WO1997004127A1 - Analyse diagnostique de la schizophrenie consistant a analyser des variations alleliques dans le gene de la phospholipase cytosolique a¿2? - Google Patents

Analyse diagnostique de la schizophrenie consistant a analyser des variations alleliques dans le gene de la phospholipase cytosolique a¿2? Download PDF

Info

Publication number
WO1997004127A1
WO1997004127A1 PCT/GB1996/001795 GB9601795W WO9704127A1 WO 1997004127 A1 WO1997004127 A1 WO 1997004127A1 GB 9601795 W GB9601795 W GB 9601795W WO 9704127 A1 WO9704127 A1 WO 9704127A1
Authority
WO
WIPO (PCT)
Prior art keywords
alleles
schizophrenia
cpla2
gene
dha
Prior art date
Application number
PCT/GB1996/001795
Other languages
English (en)
Inventor
David Frederick Horrobin
Craig James Hudson
James Kennedy
Original Assignee
Scotia Holdings Plc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Scotia Holdings Plc filed Critical Scotia Holdings Plc
Priority to AU66213/96A priority Critical patent/AU6621396A/en
Publication of WO1997004127A1 publication Critical patent/WO1997004127A1/fr

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • 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

Definitions

  • the invention relates to a diagnostic test for schizophrenia.
  • Schizophrenia is a common and devastating psychiatric disorder which affects between 0.5% and 1.5% of the population in most parts of the world. Perhaps ten times as many relatives, friends, colleagues, teachers and employers have had their lives adversely affected by this disease. The economic costs are high since most patients begin to develop symptoms between the ages of 15 and 35, yet live a relatively normal life span. Many homeless people are schizophrenic.
  • PLA2 cytoplasmic form of PLA2
  • cPLA2 cytoplasmic form of PLA2
  • a A arachidonic acid
  • the cPLA2 gene has been identified, as has a region adjacent to the cPLA2 gene on chromosome 1 which is believed to be the promoter region for the gene (Tay et al, Biochim Biophys Acta 1994; 1211: 345-347 and Tay et al, Genomics 1995; 26: 138-141). Promoter regions are believed to regulate the expression of the gene and to determine the amount of active gene product produced.
  • each gene there are two copies of each gene, one copy being derived from the mother and one from the father.
  • Each gene may have several possible different variants known as alleles. Which alleles are present will determine what characteristics are expressed in an individual. If the two genes derived from the maternal and paternal chromosomes are the same alleles, the individual is said to be homozygous for that gene. If the alleles are different, the individual is said to be heterozygous for that gene.
  • Niacin given at a dose of over lOOmg by mouth, induces marked facial flushing in normal individuals. Some schizophrenic individuals flush normally, whereas others fail to flush in response to niacin. There is some evidence that schizophrenics who fail to flush in response to niacin represent a more tightly defined group. In a group of 10 schizophrenics who were defined as niacin non-flushers, this was reflected in the A7-A10 alleles present.
  • the invention provides a method of identifying individuals genotypically predisposed to schizophrenia characterised by establishing the presence of abnormal alleles in the promoter region of the cytoplasmic phospholipase A2 (CPLA2) gene of chromosome 1.
  • CPLA2 cytoplasmic phospholipase A2
  • SSRs polyadenine simple sequence repeats
  • the method may be carried out by (i) taking a tissue sample and extracting genetic material from it; (ii) amplifying the poly-A sequence of the promoter region of the CPLA2 gene; (iii) determining whether A7-A10 or other longer alleles than A1-A6 are present, such presence indicating a positive diagnosis.
  • the invention also provides correspondingly a diagnostic test or diagnostic kit for such methods, as set out in the claims hereafter.
  • An alteration associated with the cPLA2 gene may give rise to disease, either causing the disease itself or acting as a modifier that allows for the expression of another mutant gene. It is possible that, alone, a mutation of the cPLA2 gene may be necessary but not a sufficient pathologic process in the development of schizophrenia. Either way the presence of the abnormal alleles will identify individuals at risk of developing schizophrenia.
  • a diagnostic indicator of schizophrenia based on identification of the alleles present at the promoter region of the cPLA2 locus on human chromosome 1, and thus a method of indicating which individuals may be schizophrenic, or at risk of developing schizophrenia, by identification of such alleles.
  • test or diagnostic kit for, and use of such a test or kit in, diagnosis of individuals at risk of schizophrenia or who are carrying genes which confer a risk of schizophrenia, which test or kit comprises means for determining the types of alleles present in the promoter region of the cPLA2 gene of human chromosome 1.
  • the methodology for identifying the alleles may be that described by Tay et al or that modified by us as described in detail later or may be any type of methodology known or yet to be discovered which allows accurate identification of the alleles.
