Genes affected by cholesterol treatment and during adipogenesis

• US 20030180764A1
• Filed: 01/08/2003
• Published: 09/25/2003
• Est. Priority Date: 01/09/2002
• Status: Abandoned Application

• Current Assignee: Lynx Therapeutics, Inc. (Illumina Incorporated)
• Original Assignee: Lynx Therapeutics, Inc. (Illumina Incorporated)
• Inventors: Shang, Jin, Bowen, Benjamin
• Application Number:
  US10/339,793
• Publication Number:
  US 20030180764A1
• Time in Patent Office: Days
• US Class Current: 435/6
• CPC Class Codes: C07K 14/47 from mammals
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/158 Expression markers
• CPC Class Codes: G01N 2800/044 Hyperlipemia or hypolipemia, e.g. dyslipidaemia, obesity
• CPC Class Codes: G01N 33/92 involving lipids, e.g. cholesterol , lipoproteins, or their receptors steroid hormones G01N33/743

Abstract

Genes, nucleic acids, proteins, antibodies, marker sets, and arrays are provided. Methods of detecting conditions associated with elevated cholesterol and lipid, as well as during adipogenesis, are also provided.

Claims

1. A composition comprising at least one expression vector, which expression vector comprises a nucleic acid comprising:

(a) at least one polynucleotide sequence selected from the group consisting of SEQ ID NO;

1-SEQ ID NO;

443, or a polynucleotide sequence complementary thereto;

(b) at least one polynucleotide sequence that hybridizes under stringent conditions to a polynucleotide sequence of (a);

(c) at least one polynucleotide sequence that is at least about 70% identical to a polynucleotide sequence of (a);

(d) at least one polynucleotide that encodes a polypeptide or peptide comprising a subsequence encoded by a polynucleotide sequence of (a);

(e) at least one polynucleotide sequence that hybridizes to a nucleic acid that is physically linked in the human genome to a nucleic acid comprising a polynucleotide sequence of (a), (b), (c) or (d);

or,

(f) at least one polynucleotide sequence comprising at least about 10 contiguous nucleotides of a polynucleotide sequence selected from the group consisting of SEQ ID NO;

1-SEQ ID NO;

443, or a sequence complementary thereto.

2. The vector of claim 1, wherein the vector comprises a promoter operably linked to the nucleic acid comprising the polynucleotide sequence of (a), (b), (c), (d), (e) or (f).

3. The vector of claim 1, wherein the nucleic acid encodes a polypeptide.

4. The vector of claim 1, wherein the nucleic acid encodes a sense or antisense RNA.

5. A composition comprising the at least one expression vector of claim 1 and an excipient.

6. The composition of claim 5, wherein the excipient is a pharmaceutically acceptable excipient.

7. A cell comprising the vector of claim 1.

8. A labeled probe comprising a nucleic acid sequence comprising:

(a) at least one polynucleotide sequence selected from the group consisting of SEQ ID NO;

1-SEQ ID NO;

443, or a polynucleotide sequence complementary thereto;

(b) at least one polynucleotide sequence that hybridizes under stringent conditions to a polynucleotide sequence of (a);

(c) at least one polynucleotide sequence that is at least about 70% identical to a polynucleotide sequence of (a);

(d) at least one polynucleotide that encodes a polypeptide or peptide comprising a subsequence encoded by a polynucleotide sequence of (a);

(e) at least one polynucleotide sequence that hybridizes to a nucleic acid that is physically linked in the human genome to a nucleic acid comprising a polynucleotide sequence of (a), (b), (c) or (d);

or,

(f) at least one polynucleotide sequence comprising at least about 10 contiguous nucleotides of a polynucleotide sequence selected from the group consisting of SEQ ID NO;

1-SEQ ID NO;

443, or a sequence complementary thereto.

9. The labeled probe of claim 8, the subsequence comprising at least about 12 nucleotides.

10. The labeled probe of claim 8, the subsequence comprising at least about 14 nucleotides.

11. The labeled probe of claim 8, the subsequence comprising at least about 16 nucleotides.

12. The labeled probe of claim 8, the subsequence comprising at least about 17 nucleotides.

13. The labeled probe of claim 8, comprising an isotopic, fluorescent, fluorogenic, or colorimetric label.

14. The labeled probe of claim 8, comprising a DNA or RNA molecule.

15. The labeled probe of claim 8, comprising a cDNA, an amplification product, a transcript, a restriction fragment, or an oligonucleotide.

