Single nucleotide polymorphisms and mutations on Alpha-2-Macroglobulin
First Claim
1. A method for identifying a polymorphism or combination of polymorphisms associated with an A2M-mediated disease or disorder, comprising testing one or more polymorphisms in an A2M gene individually and/or in combinations for genetic association with an A2M-mediated disease or disorder, wherein the one or more polymorphisms is/are selected from the group consisting of 6i, 12i.1, 12i.2, 12e, 14e, 14i.1, 14i.2, 17i.1, 20e, 20i, 21i, 28i and 30e.
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Accused Products
Abstract
The present invention is related to the discovery of several single nucleotide polymorphisms (SNPs) and/or mutations in the Alpha-2-Macroglobulin gene (A2M), which are risk factors for Alzheimer'"'"'s Disease (AD). More specifically, aspects of the invention concern nucleic acids corresponding to the A2M gene or fragments thereof, which contain one or more of the SNPs and/or mutations described herein, peptides or proteins encoded by said nucleic acids, antibodies to said peptides or proteins and methods of making said compositions, diagnostic methods, methods of data analysis, and pharmaceutical discovery and preparation methods.
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Citations
70 Claims
- 1. A method for identifying a polymorphism or combination of polymorphisms associated with an A2M-mediated disease or disorder, comprising testing one or more polymorphisms in an A2M gene individually and/or in combinations for genetic association with an A2M-mediated disease or disorder, wherein the one or more polymorphisms is/are selected from the group consisting of 6i, 12i.1, 12i.2, 12e, 14e, 14i.1, 14i.2, 17i.1, 20e, 20i, 21i, 28i and 30e.
- 2. A method for identifying a polymorphism or combination of polymorphisms associated with a neurodegenerative disease or disorder, comprising testing one or more polymorphisms in an A2M gene individually and/or in combinations for genetic association with a neurodegenerative disease or disorder, wherein the one or more polymorphisms is/are selected from the group consisting of 6i, 12i.1, 12i.2, 12e, 14e, 14i.1, 14i.2, 17i.1, 20e, 20i, 21i, 28i and 30e.
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6. A method of genotyping a cell comprising:
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obtaining from an individual a biological sample containing an alpha-2-macroglobulin nucleic acid or portion thereof, and determining the identity of one or more nucleotides in said alpha-2-macroglobulin nucleic acid or portion thereof wherein said one or more nucleotides are located at a position selected from the group consisting of 6i, 12i.1, 12i.2, 12e, 14e, 14i.1, 14i.2, 17i.1, 20e, 20i, 21i, 28i and 30e. - View Dependent Claims (7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20)
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21. A method of genotyping a cell comprising:
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obtaining from an individual a biological sample containing an alpha-2-macroglobulin polypeptide or portion thereof; and
determining the identity of one or more amino acids in said alpha-2-macroglobulin polypeptide or portion thereof wherein said one or more amino acids are located at a position selected from the group consisting of 14e, 20e and 30e.
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22. A method of identifying a subject at risk for Alzheimer'"'"'s Disease, said method comprising:
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obtaining from said subject a biological sample containing an alpha-2-macroglobulin nucleic acid or portion thereof; and
determining the presence or absence of one or more polymorphisms or mutations in said alpha-2-macroglobulin nucleic acid or portion thereof wherein said one or more polymorphisms or mutations occur at a position selected from the group consisting of 6i, 12i.1, 12i.2, 12e, 14e, 14i.1, 14i.2, 17i.1, 20e, 20i, 21i, 28i and 30e. - View Dependent Claims (23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39)
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40. A method of identifying a subject at risk for Alzheimer'"'"'s Disease, said method comprising:
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obtaining from said subject a biological sample containing an alpha-2-macroglobulin polypeptide or portion thereof; and
determining the presence or absence of one or more polymorphisms or mutations in said alpha-2-macroglobulin polypeptide or portion thereof wherein said one or more polymorphisms or mutations occur at a position selected from the group consisting of 14e, 20e and 30e.
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41. A method of identifying a compound that modulates an alpha-2-macroglobulin activity comprising:
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providing a plurality of cells that express the LRP receptor;
contacting said cells with a candidate compound;
contacting said cells with an alpha-2-macroglobulin polypeptide comprising at least one polymorphism or mutation having a position selected from the group consisting of 14e, 20e, and 30e; and
identifying a compound that modulates an alpha-2-macroglobulin activity. - View Dependent Claims (42, 43, 44, 45, 46, 47, 48, 51)
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49. A method of identifying a compound that modulates an alpha-2-macroglobulin activity comprising:
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providing an alpha-2-macroglobulin polypeptide comprising at least one of the polymorphisms or mutations having a position selected from the group consisting of 14e, 20e, and 30e;
contacting said alpha-2-macroglobulin polypeptide with said compound;
contacting said alpha-2-macroglobulin polypeptide with methylamine; and
identifying a compound that modulates an alpha-2-macroglobulin activity by detecting a modulation in the activation of said alpha-2-macroglobulin polypeptide.
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50. A method of identifying a compound that modulates an alpha-2-macroglobulin activity comprising:
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providing an alpha-2-macroglobulin polypeptide comprising at least one of the polymorphisms or mutations having a position selected from the group consisting of 14e, 20e, and 30e;
contacting said alpha-2macroglobulin polypeptide with said compound;
contacting said alpha-2-macroglobulin polypeptide with amyloid β
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identifying a compound that modulates an alpha-2-macroglobulin activity by detecting a modulation in the formation of a complex of amyloid β and
said alpha-2-macroglobulin polypeptide.
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- 52. A purified or isolated nucleic acid comprising an alpha-2-macroglobulin sequence having a polymorphism or mutation at a position selected from the group consisting of 6i, 12i.1, 12i.2, 12e, 14e, 14i.1, 14i.2, 17i.1, 20e, 20i, 21i, 28i and 30e, wherein the nucleotide or nucleotide sequence at said position is other than an A2M-1.
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57. A purified or isolated nucleic acid comprising a fragment of at least 16 consecutive nucleotides of SEQ ID NO:
- 1 having a polymorphism or mutation at a position selected from the group consisting of 6i, 12i.1, 12i.2, 12e, 14e, 14i.1, 14i, 17i.1, 20e, 20i, 21i, 28i and 30e, wherein the nucleotide or nucleotide at said position is other than an A2M-1 or a sequence complementary thereto.
- View Dependent Claims (63, 64, 66)
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59. A purified or isolated polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:
- 9-15 having a polymorphism or mutation at a position selected from the group consisting of 14e, 20e and 30e, wherein the amino acid at said position is other than A2M-1.
- View Dependent Claims (60)
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61. A purified or isolated polypeptide comprising a fragment of an amino acid sequence selected from the group consisting of SEQ ID NOs:
- 9-15 having a polymorphism or mutation at a position selected from the group consisting of 14e, 20e and 30e, wherein the amino acid mutation at said position is other than A2M-1.
- View Dependent Claims (62, 65, 67, 68)
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69. A method of expressing an alpha-2-macroglobulin polypeptide comprising:
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providing a construct comprising a promoter operably linked to an alpha-2-macroglobulin nucleic acid having a polymorphism or mutation at a position selected from the group consisting of 14e, 20e and 30e, wherein the nucleotide at said position is other than an A2M-1; and
expressing said alpha-2-macroglobulin from said construct. - View Dependent Claims (70)
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Specification