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  Pharmaceutical Patents  

 

Title:  Method of identifying a PPARgamma-agonist compound having a decreased likelihood of inducing dose-dependent peripheral edema
United States Patent: 
7,482,124
Issued: 
January 27, 2009

Inventors:
 Ranade; Koustubh (Princeton, NJ), Delmonte; Terrye Aigeldinger (Ewing, NJ), Geese; William J. (Doylestown, PA)
Assignee:
  Bristol-Myers Squibb Company (Princeton, NJ)
Appl. No.:
 11/483,290
Filed:
 July 7, 2006


 

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Abstract

The invention provides novel polynucleotides and polypeptides associated with the incidence of PPAR-agonist induced edema. The invention also provides polynucleotide fragments corresponding to the genomic and/or coding regions of these polynucleotides which comprise at least one polymorphic locus per fragment. Allele-specific primers and probes which hybridize to these regions, and/or which comprise at least one polymorphic locus are also provided. The polynucleotides, primers, and probes of the present invention are useful in phenotype correlations, medicine, and genetic analysis. Also provided are vectors, host cells, antibodies, and recombinant and synthetic methods for producing said polynucleotides and/or polypeptides. The invention further relates to diagnostic and therapeutic methods for applying these novel polynucleotides and polypeptides to the diagnosis, treatment, and/or prevention of various diseases and/or disorders, particularly PPAR-agonist induced edema or related indications. The invention further relates to screening methods for identifying agonists of PPAR proteins with decreased risk of inducing peripheral edema in patients.

Description of the Invention

SUMMARY OF THE INVENTION

The invention relates to a nucleic acid molecule which comprises, or alternatively consists of, at least one single nucleotide polymorphism within the renin genomic sequence at a specific polymorphic locus. In a particular embodiment the invention relates to the variant allele of the renin gene or polynucleotide having at least one single nucleotide polymorphism, which variant allele differs from a reference allele by one nucleotide at the site(s) identified in FIGS. 1A-M, FIGS. 2A-M, FIGS. 3A-M, FIGS. 4A-M, FIGS. 5A-M, FIGS. 6A-M, and/or FIGS. 7A-M (see Original Patent), or elsewhere herein. The complementary sequence of each of these nucleic acid molecules are also provided. The nucleic acid molecules can be comprised of DNA or RNA, can be double- or single-stranded, and may comprise fragments. Fragments can be, for example, about 5 to about 10, about 5 to about 15, about 10 to about 20, about 15 to about 25, about 10 to about 30, about 10 to about 50, or about 10 to about 100 bases long, and preferably comprise at least one polymorphic allele.

In another embodiment, the invention relates to the reference or wild type allele of the renin gene or polynucleotide having a polymorphic locus, in which said reference or wild type allele differs from a variant allele by one nucleotide at the polymorphic site(s) identified in FIGS. 1A-M, FIGS. 2A-M, FIGS. 3A-M, FIGS. 4A-M, FIGS. 5A-M, FIGS. 6A-M, and/or FIGS. 7A-M (see Original Patent), or elsewhere herein. The complementary sequence of each of these nucleic acid molecules are also provided. The nucleic acid molecules can be comprised of DNA or RNA, can be double- or single-stranded, and may comprise fragments. Fragments can be, for example, about 5 to about 10, about 5 to about 15, about 10 to about 20, about 15 to about 25, about 10 to about 30, about 10 to about 50, or about 10 to about 100 bases long, and preferably comprise at least one polymorphic locus.

The invention further provides variant and reference allele-specific oligonucleotides that hybridize to a Renin-SNP3, Renin-SNP5, and/or Renin-SNP7 nucleic acid molecule comprising at least one polymorphic locus, in addition to the complement of said oligonucleotide. These oligonucleotides can be probes or primers.

The invention further provides oligonucleotides that may be used to amplify a portion of either the variant or reference sequences of Renin-SNP3, Renin-SNP5, and/or Renin-SNP7 comprising at least one polymorphic locus of the present invention, in addition to providing oligonucleotides that may be used to sequence said amplified sequence. The invention further provides a method of analyzing a nucleic acid from a DNA sample using said amplification and sequencing primers to assess whether said sample contains the reference or variant nucleotide (allele) at the polymorphic locus, comprising the steps of amplifying a sequence using appropriate oligonucleotide primers for amplifying across a polymorphic locus, and sequencing the resulting amplified product using appropriate sequencing primers to sequence said product to determine whether the variant or reference base is present at the polymorphic locus.

The invention further provides a method of analyzing a nucleic acid from patient sample(s) using said amplification and sequencing primers to assess whether said sample(s) contain the reference or variant nucleotide (allele) at the polymorphic locus of Renin-SNP3, Renin-SNP5, and/or Renin-SNP7 in an effort to identify populations at risk of developing dose-dependent peripheral edema upon administration of a PPAR-agonist, comprising the steps of amplifying a sequence using appropriate oligonucleotide primers for amplifying across a polymorphic locus, and sequencing the resulting amplified product using appropriate sequencing primers to sequence said product to determine whether the variant or reference nucleotide is present at the polymorphic locus.

The invention further provides oligonucleotides that may be used to genotype patient sample(s) to assess whether said sample(s) contain the reference or variant nucleotide (allele) of Renin-SNP3, Renin-SNP5, and/or Renin-SNP7 at the polymorphic site(s). The invention provide a method of using oligonucleotides that may be used to genotype a patient sample to assess whether said sample contains the reference or variant nucleotide (allele) at the polymorphic locus. An embodiment of the method comprises the steps of amplifying a sequence using appropriate oligonucleotide primers for amplifying across a polymorphic locus, and subjecting the product of said amplification to a genetic bit analysis (GBA) reaction.

The invention provides a method of using oligonucleotides that may be used to genotype patient sample(s) to identify individual(s) at risk of developing dose-dependent peripheral edema upon administration of a PPAR-agonist to assess whether said sample(s) contains the reference or variant nucleotide (allele) of Renin-SNP3, Renin-SNP5, and/or Renin-SNP7 at one or more polymorphic loci. An embodiment of the method comprises the steps of amplifying a sequence using appropriate oligonucleotide primers for amplifying across a polymorphic locus, and subjecting the product of said amplification to a genetic bit analysis (GBA) reaction, and optionally determining the statistical association between either the reference or variant allele at the polymorphic site(s) to the incidence of dose-dependent peripheral edema.

The invention provides a method of using oligonucleotides that may be used to genotype patient sample(s) to identify ethnic population(s) that may be at risk of developing dose-dependent peripheral edema upon administration of a PPAR-agonist to assess whether said sample(s) contains the reference or variant nucleotide (allele) of Renin-SNP3, Renin-SNP5, and/or Renin-SNP7 at one or more polymorphic loci comprising the steps of amplifying a sequence using appropriate oligonucleotide primers for amplifying across a polymorphic locus, and subjecting the product of said amplification to a genetic bit analysis (GBA) reaction, and optionally determining the statistical association between either the reference or variant allele at the polymorphic site(s) to the incidence of dose-dependent peripheral edema.