  • the alleles are in particular polyadenine (poly A) alleles, specifically those identified as alleles A1-A10 in the table herein.
  • poly A polyadenine
  • identification is suitably by using primers flanking the poly-A repeat tracts, labelling, amplifying the labelled primers by polymerase chain reaction, and determining the size of the alleles.
  • the invention further extends to the prevention of schizophrenia, based on the suggestion that in schizophrenia there is excessive activity of cPLA2.
  • Elevated circulating levels of cPLA2 have been detected in schizophrenic patients, also elevated levels of phospholipid breakdown products have been detected in the brains of schizophrenic individuals by nuclear magnetic resonance scanning, and in the red cell membranes of schizophrenics there appear to be reduced phospholipid concentrations of two important essential fatty acids, docosahexaenoic acid (DHA) and arachidonic acid (AA), these two essential fatty acids (EFAs) being removed from phospholipids by cPLA2, suggesting increased activity of this enzyme. Since normal membrane composition is required for normal nerve cell function, this excessive activity of cPLA2 may be responsible for abnormal nerve cell function and hence for the abnormal behavioural and other manifestations of schizophrenia.
  • DHA docosahexaenoic acid
  • AA arachidonic acid
  • One way of reducing the impact of excessive cPLA2 activity is to make available increased amounts of the two main EFAs which are removed from cell phospholipids by cPLA2, arachidonic acid and docosahexaenoic acid: the presence of increased amounts of these two fatty acids increases the chance of incorporation of the AA and DHA into membranes tending to normalise them and thus reduce the impact of the presence of excess cPLA2 activity.
  • the dose of each of these fatty acids per day may be in the range of from 10 mg to 100 g, preferably 100 mg to 10 g, and very preferably 500 mg to 5 g.
  • the fatty acids may be presented orally, parenterally or topically in any form which may be biologically assimilated into the body.
  • Possible forms of administration may include free fatty acids, lithium, sodium, potassium or other salts, any esters, any amides, and mono-, di- or triglycerides, any phospholipids, or any other appropriate form.
  • a mix of triglycerides containing DHA and AA, or a triglyceride containing at least one molecule of AA and one of DHA, with the other fatty acid on the triglyceride being either AA, DHA or another fatty acid, or a triglyceride prepared from a fatty acid mix containing at least 10% and preferably at least 20% or very preferably at least 30% each of DHA and AA are particularly desirable variants of the invention. They may be made by methods per se known, for example those of the inventor's published EP-A-0609001 and EP-A-0611569 to which reference may be made. Alternatively the 1,3-propane diol esters of the applicant's co-pending PCT filing no. GB96/01053 may be used, particularly to deliver the AA and DHA.
  • cPLA2 activity is excessive, it may also be appropriate to administer with the fatty acids an inhibitor of cPLA2.
  • This could be a drug such as mepacrine or a glucocorticoid, but more desirable would be a fatty acid which itself had activity in inhibiting cPLA2.
  • cPLA2 can be physiologically inhibited by increasing the amounts of cyclic AMP (cAMP) in cells.
  • Cellular cAMP concentrations may be enhanced by the presence of prostaglandin El (PGE1) which is a powerful stimulator of cAMP formation.
  • PGE1 prostaglandin El
  • the levels of PGE1 may be increased by its immediate precursor, dihomogammalinolenic acid (DGLA) or by the immediate precursor of DGLA, gammalinolenic acid (GLA).
  • GLA or DGLA may be given in any appropriate form and amount as described above for A A and for DHA.
  • two forms of GLA and/or DGLA may be particularly appropriate.
  • One is the derivative of ascorbic acid, ascorbyl-GLA or ascorbyl-DGLA. This is because, as described in previous patent applications by the inventor, published as European patent application no's. 95 301316.6 (EP-A-0675120) and 95 304498.9 (EP-A-0694302) to which reference may be made, the presence of ascorbic acid greatly stimulates the conversion of GLA or DGLA to PGE1 and hence will greatly increase the formation of cAMP.
  • the other preferred form is in a triglyceride or triglyceride mix in which AA and DHA are also present.
  • a triglyceride containing approximately equal amounts of AA, DHA and either GLA or DGLA may be used, such triglyceride being present in a triglyceride mix, preferably at a concentration of above 10% and very preferably at a concentration of above 20%.
  • a triglyceride mix may be prepared from an approximately equimolar mix of the three fatty acids, AA, DHA and/or GLA or DGLA, the total concentration of the three fatty acids in the mix being greater than 40%, preferably greater than 50% and very preferably greater than 80%.
