WO2006002930A2 - Polymorphisme fcgammariia et son utilisation dans un diagnostic - Google Patents

Polymorphisme fcgammariia et son utilisation dans un diagnostic Download PDF

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WO2006002930A2
WO2006002930A2 PCT/EP2005/007073 EP2005007073W WO2006002930A2 WO 2006002930 A2 WO2006002930 A2 WO 2006002930A2 EP 2005007073 W EP2005007073 W EP 2005007073W WO 2006002930 A2 WO2006002930 A2 WO 2006002930A2
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fcγriia
patients
cells
antibody
risk
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PCT/EP2005/007073
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WO2006002930A3 (fr
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Bernhard Stockmeyer
Ahmed Sheriff
Udo Gaipl
Reinhard Voll
Joachim Robert Kalden
Werner G. Daniel
Dorette Raaz
Christoph Garlichs
Martin Herrmann
Peter Kern
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Friedrich-Alexander- Universitaet Erlangen- Nuernberg
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Publication of WO2006002930A2 publication Critical patent/WO2006002930A2/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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6854—Immunoglobulins
    • G01N33/6857—Antibody fragments
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • 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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/70503—Immunoglobulin superfamily, e.g. VCAMs, PECAM, LFA-3
    • G01N2333/70535—Fc-receptors, e.g. CD16, CD32, CD64 (CD2314/705F)
    • 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
    • G01N2800/324—Coronary artery diseases, e.g. angina pectoris, myocardial infarction

Definitions

  • the present invention is directed to a method of determining the risk of a patient of developing or suffering from acute coronary syndrome as well as to an antibody for use in this method.
  • the present invention is furthermore directed to a diagnostic kit and particles for use in this method as well as the use thereof in the diagnosis and prevention of several diseases.
  • Coronary artery disease is the leading cause of death in the industrialized world.
  • CAD can progress into destabilization of atherosclerotic plaques, leading clinically to acute coronary syndromes (ACS) consisting of unstable angina pectoris (UAP), non-ST- elevation myocardial infarction or ST-elevation myocardial infarction.
  • ACS acute coronary syndromes
  • UAP unstable angina pectoris
  • ST-elevation myocardial infarction ST-elevation myocardial infarction.
  • Development of ACS is accompanied by high cardiovascular mortality and morbidity. Therefore, an early and specific prediction of coronary risk is essential for the stratification of the treatment.
  • Atherosclerosis by nature, is a chronic inflammatory disease (1). Therefore, the pathophysiological role of C-reactive protein (CRP) within the chronic stable phase as well as within ACS has been studied extensively. Chronically elevated serum levels of CRP implicate increased risk for destabilization or death.
  • CRP C-reactive protein
  • CRP CRP-induced complement activation via the classical pathway. This in turn triggers the influx of neutrophils. It decorates the surface of the ligand with opsonizing complement fragments and enhances phagocytosis of the cells that have bound CRP and complement. CRP also acts as an opsonin by interacting with Fc receptors (4). In addition to binding to the membranes of injured viable cells, CRP also binds to the membranes and nuclear constituents of necrotic cells. However, genetically determined factors with regard to the action of CRP in CAD have rarely been studied yet. Fc ⁇ RIIa, a receptor well established to interact with the Fc portions of IgG has recently been reported also to directly bind CRP (5). However, there are conflicting data on this issue (6,7).
  • Fc ⁇ R bridge the humoral and cellular arms of the immune system.
  • Three main classes of human leukocyte Fc ⁇ R Fc ⁇ RI (CD64), Fc ⁇ RII (CD32), and Fc ⁇ RIII (CD 16)) are encoded by eight Fc ⁇ R genes (8).
  • Fc ⁇ R use the specificity of antibodies and endow the cells with potent cellular effector functions. They are crucial for the clearance of immune complexes. They regulate antibody production and are involved in the regulation of B cell and T cell development (9). The heterogeneity of Fc ⁇ R is essential for regulation and fine-tuning of the immune response (10).
  • Fc ⁇ RIIa is expressed on most myeloid cells, and bears either an arginine (R131) or a histidine (H131) at extracellular amino acid position 131 (11). This substitution dictates receptor binding capacity of complexed IgG2 and IgG3, Fc ⁇ RIIa- R131 being the receptor with lower binding capacity (12,13).
  • Fc ⁇ RIIa containing the arginine (Fc ⁇ RIIa-R131), displays a high avidity for CRP, whereas Fc ⁇ RIIa-H131 displays a low avidity (14).