The invention further provides a method of analyzing a nucleic acid from one or more individuals. The method allows the determination of whether the reference or variant base is present at any one, or more, of the polymorphic sites identified FIGS. 1A-M, FIGS. 2A-M, FIGS. 3A-M, FIGS. 4A-M, FIGS. 5A-M, FIGS. 6A-M, and/or FIGS. 7A-M, or elsewhere herein. Optionally, a set of nucleotides occupying a set of the polymorphic loci shown in FIGS. 1A-M, FIGS. 2A-M, FIGS. 3A-M, FIGS. 4A-M, FIGS. 5A-M, FIGS. 6A-M, and/or FIGS. 7A-M, or elsewhere herein, is determined. This type of analysis can be performed on a number of individuals, who are also tested (previously, concurrently or subsequently) for the presence of a dose-dependent edema phenotype or related disorder. The presence or absence of a dose-dependent edema disease phenotype is then correlated with said nucleotide or set of nucleotides present at the polymorphic locus or loci in the individuals tested.

The invention further relates to a method of predicting the presence, absence, likelihood of the presence or absence, or severity of a dose-dependent peripheral edema or related disorder associated with a particular genotype. The method comprises obtaining a nucleic acid sample from an individual and determining the identity of one or more nucleotides at specific polymorphic loci of Renin-SNP3, Renin-SNP5, and/or Renin-SNP7 nucleic acid molecules described herein, wherein the presence of a particular base at that site is correlated with the incidence of dose-dependent peripheral edema or related disorder, thereby predicting the presence, absence, likelihood of the presence or absence, or severity, of the dose-dependent peripheral edema phenotype or related disorder in the individual.

The invention further relates to polynucleotides having one or more polymorphic loci comprising one or more variant alleles of Renin-SNP3, Renin-SNP5, and/or Renin-SNP7. The invention also relates to said polynucleotides lacking a start codon. The invention further relates to polynucleotides of the present invention containing one or more variant alleles wherein said polynucleotides encode a polypeptide of the present invention. The invention relates to polypeptides of the present invention containing one or more variant amino acids encoded by one or more variant alleles.

The present invention relates to antisense oligonucleotides capable of hybridizing to the Renin-SNP3, Renin-SNP5, and/or Renin-SNP7 polynucleotides of the present invention. Preferably, such antisense oligonucleotides are capable of discriminating between the reference or variant allele of the polynucleotide, preferably at one or more polymorphic sites of said polynucleotide.

The present invention relates to siRNA or RNAi oligonucleotides capable of hybridizing to the Renin-SNP3, Renin-SNP5, and/or Renin-SNP7 polynucleotides of the present invention. Preferably, such siRNA or RNAi oligonucleotides are capable of discriminating between the reference or variant allele of the polynucleotide, preferably at one or more polymorphic sites of said polynucleotide.

The present invention also relates to zinc finger proteins capable of binding to the Renin-SNP3, Renin-SNP5, and/or Renin-SNP7 polynucleotides of the present invention. Preferably, such zinc finger proteins are capable of discriminating between the reference or variant allele of the polynucleotide, preferably at one or more polymorphic sites of said polynucleotide.

The present invention also relates to recombinant vectors, which include the isolated Renin-SNP3, Renin-SNP5, and/or Renin-SNP7 nucleic acid molecules of the present invention, and to host cells containing the recombinant vectors, as well as to methods of making such vectors and host cells, in addition to their use in the production of polypeptides or peptides provided herein using recombinant techniques. Synthetic methods for producing the polypeptides and polynucleotides of the present invention are provided. Also provided are diagnostic methods for detecting diseases, disorders, and/or conditions related to the polypeptides and polynucleotides provided herein, and therapeutic methods for treating such diseases, disorders, and/or conditions. The invention further relates to screening methods for identifying binding partners of the polypeptides.

The invention relates to a method of analyzing at least one nucleic acid sample, comprising the step of determining the nucleic acid sequence from one or more samples at one or more polymorphic loci in the human renin gene selected from the group consisting of Renin-SNP3, Renin-SNP5, and/or Renin-SNP7, or any combination thereof, wherein the presence of the reference allele at said one or more polymorphic loci is indicative of an increased risk of developing dose-dependent peripheral edema in a patient receiving PPAR-agonist therapy.

The invention relates to a method of analyzing at least one nucleic acid sample, comprising the step of determining the nucleic acid sequence from one or more samples at one or more polymorphic loci in the human renin gene selected from the group consisting of Renin-SNP3, Renin-SNP5, and/or Renin-SNP7, or any combination thereof, wherein the presence of the variant allele at said one or more polymorphic loci is indicative of a decreased risk of developing dose-dependent peripheral edema in a patient receiving PPAR-agonist therapy.

The invention further relates to a method of constructing haplotypes using the isolated nucleic acids referred to in FIGS. 1A-M, FIGS. 2A-M, FIGS. 3A-M, FIGS. 4A-M, FIGS. 5A-M, FIGS. 6A-M, FIGS. 7A-M, FIGS. 13A-B, FIGS. 14A-B, FIGS. 18A-B, and/or FIGS. 19A-B or elsewhere herein, comprising the step of grouping at least two said nucleic acids.

The invention further relates to a method of constructing haplotypes using the ET1-SNP1, Beta1-SNP1, Renin-SNP3, Renin-SNP5, and/or Renin-SNP7 comprising the step of using said haplotypes to identify an individual for the presence of dose-dependent peripheral edema or related disease phenotype, and correlating the presence of the disease phenotype with said haplotype.

The invention further relates to a library of nucleic acids, each of which comprises one or more polymorphic positions within a gene encoding the human renin protein, wherein said polymorphic positions are selected the polymorphic positions provided in Table I.

The invention further relates to a library of nucleic acids, wherein the sequence at said aforementioned polymorphic position is selected from the group consisting of the polymorphic position identified in FIGS. 1A-M, FIGS. 2A-M, FIGS. 3A-M, FIGS. 4A-M, FIGS. 5A-M, FIGS. 6A-M, and/or FIGS. 7A-M, or elsewhere herein, the complimentary sequence of said sequences, and/or fragments of said sequences.

The invention further relates to a kit for identifying an individual at risk of developing dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of a PPAR-agonist, wherein said kit comprises oligonucleotide primers capable of identifying the nucleotide residing at one or more polymorphic loci of the human renin gene, wherein the presence of the variant allele at said one or more polymorphic loci is indicative of a decreased risk of developing dose-dependent peripheral edema in a patient receiving PPAR-agonist therapy, while the presence of the reference allele at said one or more polymorphic loci is indicative of an increased risk of developing dose-dependent peripheral edema in a patient receiving PPAR-agonist therapy.