16. The labeled probe of claim 8, comprising an oligonucleotide consisting of a polynucleotide sequence selected from SEQ ID NO:

1 to SEQ ID NO;

443.

17. The labeled probe of claim 8, wherein the labeled probe is a member of an array of probes comprising a plurality of nucleic acids comprising two or more polynucleotide sequences selected from (a), (b), (c), (d), (e) and/or (f).

18. An array of probes according to claim 17, wherein the plurality of nucleic acids are logically or physically arrayed.

19. A marker set for evaluating a condition or characteristic associated with elevated cholesterol or lipid and/or adipogenesis comprising a plurality of members, which members comprise nucleic acids, polypeptides and/or peptides comprising:

(a) one or more polynucleotide sequence selected from the group consisting of SEQ ID NO;

1-SEQ ID NO;

443, or a polynucleotide sequence complementary thereto;

(b) one or more polynucleotide sequence that hybridizes under stringent conditions to a polynucleotide sequence of (a);

(c) one or more polynucleotide sequence that is at least about 70% identical to a polynucleotide sequence of (a);

(d) one or more polynucleotide that encodes a polypeptide or peptide comprising a subsequence encoded by a polynucleotide sequence of (a);

(e) one or more polynucleotide sequence that hybridizes to a nucleic acid that is physically linked in the human genome to a nucleic acid comprising a polynucleotide sequence of (a), (b), (c) or (d); and

/or,

(f) one or more polynucleotide sequence comprising at least about 10 contiguous nucleotides of a polynucleotide sequence selected from the group consisting of SEQ ID NO;

1-SEQ ID NO;

443, or a sequence complementary thereto;

(g) one or more polypeptides or peptides comprising an amino acid sequence encoded by a polynucleotide of (a), (b), (c), (d), or (e); and

/or,

(h) one or more antibodies specific for a polypeptide or peptide sequence of (g).

20. The marker set of claim 19, comprising a plurality of oligonucleotides.

21. The marker set of claim 20, wherein the oligonucleotides are synthetic oligonucleotides.

22. The marker set of claim 19, comprising a plurality of amplification products or expression products.

23. The marker set of claim 19, comprising a plurality of labeled nucleic acid probes.

24. The marker set of claim 19, comprising a plurality of polypeptides or peptides.

25. The marker set of claim 19, comprising a plurality of antibodies.

26. The marker set of claim 19, comprising a plurality of members, which members include nucleic acids and polypeptides.

27. The marker set of claim 19, wherein the members of the marker set are logically or physically arrayed.

28. The marker set of claim 19, wherein the members of the marker set are physically arrayed in a solid phase or liquid phase array.

29. The marker set of claim 28, wherein the array comprises a bead array.

30. The marker set of claim 19, comprising a majority of sequences or subsequences selected from SEQ ID NO:

1-SEQ ID NO;

443.

31. The marker set of claim 19, comprising SEQ ID NO:

1-SEQ ID NO;

443.

32. The marker set of claim 19, wherein the condition or characteristic associated with elevated cholesterol or lipid and/or adipogenesis is predicted by hybridizing the nucleic acids of the marker set to a DNA or RNA sample from a cell or tissue, and detecting at least one polymorphic polynucleotide or differentially expressed expression product.

33. The marker set of claim 19, wherein the condition or characteristic is associated with high cholesterol or fat exposure.

34. The marker set of claim 19, wherein the condition or characteristic is selected from among obesity, atherosclerosis, diabetes mellitus and coronary artery heart disease.

35. An array comprising the marker set of claim 19.

36. A method for modulating a physiologic or pathologic response to elevated cholesterol or lipid and/or adipogenesis in a cell, tissue or organism, the method comprising:

modulating expression or activity of at least one polypeptide encoded by a nucleic acid comprising;

(a) at least one polynucleotide sequence selected from the group consisting of SEQ ID NO;

1-SEQ ID NO;

443, or a polynucleotide sequence complementary thereto;

(b) at least one polynucleotide sequence that hybridizes under stringent conditions to a polynucleotide sequence of (a);

(c) at least one polynucleotide sequence that is at least about 70% identical to a polynucleotide sequence of (a);

(d) at least one polynucleotide that encodes a polypeptide or peptide comprising a subsequence encoded by a polynucleotide sequence of (a);

(e) at least one polynucleotide sequence that hybridizes to a nucleic acid that is physically linked in the human genome to a nucleic acid comprising a polynucleotide sequence of (a), (b), (c) or (d);

or,

(f) at least one polynucleotide sequence comprising at least about 10 contiguous nucleotides of a polynucleotide sequence selected from the group consisting of SEQ ID NO;

1-SEQ ID NO;

443, or a sequence complementary thereto.