  • Fc ⁇ RIIa-R131 displays a high avidity for CRP
  • Fc ⁇ RIIa-H131 displays a low avidity
  • Gardemann et al. (20) hypothesized that the Fc ⁇ RIIa Rl 3 IH polymorphism has an impact on coronary heart disease in a German cohort. This polymorphism was analysed in 510 healthy man and 2391 male participants with coronary angiography. No associations were observed between Fc7RIIa-R131H polymorphism and the risks of coronary artery disease and myocardial infarction following genotyping in the total sample. Only when the study sample was restricted to low-risk groups of all the individuals the Fc ⁇ RIIa-R13 IH polymorphism was linked to a risk of CAD and MI. However, the conclusion of Gardemann et al. was that the above polymorphism is not an independent risk indicator of CAD and MI and that the impact of this gene variation is restricted to older individuals who are at low risk for this disease.
  • the Fc ⁇ RIIa polymorphism provides a means for determining the individual risk of a patient of developing or suffering from ACS and in particular UAP and MI.
  • this polymorphism has a strong and statistically significant relation to ACS without being restricted to a subpopulation such as older individuals or distinct ethnic groups.
  • the present invention shows the inventive effects by means of a study population which is comparable to that of Gardemann et al., i. e. patients of Caucasian ethnicity. Therefore, the Fc ⁇ RIIa polymorphism can be used for a precise and rapid detection of the individual risk to suffer from acute coronary syndrome as well as many related diseases.
  • the geno- and/or phenotyping of Fc ⁇ R in patients with atherosclerosis results in the following, clinically significant benefits:
  • an improved risk stratification by using geno- and/or phenotyping of Fc ⁇ R positively influences decisions about the necessity of hospitalisation and the intensity of medical care (for example: do the patients have to be monitored on the expensive intensive care unit or is it justified by improved risk stratification to monitor the patient less frequently on the less expensive regular ward; i.e. improved risk stratification by using geno- and/or phenotyping of Fc ⁇ R reduces costs for hospitalisation);
  • Fc ⁇ RII is expressed on platelets. Herewith, platelets aggregate and release prothrombotic substances leading to thrombotic complications of atherosclerosis. Evaluation of Fc ⁇ RII geno- and / or phenotyping allows better dosage of the anti-platelet therapy in patients with atherosclerosis;
  • Fc ⁇ R geno- and / or phenotype allows a more distinguished interpretation of the prognostic value of increased CRP blood levels in patients with atherosclerosis. It allows a genetic explanation, why CRP levels differ interindividually resulting in distinguished prognosis among patients with equally increased CRP levels.
  • the present invention introduces a method for the diagnosis (first diagnosis or at follow up) of atherosclerosis- related risks by using a system for determining the Fc ⁇ RIIa geno- and/or phenotype.
  • This test system is used for the risk stratification of patients in the primary or secondary prevention or for decision making in the therapy of the following diseases:
  • Coronary artery disease and its clinical manifestations such as stable angina, unstable angina, non-Q-wave infarction (non-ST-segment myocardial infarction), Q-wave infarction (ST-segment myocardial infarction), and ischemic cardiomyopathy;
  • Coronary artery disease with regard to early complications of myocardial infarction (i.e. re-infarction, left ventricular failure, cardiogenic shock, rhythm disturbances); coronary artery disease with regard to late complications of myocardial infarction (i.e.
  • vasospastic angina in patients with coronary artery disease after bypass-surgery; for risk stratification of sudden cardiac death; in patients with atherogenic risk factors such as arterial hypertension, diabetes mellitus, hyperlipoproteinemia, the metabolic syndrome, increase of Lipoprotein (a), hyperfibrinogenemia, and hyperhomocysteinemia; in antiphosholipid-antibody syndromes; in genetically caused tissue-plasminogen activator deficiencies; in patients with vasculitis, which are associated with increased risk for atherosclerotic complications; in patients with chronic renal insufficiency of various origins, which are associated with increased risk for atherosclerotic complications; in transplant vasculopathy, i.e.
  • a diagnostic system for the determination of the Fc7 receptor (FcR) polymorphisms (Fc ⁇ RIIa -R131 (arginine at position 131), Fc ⁇ RIIa -H131 (histidine at position 131)), respectively, which comprises a mixture containing at least one substance which is able to detect Fc ⁇ receptor (FcR) polymorphisms (Fc ⁇ RIIa -Rl 31 (arginine at position 131), FcRIIa -H131 (histidine at position 131)), respectively, especially, for the diagnosis of atherosclerotically caused risks, is disclosed herein.