  • the alleles present may be identified by any method known to those skilled in the art at present or by any method which may be developed in the future. One method of doing so, based on the work of Tay et al, is in summary to use primers and the polymerase chain reaction as described by Tay et al, to amplify the relevant region of the cPLA2 gene and prepare appropriate gels. The different alleles are identified by reading the gels and noting the number of repeats in the relevant region. Patients may thus be identified as homozygous or heterozygous and those who have A7-A10 alleles identified as at risk of developing schizophrenia.
  • Tay et al collected 20 ml of blood from 50 unrelated healthy donors and extracted genomic DNA by standard established techniques. Primers were designed to flank the cytosine-adenine (CA) and adenine (A) repeat tracts. These primers were end-labelled by incubation with 10 UT4 polynucleotide kinase (Boehringer Mannheim) and 50 microcuries of 22p_ATP (6000 Ci/mmol, Amersham). The labelled primers were then used to amplify the genomic DNA using the polymerase chain reaction. The amplified DNA was extracted and loaded on to a sequencing gel and analysed. The size of each allele was determined by comparison of the PCR products to a sequencing ladder. Full technical details of the method are published in Genomics 26: 138-141, 1995.
  • Table 1 shows the allele frequencies in the 50 normal controls described by Tay et al. We used exactly the same techniques as described by Tay et al and as summarised above to extract DNA from the blood samples obtained from schizophrenics and to identify the alleles present at the polymorphic A locus. The results for the overall 50 schizophrenic populations and for the 10 who did not flush in response to niacin are also shown in table 1. As can be seen, the normal population has 92% A1-A6 alleles with only 8% as A7-A10. In contrast, the 50 schizophrenics have only 38% A1-A6 alleles and 62% as A7-A10.
  • the schizophrenics who are further defined as being non-flushers have none of their alleles as A 1-A6, all being A7-A10. Thus in these non-flushing schizophrenics both of the poly-A alleles derived from the mother and father must be A7-A10.
  • This method will nominally make up enough reaction mix for 30 reactions. However, allow at least 10% (i.e. 3 reactions) extra for pipet enor, therefore, this will set up 27 reactions for PCR.
  • Genomic DNA samples should be diluted to 50ng/ ⁇ l.
  • DNA markers (3 2 P-labelled): ⁇ BR322/Mspi (New England Biolabs)
  • Loading Buffer #2 95% formamide, 0.5% bromophenol blue, 0.5% xylene cyanol
  • BioMax-MS-1 film use with an intensifying screen, and expose for one hour at -70°C.
  • BioMax-MR-1 film expose for 3 hours at -70°C (an intensifying screen is not necessary).
  • band 1 4mm
  • band 2 7mm from the 147 band of the DNA marker.
  • the product of the above example has been subject to hplc triglyceride analysis and gc fatty acid analysis, by standard methods.
  • gc analysis the preparation of the methyl ester derivatives of fatty acids is well known.
  • Boron trifluoride in methanol (12- 14% w/v) was used as catalyst.
  • lOOmg of each of the triglycerides was transesterfied and analysed in a Hewlett Packard 5890 Series II equipped with a SupelcowaxTM 10 capillary column (30m x 0.53mm x l.O ⁇ m).
  • Injector temperature set at 220°C and detector temperature at 250°C, the oven temperature was programmed starting at 180°C for 5 min after which is increased at a rate of 2°C/min until 210°C was reached and maintained at this temperature for a further 15 mins.
  • l ⁇ l of each of the methyl esters of the fatty acids was injected using an autosampler, 7673 from Hewlett Packard. Each of the methyl esters of the fatty acids were identified by injecting standards.
  • the results of the gc and hplc analyses are as follows: -
  • a triglyceride mix prepared from a mix comprising 15-30% of each of three fatty acids, AA, DHA and GLA or DGLA is reacted together under appropriate chemical or enzymic conditions as well known in the art and shown in the applicant's published patent applications refened to herein, to produce a triglyceride for oral or parenteral administration and administered in the amounts set out herein.
  • All the above may be formulated in any appropriate dosage form, including soft or hard gelatin capsules, microcapsules presented alone or in the form of powders or other forms such as tablets, emulsions, suspensions and any other appropriate formulations for oral, enteral, parenteral or topical use such that the fatty acids may reach the body in a biologically assimilable form. Many such variations of presentation are known to those skilled in the art.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Genetics & Genomics (AREA)
  • General Health & Medical Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Zoology (AREA)
  • Engineering & Computer Science (AREA)
  • Wood Science & Technology (AREA)
  • Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Biotechnology (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • Microbiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Abstract