37. The method of claim 36, comprising modulating expression or activity of at least one polypeptide contributing to a condition selected from obesity, atherosclerosis, diabetes mellitus, or coronary artery heart disease.

38. The method of claim 36, comprising modulating a physiologic or pathologic response to elevated cholesterol or lipid and/or adipogenesis in one or more cell-types selected from the group comprising liver, adipose tissue, gall bladder, pancreas, monocytes, macrophages, foam cells, T cells, endothelia and smooth muscle derived from blood vessels and gut, fibroblasts, glia and nerve cells.

39. The method of claim 36, comprising modulating expression by expressing an exogenous nucleic acid comprising a polynucleotide sequence selected from SEQ ID NO:

1 to SEQ ID NO;

443.

40. The method of claim 36, comprising modulating expression in a cell line or non-human mammal.

41. The method of claim 40, wherein the non-human mammal comprises a mouse, a rat, a dog, a rabbit, a pig, a sheep or a non-human primate

42. The method of claim 39, comprising modulating expression by inducing or suppressing expression of an endogenous nucleic acid.

43. The method of claim 42, wherein the endogenous nucleic acid encodes a polypeptide comprising a subsequence encoded by a sequence selected from among SEQ ID NO:

1-SEQ ID NO;

443, or homologues thereof.

44. The method of claim 39, comprising introducing an exogenous nucleic acid comprising at least one promoter, which promoter regulates expression of the endogenous nucleic acid modulating cholesterol or lipid homeostasis and metabolism.

45. The method of claim 39, wherein expression is modulated in response to cholesterol and/or lipid.

46. The method of claim 39, further comprising detecting altered expression or activity of an expression product encoded by a nucleic acid comprising a polynucleotide sequence selected from SEQ ID NO:

1-SEQ ID NO;

443, or conservative variants thereof.

47. The method of claim 46, comprising detecting altered expression or activity in a high throughput assay.

48. The method of claim 45, comprising detecting altered expression or activity in response to administration of a pharmaceutical agent.

49. The method of claim 45, comprising detecting altered expression or activity in response to diet.

50. The method of claim 45, wherein a plurality of expression products are detected.

51. The method of claim 50, wherein the plurality of expression products are detected in an array.

52. The method of claim 51, wherein the array comprises a bead array.

53. The method of claim 45, wherein a data record comprising the altered expression or activity is recorded in a database.

54. The method of claim 52, wherein the database comprises a plurality of character strings recorded on a computer or in a computer readable medium.

56. The method of claim 36, wherein the expression product comprises an RNA.

57. The method of claim 36, wherein the expression product comprises a protein or polypeptide.

58. The method of claim 36, wherein the detecting step comprises qualitative detection.

59. The method of claim 36, wherein the detecting step comprises quantitative detection.

55. A method for evaluating a condition or characteristic associated with a physiologic or pathologic response to excessive cholesterol or lipid and/or adipogenesis in a subject, the method comprising:

(i) providing a subject cell or tissue sample of nucleic acids;

(ii) detecting at least one polymorphic nucleic acid or at least one expression product corresponding to a polynucleotide sequence comprising;

(a) at least one polynucleotide sequence selected from the group consisting of SEQ ID NO;

1-SEQ ID NO;

443, or a polynucleotide sequence complementary thereto;

(b) at least one polynucleotide sequence that hybridizes under stringent conditions to a polynucleotide sequence of (a);

(c) at least one polynucleotide sequence that is at least about 70% identical to a polynucleotide sequence of (a);

(d) at least one polynucleotide that encodes a polypeptide or peptide comprising a subsequence encoded by a polynucleotide sequence of (a);

(e) at least one polynucleotide sequence that hybridizes to a nucleic acid that is physically linked in the human genome to a nucleic acid comprising a polynucleotide sequence of (a), (b), (c) or (d);

or,

(f) at least one polynucleotide sequence comprising at least about 10 contiguous nucleotides of a polynucleotide sequence selected from the group consisting of SEQ ID NO;

1-SEQ ID NO;

443, or a sequence complementary thereto;

wherein the polymorphic nucleic acid or expression or activity of the expression product is correlatable to at least one condition or characteristic associated with a physiologic or pathologic response to elevated cholesterol or lipid and/or adipogenesis.

