia can be grouped in a class of proteins known as high density lipoprotein (HDL) cargo proteins.
  • HDL cargo proteins any one or more HDL cargo protein may be used as a marker to determine the risk of a female subject developing PE.
  • Cardiovascular disease or “CVD” are used herein to refer to artherosclerosis and/or coronary artery disease which can manifest as angina and/or myocardial infarction, for example.
  • Risk of developing PE, CVD, or normotensive SGA is used herein to refer to the risk of developing PE , CVD or normotensive SGA at some time in the future; ie at some time following the taking of a sample from the subject for testing in accordance with the invention.
  • the subject will typically not be displaying any signs or symptoms associated with PE, CVD or normotensive SGA at the time the sample is taken.
  • the methods of the invention involve observing the levels of one or more specific proteins, precursors thereof, isoforms thereof, proteolytic peptides thereof and/or subunits thereof in a sample taken from a female subject at a time when the female subject is pregnant.
  • the inventors contemplate the proteins to be useful as individual markers or in combinations of two or more (for example, in a classifier).
  • the inventors believe that relative expression levels of individual subunits of the proteins, as well as precursors, molecular isoforms and proteolytic peptides of the proteins are also important predictive markers.
  • detecting one or more proteins it should be taken to include reference to detecting one or more precursors, isoforms, proteolytic peptides and/or subunits of said protein(s), unless the context requires otherwise.
  • reference to detecting one or more proteins, precursors, isoforms, subunits and/or proteolytic peptides should be taken to include reference to detecting one or more nucleic acid encoding said protein(s), precursor(s), isoform(s), proteolytic peptide(s) and/or subunit(s).
  • preproteins prepeptides, preproproteins and prepropeptides including an N-terminal leader sequence.
  • methods of the invention may also include observing the levels of one or more nucleic acids (specifically transcripts or cDNA molecules based thereon) encoding the proteins, precursors and/or isoforms described herein.
  • the methods of the invention involve at least taking a sample from a female subject, detecting in the sample one or more proteins, subunits, precursors, proteolytic peptides and/or isoforms thereof, and/or nucleic acids encoding any one or more thereof, and comparing the level of the one or more proteins, subunits, precursors, proteolytic peptides isoforms and/or nucleic acids against the level of the one or more proteins, subunits, precursors, isoforms, proteolytic peptides and/or nucleic acids in a standard.
  • the difference in the level of the one or more proteins, subunits, precursors, isoforms, proteolytic peptides and/or nucleic acids in the sample compared to the standard is indicative of the risk of developing PE and/or the risk of developing CVD, or the risk of developing normotensive SGA, as the case may be.
  • the terms “higher” and “lower” or “increased” and “decreased” and like terms may be used. Such terms should be taken broadly to include any change in the level of protein or nucleic acid compared to a standard. It should be appreciated that the methods of the invention may be combined with analysis of one or more other biological markers (for example, metabolites and genetic markers) or clinical observations which are known to be associated with PE and/or CVD 5 as the case may be. In a particular embodiment, methods for predicting the risk of developing CVD take into account the predicted risk of the same subject developing PE, an increased risk of developing PE being indicative of an increased risk of also developing CVD.
  • the female subject is pregnant at the time at which the sample is taken.
  • the female subject is preferably in the early stages of pregnancy, for example up to or including approximately 24 weeks, more preferably at 20 weeks of gestation or less. In one embodiment, this may also be appropriate for methods of predicting CVD.
  • exemplary precursors, isoforms, proteolytic fragments and/or subunits of use in the invention include:
  • a fibrinogen fragment with an approximate molecular weight of 27 kDa A fibrinogen fragment with an approximate molecular weight of 25kDa
  • the method includes detecting each of Apolipoprotein AI, pregnancy zone protein and/or alpha-2-macroglobulin, and Fibrinogen beta chain, and/or nucleic acids encoding same.
  • the method includes detecting fibronectm I isoform 3.
  • PEDF alone is used as a marker to assess the risk of PE-AGA.
  • an isoform of PEDF with an approximate pi of 5.4 is used as a marker.
  • the one or more proteins are chosen from the group of proteins known as HDL cargo proteins (as herein before defined).
  • the HDL cargo proteins are chosen from the group consisting of: apoM, apoE, Clusterin (apoJ), apoA-I, Serum amyloid A4, apoC-III, C3, C4A, Vitronectin,
  • the sample is preferably a blood sample, including plasma or serum samples.
  • a urine sample or a cervical fluid sample may be used.
  • samples can be taken from the patient using standard techniques known in the art.
  • high abundance proteins which have the potential to make it difficult to analyse may be removed from the sample.
  • Top6 or Top7 depletion may be used (as described herein after under the heading "Multi affinity removal system (MARS) for major abundance proteins").
  • MERS Multi affinity removal system
  • the sample may also be subject to proteolytic digestion.
  • detection of a protein, subunit, proteolytic peptide, precursor and/or isoform in accordance with the invention should be taken to include detection of any one or more fragments thereof. Fragments should be of a length sufficient to ensure specificity to the protein of interest. Such fragments will typically be at least 8 amino acids in length, more preferably at least 10, 15 or 20 amino acids in length.
  • the kit may comprise one or more antibody specific to the one or more proteins/subunits/precursors/isoforms/proteolytic peptides described herein, hi a particular embodiment, ELISA is used and the kit comprises one or more capture and/or detection antibody for one or more protein/subunit/precursor/isoform/proteolytic peptide of interest.
  • Blood was collected by venipuncture into BD EDTA- Vacutainer® collection tubes, placed on ice, centrifuged at 2400 ⁇ g for 10 min at 4 °C, and biobanked at -8O 0 C within 4 hours of collection.

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Abstract

L’invention concerne des biomarqueurs et des procédés pour utilisation dans la prédiction du risque qu’une femme développe un éclampsisme et/ou une maladie cardiovasculaire.
PCT/NZ2009/000026 2008-02-28 2009-02-27 Biomarqueurs pour la prédiction d’un éclampsisme et/ou d’une maladie cardiovasculaire WO2009108073A1 (fr)

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