  • nucleic acids for the detection of the polymorphism or monoclonal antibodies against the R- and/or the H-type of the Fc ⁇ RIIa and/or CRP and/or CRP derivatives and/or CRP parts and/or IgG can be included.
  • markers like eg. dyes, especially, fluorescent dyes/molecules can be coupled.
  • the mixtures, substances, molecules described above may be used in a diagnostic system for the analysis of cells, especially, blood cells like antigen presenting cells (monocytes, dendritic cells, macrophages, B cells), granulocytes, eosinophiles.
  • This kind of application can contain a method for nucleotide analysis of Fc ⁇ RIIa eg. PCR, RT-PCR, Southern Blot, Northern Blot, RFLP analysis, sequencing.
  • An application like this can alternatively contain a method for protein analysis of Fc ⁇ RIIa eg. SDS gel electrophoresis, Western Blot, protein sequencing.
  • a diagnostic application like this can also contain a method for protein expression analysis of Fc ⁇ RIIa eg. ELISA, FACS analysis, immune histochemical analysis.
  • monoclonal antibodies against the R- and/or the H-type of the Fc ⁇ RIIa, and/or CRP and/or CRP derivatives and/or CRP parts and/or IgG like eg. human IgG2 and/or murine IgGl, which is coupled/coated to particles (eg. beads, latex beads) are used.
  • particles eg. beads, latex beads
  • the incubation of the cells which shall be analysed with the monoclonal antibodies against the R- and/or the H-type of the Fc ⁇ RIIa and/or CRP and/or CRP derivatives and/or CRP parts and/or IgG like eg. humane IgG2 and/or murine IgGl, will be performed at a temperature of 37°C or below 37°C, especially, at temperatures between 2 - 25 0 C.
  • additional particles can be used which show typical expression patterns and expression levels of Fc ⁇ RIIa phenotypes like RR (with two alleles with arginine at position 131), or RH (one allele arginine and the other histidine), or HH (two alleles histidine).
  • These particles can be cells (eukaryotic and/or prokaryotic), fixed cells, embedded cells, beads of divers materials, liposomes.
  • the material used must contain the appropriate mixture of Fc ⁇ RIIa and a, for carriers of the characteristics, typical expression level.
  • the particles can then serve as standards for protein expression analyses.
  • an ex-vivo method of determining the risk of a patient of developing or of suffering from acute coronary syndrome comprising the steps of: a) detecting the Fc ⁇ RIIa genotype or phenotype of said patient at amino acid position 131 (R/H); b) determining and classifying the individual risk of said patient in the following order:
  • a precise risk assessment for an individual patient can be made. For example, a blood sample is taken from the patient soon after he or she arrived at the medical institution or the physician. Subsequently a genotyping of the respective polymorphism is done for example by means of PCR. As soon as the results of this analysis are known (and thus the patient's individual risk regarding ACS), the physician in charge may initiate the required therapeutical steps in order to provide the best possible and most cost-effective treatment of said patient.
  • the method can be used for the detection of the individial risk of developping or suffering from unstable angina pectoris (UAP), non- ST-elevation and ST-elevation myocardial infarction (MI).
  • UAP unstable angina pectoris
  • MI ST-elevation myocardial infarction
  • step a) one or more substances are preferably used which are capable of detecting the Fc ⁇ RIIa polymorphism 131 R/H.
  • said one or more substances are selected from nucleic acids, antibodies raised against the R and/or H type of FcTRIIa, CRP or derivatives or fragments thereof, and/or IgG.
  • the antibodies used in this invention may be selected from a group, which consists of polyclonal antibodies, monoclonal antibodies, chimeric antibodies and synthetic antibodies. It is noted that monoclonal antibodies are most preferred in this invention.
  • the antibody according to the invention can be additionally linked to a detectable agent.
  • antibody is used herein for intact antibodies as well as antibody fragments, which have a certain ability to selectively bind to an epitop. Such fragments include, without limitations, Fab, F(ab') 2 und Fv antibody fragment.
  • epitop means any antigen determinant of an antigen, to which the paratop of an antibody can bind. Epitop determinants usually consist of chemically active surface groups of molecules (e.g. amino acid or sugar residues) and usually display a three-dimensional structure as well as specific physical properties.
  • the antibodies according to the invention can be produced according to any known procedure.