The invention further relates to a kit for identifying an individual at risk of developing dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of a PPAR-agonist, wherein said kit comprises oligonucleotide primers capable of identifying the nucleotide residing at one or more polymorphic loci of the human renin gene, wherein the presence of the variant allele at said one or more polymorphic loci is indicative of a decreased risk of developing dose-dependent peripheral edema in a patient receiving PPAR-agonist therapy, while the presence of the reference allele at said one or more polymorphic loci is indicative of an increased risk of developing dose-dependent peripheral edema in a patient receiving PPAR-agonist therapy, and wherein said oligonucleotides hybridize immediately adjacent to said one or more polymorphic positions, or wherein said primer(s) hybridizes to said polymorphic positions such that the central position of the primer aligns with the polymorphic position of said gene.

The invention further relates to a method for predicting the likelihood that an individual will be diagnosed as being at risk of developing dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of a PPAR-agonist comprising the step of determining the nucleotide present within at least one or more nucleic acid sample(s) from an individual to be assessed at one or more polymorphic position(s) of the human renin gene sequence selected from the group consisting of: SEQ ID NOS: 1, 2, 3, 4, 5, 6, and/or 7, wherein the presence of the reference nucleotide at the one or more polymorphic position(s) indicates that the individual has an increased likelihood of being diagnosed as at risk of developing dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of an PPAR-agonist as compared to an individual having the variant allele at said polymorphic position(s).

The invention further relates to a method for predicting the likelihood that an individual will be diagnosed as being at risk of developing a dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of a PPAR-agonist comprising the step of determining the nucleotide present within at least one or more nucleic acid sample(s) from an individual to be assessed at one or more polymorphic position(s) of the human renin gene sequence selected from the group consisting of: SEQ ID NOS:1, 2, 3, 4, 5, 6, and/or 7, wherein the presence of the variant nucleotide at the one or more polymorphic position(s) indicates that the individual has an decreased likelihood of being diagnosed as at risk of developing dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of an PPAR-agonist as compared to an individual having the reference allele at said polymorphic position(s).

The invention further relates to a method for predicting the likelihood that an individual will be diagnosed as being at risk of developing dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of a PPAR-agonist comprising the step of determining the nucleotide present within at least one or more nucleic acid sample(s) from an individual to be assessed at one or more polymorphic position(s) of the human renin gene sequence selected from the group consisting of: nucleotide position 12586 of SEQ ID NOS:1 or 2; nucleotide position 10096 of SEQ ID NOS: 3 or 4; nucleotide position 13076 of SEQ ID NOS:5 or 6; and nucleotide positions 12586, 10096, and/or 13076 of SEQ ID NO:7, wherein the presence of the reference nucleotide at the one or more polymorphic position(s) indicates that the individual has an increased likelihood of being diagnosed as at risk of developing dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of a PPAR-agonist as compared to an individual having the variant allele at said polymorphic position(s).

The invention further relates to a method for predicting the likelihood that an individual will be diagnosed as being at risk of developing a dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of a PPAR-agonist comprising the step of determining the nucleotide present within at least one or more nucleic acid sample(s) from an individual to be assessed at one or more polymorphic position(s) of the human renin gene sequence selected from the group consisting of: nucleotide position 12586 of SEQ ID NOS:1 or 2; nucleotide position 10096 of SEQ ID NOS:3 or 4; nucleotide position 13076 of SEQ ID NOS:5 or 6; and nucleotide positions 12586, 10096, and/or 13076 of SEQ ID NO:7, wherein the presence of the variant nucleotide at the one or more polymorphic position(s) indicates that the individual has a decreased likelihood of being diagnosed as at risk of developing dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of a PPAR-agonist as compared to an individual having the reference allele at said polymorphic position(s).

The present invention is also directed to methods of predicting whether a patient administered a PPAR-agonist will respond to PPAR-agonist therapy; for predicting whether a patient will respond to specific doses of a PPAR-agonist; whether the level of the administered PPAR-agonist needs to be increased or decreased to achieve the desired level of human renin expression identified as representing a responsive level; whether a patient has an increased risk of developing dose-dependent peripheral edema upon the administration of a pharmaceutically acceptable level of a PPAR-agonist; whether said patient requires a lower level of administered PPAR agonist to limit the risk of developing said dose-dependent peripheral edema; or whether said patient may be administered a higher level of administered PPAR agonist without the risk of developing said dose-dependent peripheral edema, inorder to limit the risk of developing said dose-dependent peripheral edema, comprising the step of assessing the level of renin expression resulting from the administration of a PPAR-agonist relative to a control compound.

The present invention also relates to a method of screening for compounds capable of modulating PPAR-alpha and/or gamma, but are predicted to not increase an individuals likelihood of developing dose-dependent edema upon the administration of the same. In specific embodiments of the invention, such systems may comprise renin expressing cell lines incubated in the presence or absence of one or more drugs, compounds, or other therapeutic agents; followed by the step of measuring the level of induced renin expression attributable to administration of the test PPAR-agonist compounds or combinations of such compounds, and selecting the test compound with a diminished ability to induce renin expression relative to a control compound.

The invention relates to a nucleic acid molecule which comprises, or alternatively consists of, at least one single nucleotide polymorphism within the endothelin-1 genomic sequence at a specific polymorphic locus. In a particular embodiment the invention relates to the variant allele of the endothelin-1 gene or polynucleotide having at least one single nucleotide polymorphism, which variant allele differs from a reference allele by one nucleotide at the site(s) identified in FIGS. 13A-B, and/or FIGS. 14A-B, or elsewhere herein. The complementary sequence of each of these nucleic acid molecules are also provided. The nucleic acid molecules can be comprised of DNA or RNA, can be double- or single-stranded, and may comprise fragments. Fragments can be, for example, about 5 to about 10, about 5 to about 15, about 10 to about 20, about 15 to about 25, about 10 to about 30, about 10 to about 50, or about 10 to about 100 bases long, and preferably comprise at least one polymorphic allele.

In another embodiment, the invention relates to the reference or wild type allele of a gene or polynucleotide having a polymorphic locus, in which said reference or wild type allele differs from a variant allele by one nucleotide at the polymorphic site(s) identified in FIGS. 13A-B, and/or FIGS. 14A-B, or elsewhere herein. The complementary sequence of each of these nucleic acid molecules are also provided. The nucleic acid molecules can be comprised of DNA or RNA, can be double- or single-stranded, and may comprise fragments. Fragments can be, for example, about 5 to about 10, about 5 to about 15, about 10 to about 20, about 15 to about 25, about 10 to about 30, about 10 to about 50, or about 10 to about 100 bases long, and preferably comprise at least one polymorphic locus.