60. A method for identifying a gene altering a physiologic or pathologic response to elevated cholesterol or lipid and/or adipogenesis, the method comprising:

(i) providing at least one nucleic acid comprising;

(a) at least one polynucleotide sequence selected from the group consisting of SEQ ID NO;

1-SEQ ID NO;

443, or a polynucleotide sequence complementary thereto;

(b) at least one polynucleotide sequence that hybridizes under stringent conditions to a polynucleotide sequence of (a);

(c) at least one polynucleotide sequence that is at least about 70% identical to a polynucleotide sequence of (a);

(d) at least one polynucleotide that encodes a polypeptide or peptide comprising a subsequence encoded by a polynucleotide sequence of (a);

(e) at least one polynucleotide sequence that hybridizes to a nucleic acid that is physically linked in the human genome to a nucleic acid comprising a polynucleotide sequence of (a), (b), (c) or (d);

or,

(f) at least one polynucleotide sequence comprising at least about 10 contiguous nucleotides of a polynucleotide sequence selected from the group consisting of SEQ ID NO;

1-SEQ ID NO;

443, or a sequence complementary thereto; and

,

(ii) identifying at least one nucleic acid corresponding to a gene capable of altering a physiologic or pathologic response to elevated cholesterol or lipid and/or adipogenesis.

61. The method of claim 60, comprising providing at least one expression vector comprising a polynucleotide sequence selected from among the polynucleotide sequences of (a), (b), (c), (d), (e) or (f).

62. The method of claim 60, comprising providing at least one probe comprising a polynucleotide sequence selected from among the polynucleotide sequences of (a), (b), (c), (d), (e) or (f), and,

hybridizing the at least one probe to an expression product of a gene capable of altering a physiologic or pathologic response to elevated cholesterol or lipid and/or adipogenesis.

63. The method of claim 60, wherein providing the at least one nucleic acid comprises amplifying a target sequence comprising a polynucleotide sequence selected from (a), (b), (c), (d), (e) or (f).

64. The method of claim 63, wherein the amplifying comprises a quantitative reverse transcriptase-polymerase chain reaction (RT-PCR).

65. The method of claim 63, comprising identifying a target sequence that is differentially expressed in response to cholesterol and/or lipid.

66. The method of claim 60, comprising hybridizing the at least one nucleic acid to a target nucleic acid;

and, sequencing the target nucleic acid to detect a nucleotide polymorphism, which nucleotide polymorphism is associated with a condition selected from among obesity, atherosclerosis, diabetes mellitus or coronary artery heart disease.

68. The isolated or recombinant polypeptide of claim 66, comprising a fusion protein.

69. The isolated or recombinant polypeptide of claim 66, comprising a peptide or polypeptide tag.

70. The isolated or recombinant polypeptide of claim 66, wherein the peptide or polypeptide tag comprises a reporter peptide or polypeptide.

71. The isolated or recombinant polypeptide of claim 66, wherein the peptide or polypeptide tag comprises an epitope.

72. The isolated or recombinant polypeptide of claim 66, wherein the peptide or polypeptide tag comprises a signal sequence.

73. A composition comprising the isolated or recombinant polypeptide of claim 66 and an excipient.

74. The composition of claim 73, wherein the excipient is a pharmaceutically acceptable excipient.

75. An array of polypeptides comprising two or more different polypeptides of claim 66.

76. An antibody specific for an isolated or recombinant polypeptide of claim 66.

77. The antibody of claim 76, wherein the antibody comprises a monoclonal antibody or a polyclonal serum.

78. One or more isolated or recombinant polypeptides that bind to the antibody of claim 66.

67. An isolated or recombinant polypeptide comprising one or more amino acid sequences or subsequences encoded by a nucleic acid comprising:

(a) at least one polynucleotide sequence selected from the group consisting of SEQ ID NO;

1-SEQ ID NO;

443, or a polynucleotide sequence complementary thereto;

(b) at least one polynucleotide sequence that hybridizes under stringent conditions to a polynucleotide sequence of (a);

(c) at least one polynucleotide sequence that is at least about 70% identical to a polynucleotide sequence of (a);

(d) at least one polynucleotide sequence that hybridizes to a nucleic acid that is physically linked in the human genome to a nucleic acid comprising a polynucleotide sequence of (a), (b) or (c);

or,

(e) at least one polynucleotide sequence comprising at least about 10 contiguous nucleotides of a polynucleotide sequence selected from the group consisting of SEQ ID NO;

1-SEQ ID NO;

443, or a sequence complementary thereto.