  • the pure complete Fc ⁇ RIIa receptor according to the invention or a part of it can be produced and used as immunogen to immunize an animal and to produce specific antibodies.
  • monoclonal antibodies are as well commonly known. Examples include the hybridoma method (Kohler and Milstein, 1975, Nature, 256:495-497, Coligan et al., section 2.5.1 - 2.6.7; and Harlow et al., Antibodies: A Laboratory Manual, page 726 (Cold Spring Harbor Pub. 1988).), the trioma technique, the human B-cell hybridoma technique (Kozbor et al., 1983, Immunology Today 4:72), and the EBV-hybridoma technique to produce human monoclonal antibodies (Cole, et al., 1985, in Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc., pp. 77-96).
  • monoclonal antibodies can be attained by injecting a mixture which contains the receptor of the invention into mice.
  • the antibody production in the mice is checked via a serum probe.
  • the mouse is sacrificed and the spleen is removed to isolate B-cells.
  • the B cells are fused with myeloma cells resulting in hybridomas.
  • the hybridomas are cloned and the clones are analyzed. Positive clones which contain a monoclonal antibody against the protein are selected and the antibodies are isolated from the hybridoma cultures. There are many well established techniques to isolate and purify monoclonal antibodies.
  • Such techniques include affinity chromatography with protein A sepharose, size-exclusion chromatography and ion exchange chromatography. Also see for example, Coligan et al., section 2.7.1 - 2.7.12 and section ,,Immunglobulin G (IgG)", in Methods In Molecular Biology, volume 10, pages 79 - 104 (Humana Press 1992).
  • CRP and IgG are used in their protein form in order to evaluate the binding behavior of Fc ⁇ RIIa.
  • Human IgG 2 binds to Fc ⁇ RIIa 13 IH with higher affinity and murine IgG 1 binds to FcTRIIa 13 IR with higher affinity.
  • CRP C-reactive protein
  • CRP Creprivation protein
  • the amount of CRP produced by the body varies from person to person, and this is affected by an individual's genetic charcteristics and lifestyle. Higher CRP levels tend to be found in individuals who smoke, have high blood pressure, are overweight and don't exercise, whereas lean, athletic individuals tend to have lower CRP levels.
  • Fc ⁇ RII is the main receptor of CRP on human monocytes and PMN.
  • CRP protein or functional fragments or derivatives may act to evaluate the binding behavior of the patients FcTRIIa and thus the individual Fc ⁇ RIIa allele of a patient.
  • the substances my be detectably labelled.
  • the label is a dye or a coloured molecule. More preferably, the dye is a fluorescent or chemiluminescent dye. All dyes well known in the art may be used for this purpose.
  • the genotype of the patient is determined by evaluating the Fc ⁇ RIIa polymorphism 131 by a method of nucleic acid analysis.
  • This method preferably is selected from PCR, RT-PCR, Southern Blotting, Northern Blotting, RFLP-analysis, and/or nucleic acid sequencing.
  • McPherson et al. ed.
  • PCR A Practical Approach, Oxford, IRL Press 1995.
  • the Fc ⁇ RIIa polymorphism 131 is detected by a method of amino acid analysis, preferably by ELISA, FACS-analysis, and/or immunohistochemical analysis (as mentioned above).
  • the one or more substances used in the present method may be coupled or coated onto particles, preferably beads or latex beads.
  • the Fc7RIIa genotype or phenotype of the patient is detected in body cells sampled from the patient.
  • Those cells preferably are blood cells, most preferably antigen presenting cells (APCs), granulocytes and/or eosinophils.
  • APCs preferably are selected from monocytes, dendritic cells, macrophages and/or B cells.
  • the incubation of the patient's body cells with the one or more substances as defined herein is performed at a temperature of 37°C or below 37 0 C. More precisely, the temperature preferably is from about 2 to about 25°C, more preferably from 15 to 22°C, 17 to 22°C, and most preferably 18 - 2O 0 C. Usually, the temperature may be ambient temperature.
  • the present invention provides an antibody which is directed against the 131 H type of Fc ⁇ RIIa.
  • that antibody may be selected from a polyclonal antibody, a monoclonal antibody, a chimeric antibody, and a synthetic antibody.
  • the monoclonal antibody is most preferred.
  • the invention provides a diagnostic kit comprising one or more of the substances as defined above.
  • a particle is encompassed, which is comprising expression patterns or levels of expression of the Fc7R.Ha genotypes 131 R/R, 131 H/H and/or 131 R/H.