The invention further provides variant and reference allele-specific oligonucleotides that hybridize to an ET1-SNP1 nucleic acid molecule comprising at least one polymorphic locus, in addition to the complement of said oligonucleotide. These oligonucleotides can be probes or primers.

The invention further provides oligonucleotides that may be used to amplify a portion of either the variant or reference ET1-SNP1 sequences comprising at least one polymorphic locus of the present invention, in addition to providing oligonucleotides that may be used to sequence said amplified sequence. The invention further provides a method of analyzing a nucleic acid from a DNA sample using said amplification and sequencing primers to assess whether said sample contains the reference or variant nucleotide (allele) at the polymorphic locus, comprising the steps of amplifying a sequence using appropriate oligonucleotide primers for amplifying across a polymorphic locus, and sequencing the resulting amplified product using appropriate sequencing primers to sequence said product to determine whether the variant or reference base is present at the polymorphic locus.

The invention further provides a method of analyzing a nucleic acid from patient sample(s) using said amplification and sequencing primers to assess whether said sample(s) contain the ET1-SNP1 reference or variant nucleotide (allele) at the polymorphic locus in an effort to identify populations at risk of developing dose-dependent peripheral edema upon administration of a PPAR-agonist, comprising the steps of amplifying a sequence using appropriate oligonucleotide primers for amplifying across a polymorphic locus, and sequencing the resulting amplified product using appropriate sequencing primers to sequence said product to determine whether the variant or reference nucleotide is present at the polymorphic locus.

The invention further provides oligonucleotides that may be used to genotype patient sample(s) to assess whether said sample(s) contain the ET1-SNP1 reference or variant nucleotide (allele) at the polymorphic site(s). The invention provide a method of using oligonucleotides that may be used to genotype a patient sample to assess whether said sample contains the reference or variant nucleotide (allele) at the polymorphic locus. An embodiment of the method comprises the steps of amplifying a sequence using appropriate oligonucleotide primers for amplifying across a polymorphic locus, and subjecting the product of said amplification to a genetic bit analysis (GBA) reaction.

The invention provides a method of using oligonucleotides that may be used to genotype patient sample(s) to identify individual(s) at risk of developing dose-dependent peripheral edema upon administration of a PPAR-agonist to assess whether said sample(s) contains the ET1-SNP1 reference or variant nucleotide (allele) at one or more polymorphic loci. An embodiment of the method comprises the steps of amplifying a sequence using appropriate oligonucleotide primers for amplifying across a polymorphic locus, and subjecting the product of said amplification to a genetic bit analysis (GBA) reaction, and optionally determining the statistical association between either the reference or variant allele at the polymorphic site(s) to the incidence of dose-dependent peripheral edema.

The invention provides a method of using oligonucleotides that may be used to genotype patient sample(s) to identify ethnic population(s) that may be at risk of developing dose-dependent peripheral edema upon administration of a PPAR-agonist to assess whether said sample(s) contains the ET1-SNP1 reference or variant nucleotide (allele) at one or more polymorphic loci comprising the steps of amplifying a sequence using appropriate oligonucleotide primers for amplifying across a polymorphic locus, and subjecting the product of said amplification to a genetic bit analysis (GBA) reaction, and optionally determining the statistical association between either the reference or variant allele at the polymorphic site(s) to the incidence of dose-dependent peripheral edema.

The invention further provides a method of analyzing a nucleic acid from one or more individuals. The method allows the determination of whether the ET1-SNP1 reference or variant base is present at any one, or more, of the polymorphic sites identified in FIGS. 13A-B, and/or FIGS. 14A-B, or elsewhere herein. Optionally, a set of nucleotides occupying a set of the polymorphic loci shown in FIGS. 13A-B, and/or FIGS. 14A-B, or elsewhere herein, is determined. This type of analysis can be performed on a number of individuals, who are also tested (previously, concurrently or subsequently) for the presence of a dose-dependent edema phenotype or related disorder. The presence or absence of a dose-dependent edema disease phenotype is then correlated with said nucleotide or set of nucleotides present at the polymorphic locus or loci in the individuals tested.

The invention further relates to a method of predicting the presence, absence, likelihood of the presence or absence, or severity of a dose-dependent peripheral edema or related disorder associated with a particular genotype. The method comprises obtaining a nucleic acid sample from an individual and determining the identity of one or more nucleotides at specific polymorphic loci of the ET1-SNP1 nucleic acid molecules described herein, wherein the presence of a particular base at that site is correlated with the incidence of dose-dependent peripheral edema or related disorder, thereby predicting the presence, absence, likelihood of the presence or absence, or severity, of the dose-dependent peripheral edema phenotype or related disorder in the individual.

The invention further relates to ET1-SNP1 polynucleotides having one or more polymorphic loci comprising one or more variant alleles. The invention also relates to said polynucleotides lacking a start codon. The invention further relates to polynucleotides of the present invention containing one or more variant alleles wherein said polynucleotides encode a polypeptide of the present invention. The invention relates to polypeptides of the present invention containing one or more variant amino acids encoded by one or more variant alleles.

The present invention relates to antisense oligonucleotides capable of hybridizing to the ET1-SNP1 polynucleotides of the present invention. Preferably, such antisense oligonucleotides are capable of discriminating between the reference or variant allele of the polynucleotide, preferably at one or more polymorphic sites of said polynucleotide.

The present invention relates to siRNA or RNAi oligonucleotides capable of hybridizing to the ET1-SNP1 polynucleotides of the present invention. Preferably, such siRNA or RNAi oligonucleotides are capable of discriminating between the reference or variant allele of the polynucleotide, preferably at one or more polymorphic sites of said polynucleotide.

The present invention also relates to zinc finger proteins capable of binding to the ET1-SNP1 polynucleotides of the present invention. Preferably, such zinc finger proteins are capable of discriminating between the reference or variant allele of the polynucleotide, preferably at one or more polymorphic sites of said polynucleotide.

The present invention relates to antibodies directed against the ET1-SNP1 polypeptides of the present invention. Preferably, such antibodies are capable of discriminating between the reference or variant allele of the polypeptide, preferably at one or more polymorphic sites of said polynucleotide.

The present invention also relates to recombinant vectors, which include the isolated ET1-SNP1 nucleic acid molecules of the present invention, and to host cells containing the recombinant vectors, as well as to methods of making such vectors and host cells, in addition to their use in the production of polypeptides or peptides provided herein using recombinant techniques. Synthetic methods for producing the polypeptides and polynucleotides of the present invention are provided. Also provided are diagnostic methods for detecting diseases, disorders, and/or conditions related to the polypeptides and polynucleotides provided herein, and therapeutic methods for treating such diseases, disorders, and/or conditions. The invention further relates to screening methods for identifying binding partners of the polypeptides.

