EP1395680A2 - Methode zum nachweis eines polymorphismus im humanen oatpb gen - Google Patents

Methode zum nachweis eines polymorphismus im humanen oatpb gen

Info

Publication number
EP1395680A2
EP1395680A2 EP02726302A EP02726302A EP1395680A2 EP 1395680 A2 EP1395680 A2 EP 1395680A2 EP 02726302 A EP02726302 A EP 02726302A EP 02726302 A EP02726302 A EP 02726302A EP 1395680 A2 EP1395680 A2 EP 1395680A2
Authority
EP
European Patent Office
Prior art keywords
oatpb
polymorphism
human
seq
gene
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP02726302A
Other languages
English (en)
French (fr)
Inventor
Rachael Moore
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca AB
Original Assignee
AstraZeneca AB
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
Priority claimed from GB0112256A external-priority patent/GB0112256D0/en
Application filed by AstraZeneca AB filed Critical AstraZeneca AB
Publication of EP1395680A2 publication Critical patent/EP1395680A2/de
Withdrawn legal-status Critical Current

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
    • 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 human sodium independent organic anion transporting polypeptide (OATP) B gene is a member of the OATP supergene family involved in multifunctional transport of organic anions 1 .
  • SLC21A solute carriers
  • OATPB relates to SLC21 A9.
  • OATPB has a 35% identity at the amino acid level with its gene family member human OATPC (SLC21A6) 2 .
  • OATPC has been shown to be involved in the transport of drugs involved in lipid lowering e.g. statins.
  • Statins have been referred to as a first-line therapy for patients with atherosclerotic vascular diseases 3 .
  • OATPB has been shown to transport similar substrates as OATPC such as bromosulphophthalein (BSP) and sulfated steroids (e.g. dehydroepiandrosterone sulfate (DHEAS) and estrone-3- sulphate), but not bile salts.
  • OATPB has a wide tissue expression pattern, with strong expression in the liver and has been localised to the basolateral membranes of human hepatocytes .
  • a method for the detection of a polymorphism in OATPB in a human comprises determining the sequence of the human at one of the following positions: position 1113 of SEQ ID NO: 4 and/or position 312 of SEQ ID NO 5.
  • the term human includes both a human having or suspected of having a OATPB mediated response to a drag and an asymptomatic human who may be tested for predisposition or susceptibility to such a response. At each position the human may be homozygous for an allele or the human may be a heterozygote.
  • the polymorphism at position 1113 is presence of G and/or A. In one embodiment of the mvention preferably the polymorphism at position 312 is presence of Arg and/or Gin.
  • test sample of nucleic acid is conveniently a sample of blood, bronchoalveolar lavage fluid, sputum, or other body fluid or tissue obtained from an individual. It will be appreciated that the test sample may equally be a nucleic acid sequence corresponding to the sequence in the test sample, that is to say that all or a part of the region in the sample nucleic acid may firstly be amplified using any convenient technique e.g. PCR, before analysis of allelic variation.
  • Oligonucleotide arrays (DNA Chips) Solution phase hybridisation: TaqmanTM - US-5210015 & US-5487972 (Hoffmann-La
  • Patent No. 2228998 (Zeneca Limited)
  • Immunoassay techniques are known in the art e.g. A Practical Guide to ELISA by D M Kemeny, Pergamon Press 1991; Principles and Practice of Immunoassay, 2 n edition, C P Price & D J Newman, 1997, published by Stockton Press in USA & Canada and by
  • Particularly preferred methods include ARMSTM and RFLP based methods.
  • ARMSTM is an especially preferred method.
  • the methods of the invention are used to assess the pharmacogenetics of a drug transportable by OATPB.
  • Assays for example reporter-based assays, may be devised to detect whether one or more of the above polymorphisms affect transcription levels and/or message stability.
  • OATPB gene or its complementary strand comprising a variant allelic polymorphism at one or more of positions defined herein or a fragment thereof of at least 20 bases comprising at least one novel polymorphism.
  • the invention further provides a nucleotide primer which can detect a polymorphism of the invention.
  • an allele specific primer capable of detecting a OATPB gene polymorphism, preferably at one or more of the positions as defined herein.
  • An allele specific primer is used, generally together with a constant primer, in an amplification reaction such as a PCR reaction, which provides the discrimination between alleles through selective amplification of one allele at a particular sequence position e.g. as used for ARMSTM assays.
  • the allele specific primer is preferably 17- 50 nucleotides, more preferably about 17-35 nucleotides, more preferably about 17-30 nucleotides.
  • an allele specific primer or an allele specific oligonucleotide probe capable of detecting a OATPB gene polymorphism at one of the positions defined herein.
  • a diagnostic kit comprising an allele specific oligonucleotide probe of the invention and/or an allele-specific primer of the invention.
  • the single nucleotide polymorphisms of this invention may be used as genetic markers in linkage studies. This particularly applies to the polymorphisms of relatively high frequency.
  • the OATPB gene is on chromosome 11.
  • Low frequency polymorphisms may be particularly useful for haplotyping as described below.
  • a haplotype is a set of alleles found at linked polymorphic sites (such as within a gene) on a single (paternal or maternal) chromosome. If recombination within the gene is random, there may be as many as 2 n haplotypes, where 2 is the number of alleles at each SNP and n is the number of SNPs.
  • vWF von willebrand factor
  • statin drug of note is compound 3a (S-4522) in Watanabe (1997)
  • Fragments of polypeptide are at least 10 amino acids, more preferably at least 15 amino acids, more preferably at least 20 amino acids.
  • the monoclonal antibodies of the invention can be produced using alternative techniques, such as those described by Alting-Mees et al., "Monoclonal Antibody Expression Libraries: A Rapid Alternative to Hybridomas", Strategies in Molecular Biology 3: 1-9 (1990) which is incorporated herein by reference.
  • binding partners can be constructed using recombinant DNA techniques to incorporate the variable regions of a gene that encodes a specific binding antibody. Such a technique is described in Larrick et al., Biotechnology, 7: 394 (1989).
  • the antibodies may be used to detect the presence of antigen in a sample using established assay protocols, see for example "A Practical Guide to ELISA” by D. M. Kemeny, Pergamon Press, Oxford, England.
  • RNA sequence of OATPB (AB026256) was used to design PCR primers to amplify the full length of the OATPB sequence in approximately 400 base pair overlapping regions. Fifteen individual liver cDNA preparations were used as templates for PCR amplification. The products were then sequenced by dye-primer sequencing in the forward and the reverse direction. The alignment of sequence traces enabled the identification of polymorphisms. The frequency of the polymorphisms was confirmed by primer extension analysis by HPLC (WAVE) method using genomic DNA from 23 individuals and by sequencing. PCR products

Landscapes

  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Wood Science & Technology (AREA)
  • Analytical Chemistry (AREA)
  • Zoology (AREA)
  • Genetics & Genomics (AREA)
  • Engineering & Computer Science (AREA)
  • Pathology (AREA)
  • Immunology (AREA)
  • Microbiology (AREA)
  • Molecular Biology (AREA)
  • Biotechnology (AREA)
  • Biophysics (AREA)
  • Physics & Mathematics (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
EP02726302A 2001-05-18 2002-05-15 Methode zum nachweis eines polymorphismus im humanen oatpb gen Withdrawn EP1395680A2 (de)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
GB0112256 2001-05-18
GB0112256A GB0112256D0 (en) 2001-05-18 2001-05-18 Methods
US29292601P 2001-05-24 2001-05-24
US292926P 2001-05-24
PCT/GB2002/002294 WO2002095069A2 (en) 2001-05-18 2002-05-15 Methods

Publications (1)

Publication Number Publication Date
EP1395680A2 true EP1395680A2 (de) 2004-03-10

Family

ID=26246098

Family Applications (1)

Application Number Title Priority Date Filing Date
EP02726302A Withdrawn EP1395680A2 (de) 2001-05-18 2002-05-15 Methode zum nachweis eines polymorphismus im humanen oatpb gen

Country Status (3)

Country Link
EP (1) EP1395680A2 (de)
AU (1) AU2002256786A1 (de)
WO (1) WO2002095069A2 (de)

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU769361B2 (en) * 1999-05-20 2004-01-22 Bristol-Myers Squibb Company Novel organic anion transport proteins
EP1223217A4 (de) * 1999-09-21 2003-06-25 Chugai Pharmaceutical Co Ltd Transporter-gene oatp-b, c, d und e

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
None *
See also references of WO02095069A3 *

Also Published As

Publication number Publication date
WO2002095069A3 (en) 2003-10-16
AU2002256786A1 (en) 2002-12-03
WO2002095069A2 (en) 2002-11-28

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