  • This particle preferably is selected from the group consisting of cells (procaryotic and/or eucaryotic), fixed cells, embedded cells, beads and/or liposomes, wherein the beads may preferably comprise latex, sepharose, agarose and/or polystyrene.
  • the invention provides the use of the method as defined above, of the antibody as disclosed herein or the above mentioned kit for the diagnosis of acute coronary syndromes (ACS).
  • ACS is selected from the group consisting of unstable angina pectoris (UAP), non-ST-elevation and ST-elevation myocardial infarction (MI).
  • the method, antibody, kit of the invention may be used for the diagnosis/prognosis of early and late complications of ACS, for the diagnosis of an individual's risk of sudden cardiac death and for the early diagnosis (preventive diagnosis) of catastrophic antiphospholipid syndrome (Asherson's Syndrome), systemic lupus erythematosus, rheumatoid arthritis, vasculitis, multiple sclerosis, immune- mediated thrombocytic purpura and myasthenia gravis. Additionally, the use encompasses the various medical applications indicated above, i.e.
  • vasospastic angina Priorzmetal-angina
  • atherogenic risk factors such as arterial hypertension, diabetes mellitus, hyperlipoproteinemia, the metabolic syndrome, increase of Lipoprotein (a), hyperfibrinogenemia, and hyperhornocysteinemia
  • lipoprotein (a) hyperfibrinogenemia
  • hyperhornocysteinemia in antiphosholipid-antibody syndromes
  • tissue-plasminogen activator deficiencies in patients with vasculitis, which are associated with increased risk for atherosclerotic complications; in patients with chronic renal insufficiency of various origins, which are associated with increased risk for atherosclerotic complications; in transplant vasculopathy, i.e.
  • Figure IA shows the significantly altered distribution of the Fc ⁇ RIIa genotype (RR, HR or HH) within the patients with CAD and ACS as compared to NHD.
  • Figure IB illustrates the three different pathways (1, 2, and 3) to develop an AMI are indicated by arrows.
  • a significantly higher part of patients with Fc ⁇ RIIa-R/R131 genotype develop an AMI going through the stadium of UAP (pathway T).
  • Genomic DNA was isolated from PBMC using the WizzardTM DNA purification kit (Promega, USA) according to the manufacturer's instruction. Identification of the Fc ⁇ RIIa polymorphism was performed by PCR as described previously (16). Briefly, for the allele-specific amplification, primers P5G (5'-GAA AAT CCC AGA AAT TTT TCC G) (for the Fc ⁇ RIIa-R131 allele; SEQ ID NO: 1) and P4A (5'-GAA AAT CCC AGA AAT TTT TCC A) (for the Fc ⁇ RIIa-H131 allele; SEQ ID NO: 2) were combined with the common antisense primer, P 13 (5'-CTA GCA GCT CAC CAC TCC TC) (SEQ ID NO: 3).
  • Additional analyses showed a markedly reduced frequency of the Fc ⁇ RJIa-R/R genotype in SAP and Fc ⁇ RIIa-H/H genotype in ACS patients.
  • Statistical analyses proofed the sensitivity and specificity for the Non-RR genotype to detect SAP and for the Non-HH genotype to detect ACS in all patients with CAD.
  • the Non-RR genotype has a sensitivity of 96 % with a specificity of 29 % to detect SAP.
  • the Non-HH genotype has a sensitivity of 86 % with a specificity of 24 % to detect ACS.
  • Fc ⁇ R function has been extensively studied in chronic inflammatory diseases such as systemic lupus erythematosus, rheumatoid arthritis, or multiple sclerosis.
  • chronic inflammatory diseases such as systemic lupus erythematosus, rheumatoid arthritis, or multiple sclerosis.
  • Fc ⁇ R genotypes and chronic inflammatory diseases, which is discussed to be due to clearance deficiency of IgG2-containing immune complexes by the Fc ⁇ RIIa- R131.
  • Another concept assumes a detrimental inflammatory response through highly efficient Fc ⁇ R - IgG interaction due to variations in the affinity to the IgG2 subclass.
  • Fc ⁇ RIIa is expressed on monocytes/macrophages, neutrophils, and platelets which all play a role in atherogenesis and atherosclerosis (18). Binding of Fc ⁇ RIIa on platelets causes platelet-aggregation and release of platelet granula. Thereby, genetically determined variability in CRP binding to Fc ⁇ RIIa may translate into various biological effects of CRP on Fc ⁇ RIIa bearing cells and finally influence clinical outcome decisively.