The invention relates to a method of analyzing at least one nucleic acid sample, comprising the step of determining the nucleic acid sequence from one or more samples at one or more polymorphic loci in the human endothelin-1 gene selected from the group consisting of ET1-SNP1, or any combination thereof, wherein the presence of the variable allele at said one or more polymorphic loci is indicative of a decreased risk of developing dose-dependent peripheral edema in a patient receiving PPAR-agonist therapy.

The invention relates to a method of analyzing at least one nucleic acid sample, comprising the step of determining the nucleic acid sequence from one or more samples at one or more polymorphic loci in the human endothelin-1 gene selected from the group consisting of ET1-SNP1, or any combination thereof, wherein the presence of the variant allele at said one or more polymorphic loci is indicative of a decreased risk of developing dose-dependent peripheral edema in a patient receiving PPAR-agonist therapy.

The invention further relates to a library of nucleic acids, each of which comprises one or more polymorphic positions within a gene encoding the human endothelin-1 protein, wherein said polymorphic positions are selected from a group consisting of the polymorphic positions provided in FIGS. 13A-B, FIGS. 14A-B, and/or Table I (see Original Patent).

The invention further relates to a library of nucleic acids, wherein the sequence at said aforementioned polymorphic position is selected from the group consisting of the polymorphic position identified in FIGS. 13A-B, and/or FIGS. 14A-B, or elsewhere herein, the complimentary sequence of said sequences, and/or fragments of said sequences.

The invention further relates to a kit for identifying an individual at risk of developing dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of a PPAR-agonist, wherein said kit comprises oligonucleotide primers capable of identifying the nucleotide residing at one or more polymorphic loci of the human endothelin-1 gene, wherein the presence of the variant allele at said one or more polymorphic loci is indicative of a decreased risk of developing dose-dependent peripheral edema in a patient receiving PPAR-agonist therapy, while the presence of the reference allele at said one or more polymorphic loci is indicative of an increased risk of developing dose-dependent peripheral edema in a patient receiving PPAR-agonist therapy.

The invention further relates to a kit for identifying an individual at risk of developing dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of a PPAR-agonist, wherein said kit comprises oligonucleotide primers capable of identifying the nucleotide residing at one or more polymorphic loci of the human endothelin-1 gene, wherein the presence of the variant allele at said one or more polymorphic loci is indicative of a decreased risk of developing dose-dependent peripheral edema in a patient receiving PPAR-agonist therapy, while the presence of the reference allele at said one or more polymorphic loci is indicative of an increased risk of developing dose-dependent peripheral edema in a patient receiving PPAR-agonist therapy, and wherein said oligonucleotides hybridize immediately adjacent to said one or more polymorphic positions, or wherein said primer(s) hybridizes to said polymorphic positions such that the central position of the primer aligns with the polymorphic position of said gene.

The invention further relates to a method for predicting the likelihood that an individual will be diagnosed as being at risk of developing dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of a PPAR-agonist comprising the step of determining the nucleotide present within at least one or more nucleic acid sample(s) from an individual to be assessed at one or more polymorphic position(s) of the human endothelin-1 gene sequence selected from the group consisting of: SEQ ID NOS:37, and/or 39, wherein the presence of the variable nucleotide at the one or more polymorphic position(s) indicates that the individual has a decreased likelihood of being diagnosed as at risk of developing dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of an PPAR-agonist as compared to an individual having the reference allele at said polymorphic position(s).

The invention further relates to a method for predicting the likelihood that an individual will be diagnosed as being at risk of developing a dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of a PPAR-agonist comprising the step of determining the nucleotide present within at least one or more nucleic acid sample(s) from an individual to be assessed at one or more polymorphic position(s) of the human endothelin-1 gene sequence selected from the group consisting of: SEQ ID NOS:37, and/or 39, wherein the presence of the reference nucleotide at the one or more polymorphic position(s) indicates that the individual has an increased likelihood of being diagnosed as at risk of developing dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of an PPAR-agonist as compared to an individual having the variable allele at said polymorphic position(s).

The invention further relates to a method for predicting the likelihood that an individual will be diagnosed as being at risk of developing dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of a PPAR-agonist comprising the step of determining the polypeptide present within at least one or more sample(s) from an individual to be assessed at one or more polymorphic position(s) of the human endothelin-1 polypeptide sequence selected from the group consisting of: SEQ ID NOS:38, and/or 40, wherein the presence of the variable amino acid at the one or more polymorphic position(s) indicates that the individual has a decreased likelihood of being diagnosed as at risk of developing dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of an PPAR-agonist as compared to an individual having the reference allele at said polymorphic position(s).

The invention further relates to a method for predicting the likelihood that an individual will be diagnosed as being at risk of developing a dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of a PPAR-agonist comprising the step of determining the nucleotide present within at least one or more sample(s) from an individual to be assessed at one or more polymorphic position(s) of the human endothelin-1 polypeptide sequence selected from the group consisting of: SEQ ID NOS:38, and/or 40, wherein the presence of the reference amino acid at the one or more polymorphic position(s) indicates that the individual has an increased likelihood of being diagnosed as at risk of developing dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of an PPAR-agonist as compared to an individual having the reference allele at said polymorphic position(s).

The invention further relates to a method for predicting the likelihood that an individual will be diagnosed as being at risk of developing dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of a PPAR-agonist comprising the step of determining the nucleotide present within at least one or more nucleic acid sample(s) from an individual to be assessed at one or more polymorphic position(s) of the human endothelin-1 gene sequence selected from the group consisting of: nucleotide position 797 of SEQ ID NOS:37 or 39, wherein the presence of the variable nucleotide at the one or more polymorphic position(s) indicates that the individual has a decreased likelihood of being diagnosed as at risk of developing dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of a PPAR-agonist as compared to an individual having the reference allele at said polymorphic position(s).

The invention further relates to a method for predicting the likelihood that an individual will be diagnosed as being at risk of developing a dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of a PPAR-agonist comprising the step of determining the nucleotide present within at least one or more nucleic acid sample(s) from an individual to be assessed at one or more polymorphic position(s) of the human endothelin-1 gene sequence selected from the group consisting of: nucleotide position 797 of SEQ ID NOS:37 or 39, wherein the presence of the reference nucleotide at the one or more polymorphic position(s) indicates that the individual has an increased likelihood of being diagnosed as at risk of developing dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of a PPAR-agonist as compared to an individual having the variable allele at said polymorphic position(s).