Procédé et moyen permettant d'identifier des individus présentant, du fait de leur génotype, une prédisposition à la schizophrénie, qui consistent à établir la présence d'allèles anormaux dans la région promotrice du gène cPLA2 (phospholipase cytoplasmique A2) du chromosome 1.
PCT/GB1996/001795 1995-07-24 1996-07-24 Analyse diagnostique de la schizophrenie consistant a analyser des variations alleliques dans le gene de la phospholipase cytosolique a¿2? WO1997004127A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU66213/96A AU6621396A (en) 1995-07-24 1996-07-24 Diagnostic test for schizophrenia by analysing allelic variations in the cytosolic phospholipase a2 gene

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9515160.1 1995-07-24
GBGB9515160.1A GB9515160D0 (en) 1995-07-24 1995-07-24 Diagnostic test

Publications (1)

Publication Number Publication Date
WO1997004127A1 true WO1997004127A1 (fr) 1997-02-06

Family

ID=10778171

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1996/001795 WO1997004127A1 (fr) 1995-07-24 1996-07-24 Analyse diagnostique de la schizophrenie consistant a analyser des variations alleliques dans le gene de la phospholipase cytosolique a¿2?

Country Status (3)

Country Link
AU (1) AU6621396A (fr)
GB (1) GB9515160D0 (fr)
WO (1) WO1997004127A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000044360A2 (fr) * 1999-01-27 2000-08-03 Laxdale Limited Medicaments pour le traitement de troubles psychiatriques et cerebraux
US6228128B1 (en) 1997-11-10 2001-05-08 Charlotte Johansen Antimicrobial activity of laccases
EP1132483A2 (fr) * 2000-03-07 2001-09-12 President of Niigata University Méthode de diagnostic de la schizophrénie utilisant des indices objectifs
WO2005035788A2 (fr) * 2003-10-10 2005-04-21 Yissum Research Development Company Of The Hebrew University Of Jerusalem Procede et kit d'evaluation de l'anxiete ou de disposition a l'anxiete chez un sujet

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5006462A (en) * 1988-03-16 1991-04-09 Abbott Laboratories Method for the detection of schizophrenia

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5006462A (en) * 1988-03-16 1991-04-09 Abbott Laboratories Method for the detection of schizophrenia