  • Fc ⁇ RIIa genotypes may also allow risk stratification in the setting of primary prevention. According to our results, the Fc ⁇ RIIa-H/H genotype had a significantly lower frequency for ACS as compared to healthy controls. Here, early genotyping together with stratification of classical atherogenic risk factors may improve the predictive value.
  • the protective value of Fc ⁇ RIIa-H/H against ACS may contribute to the well known reduced incidence of ACS in the Japanese population (19), which has a highly increased frequency of the Fc ⁇ RIIa-H131 allele (R/R131 : 3.6%, R/H131 : 31.4%, H/H131 : 65%) (15).
  • the R/R genotype has a high frequency in patients with UAP when compared to those with SAP, NHD, or AMI.
  • the Fc ⁇ RIIa-H/H genotype is protective against ACS. Therefore, genotyping of Fc ⁇ RIIa may become part of the risk stratification in patients prone for the development of ACS.
  • SAP stable Angina pectoris
  • UAP unstable Angina pectoris
  • AMI acute Myocardial infarction
  • Fc ⁇ RIIa-R/R131 1 (4) 19 (29) 7 (37) 12 (25.5) Fc ⁇ RIIa-R/H131 18 (72) 38 (58) 10 (53) 28 (59.5) Fc ⁇ RIIa-H/H131 6 (24) 9 (14) 2 (10) 7 (15)
  • SAP stable Angina pectoris
  • UAP unstable Angina pectoris
  • AMI acute myocardial infarction
  • Relative risk of each Fc ⁇ RIIa genotype to develop an acute coronary syndrome i.e. unstable Angina pectoris or acute myocardial infarction.
  • CAD coiffy artery disease
  • NHS normal healthy controls
  • ACS acute coronary syndrome
  • SAP stable angina pectoris
  • UAP unstable angina pectoris
  • AMI acute myocardial infarction.
  • Gardemann A 3 Fc gamma RIIa-Rl 3 IH polymorphism Its impact on coronary heart disease in a German cohort. Thromb. Haemost. (2003) 90, 1218-1220.

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Abstract

L'invention concerne un procédé pour déterminer le risque d'un patient présentant de nombreuses maladies de développer ou de souffrir d'un syndrome coronaire aigu ainsi qu'un anticorps destiné à être utilisé dans le procédé. L'invention concerne un kit diagnostique et des particules destinées à être utilisées dans le procédé ainsi que leur utilisation et le diagnostic et la prévention de plusieurs maladies.
PCT/EP2005/007073 2004-06-30 2005-06-30 Polymorphisme fcgammariia et son utilisation dans un diagnostic WO2006002930A2 (fr)

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US8247370B2 (en) 2006-12-04 2012-08-21 Promedior, Inc. Conjoint therapy for treating fibrotic diseases
EP2129795A2 (fr) * 2006-12-19 2009-12-09 Synergenz Bioscience Limited Procédés et compositions pour l'évaluation de la fonction et de troubles cardiovasculaires
EP2129795A4 (fr) * 2006-12-19 2010-10-20 Synergenz Bioscience Ltd Procédés et compositions pour l'évaluation de la fonction et de troubles cardiovasculaires
US8497243B2 (en) 2007-07-06 2013-07-30 Promedior, Inc. Methods and compositions useful in the treatment of mucositis
AU2008275678B2 (en) * 2007-07-06 2014-06-26 Promedior, Inc. Treatment and diagnostic methods for fibrosis related disorders
JP2016001196A (ja) * 2007-07-06 2016-01-07 プロメディオール， インコーポレイテッド 線維化関連障害のための治療および診断方法
US9884899B2 (en) 2007-07-06 2018-02-06 Promedior, Inc. Methods for treating fibrosis using CRP antagonists
US9233140B2 (en) 2009-03-11 2016-01-12 Promedior, Inc. Treatment methods for hypersensitive disorders
US10702583B2 (en) 2009-03-11 2020-07-07 Promedior, Inc. Treatment methods for autoimmune disorders
US9296800B2 (en) 2009-06-04 2016-03-29 Promedior, Inc. Serum amyloid P derivatives and their preparation and use
US8329659B2 (en) 2009-06-17 2012-12-11 Promedior, Inc. SAP variants and their use
US9556246B2 (en) 2009-06-17 2017-01-31 Promedior, Inc. SAP variants and their use

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