The invention further relates to a method for predicting the likelihood that an individual will be diagnosed as being at risk of developing dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of a PPAR-agonist comprising the step of determining the amino acid present within at least one or more sample(s) from an individual to be assessed at one or more polymorphic position(s) of the human endothelin-1 polypeptide sequence selected from the group consisting of: amino acid position 198 of SEQ ID NOS:38 or 40, wherein the presence of the variable amino acid at the one or more polymorphic position(s) indicates that the individual has a decreased likelihood of being diagnosed as at risk of developing dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of a PPAR-agonist as compared to an individual having the reference allele at said polymorphic position(s).

The invention further relates to a method for predicting the likelihood that an individual will be diagnosed as being at risk of developing a dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of a PPAR-agonist comprising the step of determining the amino acid present within at least one or more sample(s) from an individual to be assessed at one or more polymorphic position(s) of the human endothelin-1 polypeptide sequence selected from the group consisting of: amino acid position 198 of SEQ ID NOS:38 or 40, wherein the presence of the reference amino acid at the one or more polymorphic position(s) indicates that the individual has an increased likelihood of being diagnosed as at risk of developing dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of a PPAR-agonist as compared to an individual having the variable allele at said polymorphic position(s).

The present invention is also directed to methods of predicting whether a patient administered a PPAR-agonist will respond to PPAR-agonist therapy; for predicting whether a patient will respond to specific doses of a PPAR-agonist; whether the level of the administered PPAR-agonist needs to be increased or decreased to achieve the desired level of human endothelin-1 expression identified as representing a responsive level; whether a patient has an increased risk of developing dose-dependent peripheral edema upon the administration of a pharmaceutically acceptable level of a PPAR-agonist; whether said patient requires a lower level of administered PPAR agonist to limit the risk of developing said dose-dependent peripheral edema; or whether said patient may be administered a higher level of administered PPAR agonist without the risk of developing said dose-dependent peripheral edema, inorder to limit the risk of developing said dose-dependent peripheral edema, comprising the step of assessing the level of endothelin-1 expression resulting from the administration of a PPAR-agonist relative to a control compound.

The present invention also relates to a method of screening for compounds capable of modulating PPAR-alpha and/or gamma, but are predicted to not increase an individuals likelihood of developing dose-dependent edema upon the administration of the same. In specific embodiments of the invention, such methods may comprise endothelin-1 expressing cell lines incubated in the presence or absence of one or more drugs, compounds, or other therapeutic agents; followed by the step of measuring the level of repressed endothelin-1 expression attributable to administration of the test PPAR-agonist compounds or combinations of such compounds, and selecting the test compound with a diminished ability to repress endothelin-1 expression relative to a control compound, wherein said selected test compound has a diminished ability to induce dose-dependent peripheral edema relative to a reference compound.

The invention relates to a nucleic acid molecule which comprises, or alternatively consists of, at least one single nucleotide polymorphism within the .beta.1-adrenergic receptor genomic sequence at a specific polymorphic locus. In a particular embodiment the invention relates to the variant allele of the .beta.1-adrenergic receptor gene or polynucleotide having at least one single nucleotide polymorphism, which variant allele differs from a reference allele by one nucleotide at the site(s) identified in FIGS. 18A-B, and/or FIGS. 19A-B, or elsewhere herein. The complementary sequence of each of these nucleic acid molecules are also provided. The nucleic acid molecules can be comprised of DNA or RNA, can be double- or single-stranded, and may comprise fragments. Fragments can be, for example, about 5 to about 10, about 5 to about 15, about 10 to about 20, about 15 to about 25, about 10 to about 30, about 10 to about 50, or about 10 to about 100 bases long, and preferably comprise at least one polymorphic allele.

In another embodiment, the invention relates to the reference or wild type allele of a gene or polynucleotide having a polymorphic locus, in which said reference or wild type allele differs from a variant allele by one nucleotide at the polymorphic site(s) identified in FIGS. 18A-B, and/or FIGS. 19A-B, or elsewhere herein. The complementary sequence of each of these nucleic acid molecules are also provided. The nucleic acid molecules can be comprised of DNA or RNA, can be double- or single-stranded, and may comprise fragments. Fragments can be, for example, about 5 to about 10, about 5 to about 15, about 10 to about 20, about 15 to about 25, about 10 to about 30, about 10 to about 50, or about 10 to about 100 bases long, and preferably comprise at least one polymorphic locus.

The invention further provides variant and reference allele-specific oligonucleotides that hybridize to a Beta1-SNP1 nucleic acid molecule comprising at least one polymorphic locus, in addition to the complement of said oligonucleotide. These oligonucleotides can be probes or primers.

The invention further provides oligonucleotides that may be used to amplify a portion of either the Beta1-SNP1 variant or reference sequences comprising at least one polymorphic locus of the present invention, in addition to providing oligonucleotides that may be used to sequence said amplified sequence. The invention further provides a method of analyzing a nucleic acid from a DNA sample using said amplification and sequencing primers to assess whether said sample contains the reference or variant nucleotide (allele) at the polymorphic locus, comprising the steps of amplifying a sequence using appropriate oligonucleotide primers for amplifying across a polymorphic locus, and sequencing the resulting amplified product using appropriate sequencing primers to sequence said product to determine whether the variant or reference base is present at the polymorphic locus.

The invention further provides a method of analyzing a nucleic acid from patient sample(s) using said Beta1-SNP1 amplification and sequencing primers to assess whether said sample(s) contain the reference or variant nucleotide (allele) at the polymorphic locus in an effort to identify populations at risk of developing dose-dependent peripheral edema upon administration of a PPAR-agonist, comprising the steps of amplifying a sequence using appropriate oligonucleotide primers for amplifying across a polymorphic locus, and sequencing the resulting amplified product using appropriate sequencing primers to sequence said product to determine whether the variant or reference nucleotide is present at the polymorphic locus.

The invention further provides oligonucleotides that may be used to genotype patient sample(s) to assess whether said sample(s) contain the Beta1-SNP1 reference or variant nucleotide (allele) at the polymorphic site(s). The invention provide a method of using oligonucleotides that may be used to genotype a patient sample to assess whether said sample contains the reference or variant nucleotide (allele) at the polymorphic locus. An embodiment of the method comprises the steps of amplifying a sequence using appropriate oligonucleotide primers for amplifying across a polymorphic locus, and subjecting the product of said amplification to a genetic bit analysis (GBA) reaction.

The invention provides a method of using oligonucleotides that may be used to genotype patient sample(s) to identify individual(s) at risk of developing dose-dependent peripheral edema upon administration of a PPAR-agonist to assess whether said sample(s) contains the Beta1-SNP1 reference or variant nucleotide (allele) at one or more polymorphic loci. An embodiment of the method comprises the steps of amplifying a sequence using appropriate oligonucleotide primers for amplifying across a polymorphic locus, and subjecting the product of said amplification to a genetic bit analysis (GBA) reaction, and optionally determining the statistical association between either the reference or variant allele at the polymorphic site(s) to the incidence of dose-dependent peripheral edema.

The invention provides a method of using oligonucleotides that may be used to genotype patient sample(s) to identify ethnic population(s) that may be at risk of developing dose-dependent peripheral edema upon administration of a PPAR-agonist to assess whether said sample(s) contains the Beta1-SNP1 reference or variant nucleotide (allele) at one or more polymorphic loci comprising the steps of amplifying a sequence using appropriate oligonucleotide primers for amplifying across a polymorphic locus, and subjecting the product of said amplification to a genetic bit analysis (GBA) reaction, and optionally determining the statistical association between either the reference or variant allele at the polymorphic site(s) to the incidence of dose-dependent peripheral edema.

The invention further provides a method of analyzing a nucleic acid from one or more individuals. The method allows the determination of whether the reference or variant base is present at any one, or more, of the polymorphic sites identified in FIGS. 18A-B, and/or FIGS. 19A-B, or elsewhere herein. Optionally, a set of nucleotides occupying a set of the polymorphic loci shown in FIGS. 18A-B, and/or FIGS. 19A-B, or elsewhere herein, is determined. This type of analysis can be performed on a number of individuals, who are also tested (previously, concurrently or subsequently) for the presence of a dose-dependent edema phenotype or related disorder. The presence or absence of a dose-dependent edema disease phenotype is then correlated with said nucleotide or set of nucleotides present at the polymorphic locus or loci in the individuals tested.

The invention further relates to a method of predicting the presence, absence, likelihood of the presence or absence, or severity of a dose-dependent peripheral edema or related disorder associated with a particular genotype. The method comprises obtaining a nucleic acid sample from an individual and determining the identity of one or more nucleotides at specific polymorphic loci of the Beta1-SNP1 nucleic acid molecules described herein, wherein the presence of a particular base at that site is correlated with the incidence of dose-dependent peripheral edema or related disorder, thereby predicting the presence, absence, likelihood of the presence or absence, or severity, of the dose-dependent peripheral edema phenotype or related disorder in the individual.

The invention further relates to polynucleotides having one or more polymorphic loci comprising one or more Beta1-SNP1 reference or variant alleles. The invention also relates to said polynucleotides lacking a start codon. The invention further relates to polynucleotides of the present invention containing one or more variant alleles wherein said polynucleotides encode a polypeptide of the present invention. The invention relates to polypeptides of the present invention containing one or more variant amino acids encoded by one or more variant alleles.

The present invention relates to antisense oligonucleotides capable of hybridizing to the Beta1-SNP1 polynucleotides of the present invention. Preferably, such antisense oligonucleotides are capable of discriminating between the reference or variant allele of the polynucleotide, preferably at one or more polymorphic sites of said polynucleotide.

The present invention relates to siRNA or RNAi oligonucleotides capable of hybridizing to the Beta1-SNP1 polynucleotides of the present invention. Preferably, such siRNA or RNAi oligonucleotides are capable of discriminating between the reference or variant allele of the polynucleotide, preferably at one or more polymorphic sites of said polynucleotide.

The present invention also relates to zinc finger proteins capable of binding to the Beta1-SNP1 polynucleotides of the present invention. Preferably, such zinc finger proteins are capable of discriminating between the reference or variant allele of the polynucleotide, preferably at one or more polymorphic sites of said polynucleotide.

The present invention relates to antibodies directed against the Beta1-SNP1 polypeptides of the present invention. Preferably, such antibodies are capable of discriminating between the reference or variant allele of the polypeptide, preferably at one or more polymorphic sites of said polynucleotide.

The present invention also relates to recombinant vectors, which include the isolated Beta1-SNP1 nucleic acid molecules of the present invention, and to host cells containing the recombinant vectors, as well as to methods of making such vectors and host cells, in addition to their use in the production of polypeptides or peptides provided herein using recombinant techniques. Synthetic methods for producing the polypeptides and polynucleotides of the present invention are provided. Also provided are diagnostic methods for detecting diseases, disorders, and/or conditions related to the polypeptides and polynucleotides provided herein, and therapeutic methods for treating such diseases, disorders, and/or conditions. The invention further relates to screening methods for identifying binding partners of the polypeptides.

The invention relates to a method of analyzing at least one nucleic acid sample, comprising the step of determining the nucleic acid sequence from one or more samples at one or more polymorphic loci in the human .beta.1-adrenergic receptor gene selected from the group consisting of Beta1-SNP1, or any combination thereof, wherein the presence of the variable allele at said one or more polymorphic loci is indicative of an increased risk of developing dose-dependent peripheral edema in a patient receiving PPAR-agonist therapy.

The invention relates to a method of analyzing at least one nucleic acid sample, comprising the step of determining the nucleic acid sequence from one or more samples at one or more polymorphic loci in the human .beta.1-adrenergic receptor gene selected from the group consisting of Beta1-SNP1, or any combination thereof, wherein the presence of the reference allele at said one or more polymorphic loci is indicative of a decreased risk of developing dose-dependent peripheral edema in a patient receiving PPAR-agonist therapy.

The invention further relates to a library of nucleic acids, each of which comprises one or more polymorphic positions within a gene encoding the human .beta.1-adrenergic receptor protein, wherein said polymorphic positions are selected from a group consisting of the polymorphic positions provided in FIGS. 18A-B, FIGS. 19A-B, and/or Table I.

The invention further relates to a library of nucleic acids, wherein the sequence at said aforementioned polymorphic position is selected from the group consisting of the polymorphic position identified in FIGS. 18A-B, and/or FIGS. 19A-B, or elsewhere herein, the complimentary sequence of said sequences, and/or fragments of said sequences.

The invention further relates to a kit for identifying an individual at risk of developing dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of a PPAR-agonist, wherein said kit comprises oligonucleotide primers capable of identifying the nucleotide residing at one or more polymorphic loci of the human .beta.1-adrenergic receptor gene, wherein the presence of the variant allele at said one or more polymorphic loci is indicative of an increased risk of developing dose-dependent peripheral edema in a patient receiving PPAR-agonist therapy, while the presence of the reference allele at said one or more polymorphic loci is indicative of a decreased risk of developing dose-dependent peripheral edema in a patient receiving PPAR-agonist therapy.

The invention further relates to a kit for identifying an individual at risk of developing dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of a PPAR-agonist, wherein said kit comprises oligonucleotide primers capable of identifying the nucleotide residing at one or more polymorphic loci of the human .beta.1-adrenergic receptor gene, wherein the presence of the variant allele at said one or more polymorphic loci is indicative of an increased risk of developing dose-dependent peripheral edema in a patient receiving PPAR-agonist therapy, while the presence of the reference allele at said one or more polymorphic loci is indicative of a decreased risk of developing dose-dependent peripheral edema in a patient receiving PPAR-agonist therapy, and wherein said oligonucleotides hybridize immediately adjacent to said one or more polymorphic positions, or wherein said primer(s) hybridizes to said polymorphic positions such that the central position of the primer aligns with the polymorphic position of said gene.

The invention further relates to a method for predicting the likelihood that an individual will be diagnosed as being at risk of developing dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of a PPAR-agonist comprising the step of determining the nucleotide present within at least one or more nucleic acid sample(s) from an individual to be assessed at one or more polymorphic position(s) of the human .beta.1-adrenergic receptor gene sequence selected from the group consisting of: SEQ ID NOS:50, and/or 52, wherein the presence of the variable nucleotide at the one or more polymorphic position(s) indicates that the individual has an increased likelihood of being diagnosed as at risk of developing dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of an PPAR-agonist as compared to an individual having the reference allele at said polymorphic position(s).

The invention further relates to a method for predicting the likelihood that an individual will be diagnosed as being at risk of developing a dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of a PPAR-agonist comprising the step of determining the nucleotide present within at least one or more nucleic acid sample(s) from an individual to be assessed at one or more polymorphic position(s) of the human .beta.1-adrenergic receptor gene sequence selected from the group consisting of: SEQ ID NOS:50, and/or 52, wherein the presence of the reference nucleotide at the one or more polymorphic position(s) indicates that the individual has a decreased likelihood of being diagnosed as at risk of developing dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of an PPAR-agonist as compared to an individual having the variable allele at said polymorphic position(s).

The invention further relates to a method for predicting the likelihood that an individual will be diagnosed as being at risk of developing dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of a PPAR-agonist comprising the step of determining the polypeptide present within at least one or more sample(s) from an individual to be assessed at one or more polymorphic position(s) of the human .beta.1-adrenergic receptor polypeptide sequence selected from the group consisting of: SEQ ID NOS:51, and/or 53, wherein the presence of the variable amino acid at the one or more polymorphic position(s) indicates that the individual has an increased likelihood of being diagnosed as at risk of developing dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of an PPAR-agonist as compared to an individual having the reference allele at said polymorphic position(s).

The invention further relates to a method for predicting the likelihood that an individual will be diagnosed as being at risk of developing a dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of a PPAR-agonist comprising the step of determining the nucleotide present within at least one or more sample(s) from an individual to be assessed at one or more polymorphic position(s) of the human .beta.1-adrenergic receptor polypeptide sequence selected from the group consisting of: SEQ ID NOS:50, and/or 52, wherein the presence of the reference amino acid at the one or more polymorphic position(s) indicates that the individual has a decreased likelihood of being diagnosed as at risk of developing dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of an PPAR-agonist as compared to an individual having the variable allele at said polymorphic position(s).

The invention further relates to a method for predicting the likelihood that an individual will be diagnosed as being at risk of developing dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of a PPAR-agonist comprising the step of determining the nucleotide present within at least one or more nucleic acid sample(s) from an individual to be assessed at one or more polymorphic position(s) of the human .beta.1-adrenergic receptor gene sequence selected from the group consisting of: nucleotide position 1251 of SEQ ID NOS:50 or 52, wherein the presence of the variable nucleotide at the one or more polymorphic position(s) indicates that the individual has an increased likelihood of being diagnosed as at risk of developing dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of a PPAR-agonist as compared to an individual having the reference allele at said polymorphic position(s).

The invention further relates to a method for predicting the likelihood that an individual will be diagnosed as being at risk of developing a dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of a PPAR-agonist comprising the step of determining the nucleotide present within at least one or more nucleic acid sample(s) from an individual to be assessed at one or more polymorphic position(s) of the human .beta.1-adrenergic receptor gene sequence selected from the group consisting of: nucleotide position 1251 of SEQ ID NOS:50 or 52, wherein the presence of the reference nucleotide at the one or more polymorphic position(s) indicates that the individual has a decreased likelihood of being diagnosed as at risk of developing dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of a PPAR-agonist as compared to an individual having the variable allele at said polymorphic position(s).

The invention further relates to a method for predicting the likelihood that an individual will be diagnosed as being at risk of developing dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of a PPAR-agonist comprising the step of determining the amino acid present within at least one or more sample(s) from an individual to be assessed at one or more polymorphic position(s) of the human .beta.1-adrenergic receptor polypeptide sequence selected from the group consisting of: amino acid position 389 of SEQ ID NOS:51 or 53, wherein the presence of the variable amino acid at the one or more polymorphic position(s) indicates that the individual has an increased likelihood of being diagnosed as at risk of developing dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of a PPAR-agonist as compared to an individual having the reference allele at said polymorphic position(s).

The invention further relates to a method for predicting the likelihood that an individual will be diagnosed as being at risk of developing a dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of a PPAR-agonist comprising the step of determining the amino acid present within at least one or more sample(s) from an individual to be assessed at one or more polymorphic position(s) of the human .beta.1-adrenergic receptor polypeptide sequence selected from the group consisting of: amino acid position 389 of SEQ ID NOS:51 or 53, wherein the presence of the reference amino acid at the one or more polymorphic position(s) indicates that the individual has a decreased likelihood of being diagnosed as at risk of developing dose-dependent peripheral edema or related disorder upon administration of a pharmaceutically acceptable amount of a PPAR-agonist as compared to an individual having the variable allele at said polymorphic position(s).

The present invention is also directed to methods of predicting whether a patient administered a PPAR-agonist will respond to PPAR-agonist therapy; for predicting whether a patient will respond to specific doses of a PPAR-agonist; whether the level of the administered PPAR-agonist needs to be increased or decreased to achieve the desired level of human .beta.1-adrenergic receptor expression identified as representing a responsive level; whether a patient has an increased risk of developing dose-dependent peripheral edema upon the administration of a pharmaceutically acceptable level of a PPAR-agonist; whether said patient requires a lower level of administered PPAR agonist to limit the risk of developing said dose-dependent peripheral edema; or whether said patient may be administered a higher level of administered PPAR agonist without the risk of developing said dose-dependent peripheral edema, inorder to limit the risk of developing said dose-dependent peripheral edema, comprising the step of assessing the level of endothelin-1 expression resulting from the administration of a PPAR-agonist relative to a control compound.
 

Claim 1 of 17 Claims

1. A method of identifying a PPARgamma-agonist compound having a decreased likelihood of inducing dose-dependent peripheral edema in a patient comprising the step of: (a) incubating mammalian cells that endogenously express renin with a test compound; and (b) measuring the level of induced expression of renin mRNA in response to said test compound; wherein a decreased level of induced renin mRNA expression by said test compound relative to a reference compound is indicative of a decreased risk of said test compound inducing dose-dependent peripheral edema in a patient.

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