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HORROBIN D ET AL: "The membrane hypothesis of schizophrenia", SCHIZOPHRENIA RESEARCH, vol. 13, 1994, pages 195 - 207, XP000604567 *
TAY A ET AL: "Cytosolic phospholipase A2 gene in human and rat: chromosomal localization and polymirphic markers", GENOMICS, vol. 26, no. 1, March 1995 (1995-03-01), pages 138 - 41, XP000604111 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6228128B1 (en) 1997-11-10 2001-05-08 Charlotte Johansen Antimicrobial activity of laccases
WO2000044360A2 (fr) * 1999-01-27 2000-08-03 Laxdale Limited Medicaments pour le traitement de troubles psychiatriques et cerebraux
WO2000044360A3 (fr) * 1999-01-27 2000-11-30 Laxdale Ltd Medicaments pour le traitement de troubles psychiatriques et cerebraux
EP1132483A2 (fr) * 2000-03-07 2001-09-12 President of Niigata University Méthode de diagnostic de la schizophrénie utilisant des indices objectifs
EP1132483A3 (fr) * 2000-03-07 2003-02-26 President of Niigata University Méthode de diagnostic de la schizophrénie utilisant des indices objectifs
WO2005035788A2 (fr) * 2003-10-10 2005-04-21 Yissum Research Development Company Of The Hebrew University Of Jerusalem Procede et kit d'evaluation de l'anxiete ou de disposition a l'anxiete chez un sujet
WO2005035788A3 (fr) * 2003-10-10 2005-09-15 Yissum Res Dev Co Procede et kit d'evaluation de l'anxiete ou de disposition a l'anxiete chez un sujet
US7494783B2 (en) 2003-10-10 2009-02-24 Yissum Research Development Company Of The Hebrew University Of Jerusalem Method for assessing trait anxiety by determining cholinergic status

Also Published As

Publication number Publication date
GB9515160D0 (en) 1995-09-20
AU6621396A (en) 1997-02-18

Similar Documents

Publication Publication Date Title
JP6316994B2 (ja) 心筋梗塞に関連する遺伝的多型、その検出方法および使用
JP5649263B2 (ja) 心臓血管障害および薬物応答に関連した遺伝子多型、それらの検出方法および用途
EP3093351B1 (fr) Polymorphismes génétiques associés à des maladies cardiovasculaires, procédés de détection et utilisations associées
EP2412827B1 (fr) Polymorphism génétique associée à des techniques de detection de cirrhose du foie et utilisation de ces polymorphismes
US9499868B2 (en) Determination of single nucleotide polymorphisms useful to predict response for glatiramer acetate
US7695911B2 (en) Genetic polymorphisms associated with Alzheimer's Disease, methods of detection and uses thereof
US20060014165A1 (en) Methods of diagnosis and treatment for asthma and other respiratory diseases based on haplotype association
JP2009519001A (ja) 狭窄に関連する遺伝的多型、その検出方法および使用
ES2685269T3 (es) Marcadores genéticos para predecir el grado de respuesta al tratamiento
WO2014052855A1 (fr) Procédés et compositions de dépistage et de traitement de troubles du développement
EP4177356B1 (fr) Procédés d'évaluation du risque de développer une maladie virale à l'aide d'un test génétique
AU2004257748B2 (en) Method of diagnosis and treatment for asthma based on haplotype association
Schellenberg et al. The genetics of Alzheimer’s disease
JP2009520460A (ja) 心筋梗塞に関連する遺伝的多型、その検出方法および使用
JP2004504053A (ja) 肥満症の治療および／または予防に好適である化合物の発見法
WO1997004127A1 (fr) Analyse diagnostique de la schizophrenie consistant a analyser des variations alleliques dans le gene de la phospholipase cytosolique a¿2?
US7960108B2 (en) DNA polymorphisms in sterol-regulator-element binding proteins
US20220184029A1 (en) Compositions and methods for treating neuroblastoma
Ding et al. Improved detection of the G1528C mutation in LCHAD deficiency
US20040242462A1 (en) Function and application of tob gene in central nervous systems of mammal
US20190336468A1 (en) Methods and compositions for the treatment of multiple sclerosis
US20170037471A1 (en) Methods for diagnosing & treating copper-dependent diseases
Class et al. Patent application title: DETERMINATION OF SINGLE NUCLEOTIDE POLYMORPHISMS USEFUL TO PREDICT RESPONSE FOR GLATIRAMER ACETATE Inventors: Teva Pharmaceutical Industries, Ltd.(Petach-Tikva, IL) Amir Tchelet (Hod-Hasharon, IL) Fabio Macciardi (Irvine, CA, US) Joseph Levy (Kfar-Sava, IL) Assignees: Teva Pharmaceutical Industries Ltd.
Zhang Genetic variants of lipid transport genes, dyslipidaemia and coronary heart disease.

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE HU IL IS JP KE KG KP KR KZ LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK TJ TM TR TT UA UG US UZ VN AM AZ BY KG KZ MD RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): KE LS MW SD SZ UG AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM

121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase