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Summary for Patent: 6,197,505
Title: Methods for assessing cardiovascular status and compositions for use thereof
Abstract:The present invention provides methods for assessing cardiovascular status in an individual, which comprise determining the sequence at one or more polymorphic positions within the human genes encoding angiotensin converting enzyme (ACE), angiotensinogen (AGT), and/or type 1 angiotensin II receptor (AT1). The invention also provides isolated nucleic acids encoding ACE, AGT, and AT1 polymorphisms, nucleic acid probes that hybridize to polymorphic positions, kits for the prediction of cardiovascular status, and nucleic acid and peptide targets for use in identifying candidate cardiovascular drugs.
Inventor(s): Norberg; Leif Torbjorn (Uppsala, SE), Andersson; Maria Kristina (Uppsala, SE), Lindstrom; Per Harry Rutger (Uppsala, SE)
Assignee: Pyrosequencing AB (Uppsala, SE)
Application Number:09/050,159
Patent Claims:1. An isolated nucleic acid derived from the human gene encoding angiotensin coverting enzyme (ACE), wherein said nucleic acid comprises a polymorphic position selected from the group consisting of a position in the regulatory region (SEQ ID NO: 129) numbered 5106; positions in the coding region (SEQ ID NO: 130) numbered 375, 582, 731, 1060, 2741, 3132, 3387, 3503, and 3906; and combinations of any of the foregoing.

2. A nucleic acid as defined in claim 1 wherein the sequence at said polymorphic position in the regulatory region is selected from the group consisting of 5106C and 5106T; and the sequence at said polymorphic position in the coding region is selected from the group consisting of 375A, 375C, 582C, 582T, 731A, 731G, 1060G, 1060A, 2741G, 2741T, 3132C, 3132T, 3387T, 3387C, 3503G, 3503C, 3906G, 3906A.

3. A probe which hybridizes to a polymorphic position as defined in claim 1 at high stringency, wherein high stringency conditions are selected from the goop consisting of hybridization and/or washing at 68.degree. C. in 0.2.times. SSC and hybridization and/or washing at 42.degree. C. in 50% formamide, 4.times. SSC.

4. A library of nucleic acids, each of which comprises one or more polymorphic positions within the human ACE gene, wherein said polymorphic positions are selected from the group consisting of positions in the ACE regulatory region (SEQ ID NO: 129) numbered 5106, 5349, and 5496; and positions in the ACE coding region (SEQ ID NO: 130) numbered 375, 582, 731, 1060, 1215, 2193, 2328, 2741, 3132, 3387, 3503, and 3906 and 1451-1783 (SEQ ID NO: 128).

5. A library as defined in claim 4, wherein the sequence at said polymorphic position in the regulatory region is selected from the group consisting of 5106C, 5106T, 5349A, 5349T, 5496T, and 5496C; and the sequence at said polymorphic position in the coding region is selected from the group consisting of 375A, 375C, 582C, 582T, 731A, 731G, 1060G, 1060A, 1215C, 1215T, 2193G, 2193A, 2328A, 2328G, 2741G, 2741T, 3132C, 3132T, 3387T, 3327C, 3503G, 3503C, 3906G, 3906A, and a deletion of nucleotides 1451-1783 (SEQ ID NO: 128).

6. A library of targets for cardiovascular drugs, each of said targets comprising an isolated peptide comprising one or more polymorphic positions in the ACE polypeptide sequence, wherein said polymorphic positions are encoded by nucleotides selected from the group consisting of nucleotide positions in the ACE coding region (SEQ ID NO: 130) numbered 375, 582, 731, 1060, 1215, 2193, 2328, 2741, 3132, 3387, 3503, and 3906.

7. An isolated nucleic acid comprising the human gene encoding angiotensinogen (AGT), wherein said nucleic acid comprises a polymorphic position selected from the group consisting of positions in the regulatory region (SEQ ID NO: 123) numbered 412 and 1072; positions in the coding region (SEQ ID NO:124) numbered 273, 997, and position 49 (SEQ ID NO: 126); and combinations of any of the foregoing.

8. A nucleic acid as defined in claim 7 wherein the sequence at said polymorphic position in the regulatory region is selected from the group consisting of 412C, 412T, 1072C and 1072A; and the sequence at the polymorphic position in the coding region is selected from the group consisting of 273C, 273T, 997G, 997C, and A or G at position 49 (SEQ ID NO: 126).

9. A probe which hybridizes to a polymorphic position as defined in claim 7 at high stringency, wherein high stringency conditions are selected from the group consisting of hybridization and/or washing at 68.degree. C. in 0.2.times. SSC and hybridization and/or washing at 42.degree. C. in 50% formamide, 4.times. SSC.

10. A library of nucleic acids, each of which comprises one or more polymorphic positions within the human AGT gene, wherein said polymorphic position is selected from the group consisting of positions in the regulatory region (SEQ ID NO: 123) numbered 395, 412, 432, 449, 692, 839, 1007, 1072, 1204, and 1218; positions in the coding region (SEQ ID NO: 124) numbered 273, 620, 803, 912, 997, 1116, and 1174; and position 49 in the AGT gene (SEQ ID NO: 126).

11. A library as defined in claim 10, wherein the sequence at said polymorphic position in the regulatory region is selected from the group consisting of 395T, 395A, 412C, 412T, 432G, 432A, 449T, 449C, 692C, 692T, 839G, 839A, 1007G, 1007A, 1072G, 1072A, 1204C, 1204A, 121 8A, 1218G; and the sequence at said polymnorphic position in the coding region is selected from the group consisting of 273C, 273T, 620C, 620T, 803T, 803C, 912C, 912T, 997G, 997C, 1116G, 1116A, 1174C, 11 74A, and A or G at position 49 (SEQ ID NO: 126).

12. A library of targets for cardiovascular drugs, each of said targets comprising an isolated peptide comprising one or more polymorphic positions in the AGT polypeptide, wherein said polymorphic positions are encoded by nucleotides selected from the group consisting of nucleotide positions numbered 273, 620, 803, 912, 997, 1116, and 1174 of SEQ ID NO: 124.

13. An isolated nucleic acid comprising the human gene encoding type I angiotensin II receptor (AT1), wherein said nucleic acid comprises a polymorphic position selected from the group consisting of positions in the regulatory region (SEQ ID NO: 131) numbered 1427, 1756, 1853, 2046, 2354, 2355, and 2415; a position in the coding/intron region (SEQ ID NOS: 132-133, which are contiguous) numbered 449; and combinations of the foregoing.

14. A nucleic acid as defined in claim 13 wherein the sequence at said polymorphic position in the regulatory region is selected from the group consisting of 1427A, 1427T, 1756T, 1756A, 1853T, 1853G, 2046T, 2046C, 2354A, 2354C, 2355G, 2355C, 2415A and 2415G; and the sequence at said polymorphic position in the coding/intron region is selected from the group consisting of 449G and 449C.

15. A probe which hybridizes to a polymorphic position as defined in claim 13 at high stringency, wherein high stringency conditions are selected from the group consisting of hybridization and/or washing at 68.degree. C. in 0.2.times. SSC and hybridization and/or washing at 42.degree. C. in 50% formamide, 4.times. SSC.

16. A library of nucleic acids, each of which comprises one or more polymorphic positions within the human AT1 gene, wherein said polymorphic position is selected from the group consisting of positions in the regulatory region (SEQ ID NO: 131) numbered 1427, 1756, 1853,2046,2354,2355, and 2415; and positions in the coding region (SEQ ID NOS: 132-133, which are contiguous) numbered 449, 678, 1167, and 1271.

17. A library as defined in claim 16, wherein the sequence at said polymorphic position in the regulatory region is selected from the group consisting of 1427A, 1427T, 1756T, 1756A, 1853T, 1853G, 2046T, 2046C, 2354A, 2354C, 2355G, 2355C, 2415A and 2415G; and the sequence at said polymorphic position in the coding region is selected from the group consisting of 449G, 449C, 678T, 678C, 1167A, 1167G, 1271A, and 1271C.

18. A library of targets for cardiovascular drugs, each of said targets comprising an isolated peptide comprising one or more polymorphic positions in the AT1 polypeptide, wherein said polymorphic positions are encoded by nucleotides selected from the group consisting of nucleotide positions numbered 449, 678, 1167, and 1271 of continuous SEQ ID NOS: 132-133.

19. A library of polymorphic patterns in the human ACE (SEQ ID NOS: 129-130), AGT (SEQ ID NOS: 123-127), and/or AT1 (SEQ ID NO: 132-133, which are contiguous) genes, comprising a member selected from the group consisting of: ACE 5349 A/T, AGR 1218 A; ACE 5496 C, AGR 1204 A/C; ACE 5496 C/T, AGR 1218 A, AGT 620 C/T; ACE 2193 A, AGR 1204 C, ACE 2328 G; ACE 2193 A, AGR 1204 A/C; ACE 3387 T, AGR 1218 A; ACE 3387 T, AGT 620 C/T; AGR 1204 A/C, AT1 678 C/T; AGR 1204 A/C, AT1 1271 A/C; ACE 1215 C, AGR 1204 A/C; AGR 1204 A/C, AT1 1167 A, ACE 3906 A/G; AGR 1204 A, AGT 620 C, AT1 1271 A, AT1 1167 A, AGR 395 A/T; AGR 1204 A/C, AGT 620 C/T, AT1 1271 A/C, AT1 1167 A, AGR 395 T; AGR 1204 A/C, AGT 620 C/T, AT1 1271 A/C, AT1 1167 A/G, AGR 395 T; AGR 1204 A, AT1 678 C, AT1 1167 A, AGR 395 A/T; AGR 1204 A/C, AT1 678 C/T, AT1 1167 A, AGR 395 T; AGT 620 C/T, AT1 1271 A/C, AT1 1167 A, AGR 395 T; AGT 620 C/T, AT1 1271 A/C, AT1 1167 A/G, AGR 395 T; AGT 620 C, AT1 1271 A, AT1 1167 A, AGR 395 A/T, AGT 620 C, AT1 678 A, AT1 1167 A, AGR 395 A/T; AGT 620 C/T, AT1 678 C/T, AT1 1167 A, AGR 395 T; ACE 2193 A, AGR 1218 A, AGT 803 A; ACE 2193 A, AGT 620 C/T; ACE 2328 G, AGT 620 C/T; ACE 3387 T, AGR 1204 A/C; ACE 2193 A, ACE 2328 G, AGR 1204 C; and ACE 2193 A/G, AGR 1072 G/A, AT1 1167 A/G.

20. A kit for assessing responsiveness of an individual to a treatment regimen of a cardiovascular syndrome, said kit comprising

(i) sequence determination primers and

(ii) sequence determination reagents,

wherein said primers are selected from the group consisting of primers that hybridize to polymorphic positions in human ACE, AGT, or AT1 genes; and primers that hybridize immediately adjacent to polymorphic positions in human ACE, AGT, or AT1 genes, wherein said polymorphic positions are selected from the group consisting of positions in the ACE regulatory region (SEQ ID NO: 129) numbered 5106, 5349, and 5496; positions in the ACE coding region (SEQ ID NO: 131) numbered 375, 582, 731, 1060, 1215, 2193, 2328, 2741, 3132, 3387, 3503, and 3906; positions in the AGT regulator region (SEQ ID NO: 123) numbered 395, 412, 432, 449, 692, 839, 1007, 1072, 1204 and 1218; positions in tie AGT coding region (SEQ ID NO: 124) numbered 273, 620, 803, 912, 997, 1116, and 1174; position 49 in the AGT gene (SEC ID NO; 126) position 1451 in the ACE gene (SEQ ID NO: 128); positions in the AT1 regulatory region numbered 1427, 1756, 1853, 2046, 2354, 2355, and 2415; positions in the AT1 coding region (SEQ ID NOS: 132-133, which are contiguous) numbered 449, 678, 1167, and 1271; and combinations of any of the foregoing.

21. A kit for assessing cardiovascular status, said kit comprising one or more antibodies specific for a polymorphic position within the human ACE, AGT, or AT1 polypeptides.

22. A kit as defined in claim 21, wherein said polymorphic positions are encoded by a nucleotide selected from the group consisting of nucleotide positions in the ACE coding region (SEQ ID NO: 130) numbered 375, 582, 731, 1060, 1215, 2193, 2328, 2741, 3132, 3387, 3503, and 3906; nucleotide positions in the AGT coding region (SEQ ID NO: 124) numbered 273, 620, 803, 912, 997, 1116, and 1114; positions in the AT1 coding region (SEQ ID NOS: 132-133 which are continuous) numbered 449, 678, 1167, and 1271; and combinations of any of the foregoing.

23. A method for predicting the response of a human individual having a cardiovascular syndrome to a treatment regimen of said cardiovascular syndrome, which method comprises comparing a polymorphic pattern established in one or more polymorphic positions within one or more of the ACE, AGT, or AT1 genes of said individual wit a polymorphic pattern of the same polymorphic positions of humans who have a known response to the treatment regimen.

24. A method as defined in claim 23, wherein said treatment regimen is an alteration in diet, lifestyle, and/or exercise; a surgical technique, or a pharmaceutical intervention.

25. A method as defined in claim 24, wherein said treatment regimen is a pharmaceutical intervention.

26. A method as defined in claim 25, wherein said treatment regimen comprises administering a cardiovascular drug selected from the group consisting of ACE inhibitors, angiotensin II receptor antagonists, diuretics, alpha-adrenoreceptor antagonists, cardiac glycosides, phosphodiesterase inhibitors, beta-adrenoreceptor antagonists, calcium channel blockers, HMG-CoA reductase inhibitors, imidizoline receptor blockers endothelin receptor blockers, and organic nitrites.

27. A method as defined in claim 26, wherein said polymorphic positions comprise ACE 2193 (SEQ ID NO: 130), AGT 1072 (SEQ ID NO: 123), and AT1 1167 (SEQ ID NOS. 132-133 which are contiguous).

28. A method as defined in claim 27, wherein said polymorphic pattern comprises ACE 2193 A/G, AGT 1072 G/A, and AT1 1167 A/G.

29. A method as defined in claim 23, wherein said cardiovascular syndrome is selected from the group consisting of myocardial infarction, hypertension, atherosclerosis, and stroke.

30. A method as defined in claim 23, wherein said treatment regimen is the administration of an ACE inhibitor, wherein said method comprises comparing the polymorphic pattern established by determining the sequence of (a) the ACE gene (SEQ ID NO: 130) at position 2193 in the coding region; (b) the AGT gene (SEQ ID NO: 123) at position 1072 in the regulatory region; and (c) the AT gene (SEQ ID NOS: 132-133, which are contiguous) at position 1167 in the coding region with the same polymorphic patterns of humans exhibiting different responses to said ACE inhibitor.

31. A method as defined in claim 30, wherein said polymorphic pattern comprises ACE 2193 A/G, AGT 1072 G/A, AT 1 1167 A/G.

32. A method for assessing cardiovascular status in a human individual, which method comprises comparing a polymorphic pattern established in one or more polymorphic positions within one or more of the ACE, AGT, or AT1 genes of said individual with a polymorphic pattern of the same polymorphic positions of humans who have a known cardiovascular status, wherein said polymorphic positions comprise ACE 2193 of SEQ ID NO: 130, AGT 1072 of SEQ ID NO: 123, and AT1 1167 (SEQ ID NOS: 132-133, which are contiguous).

33. A method as defined in claim 32, wherein said polymorphic pattern comprises ACE 2193 A/G, AGT 1072 G/A, and AT1 1167 A/G.

34. A method as defined in claim 32, which method comprises comparing the polymorphic pattern established by determining the sequence of (a) the ACE gene at position 2193 in the coding region; (b) the AGT gene at position 1072 in the regulatory region; and (c) the AT1 gene at position 1167 in the coding region.

35. A method as defined in claim 34, wherein said polymorphic pattern comprises ACE 2193 A/G, AGR 1072 G/A, AT1 1167 A/G.

36. A method for assessing cardiovascular status in a human individual, which method comprises comparing a polymorphic pattern established in one or more polymorphic positions within one or more of the ACE, AGT, or AT1 genes of said individual with a polymorphic pattern of the same polymorphic positions of humans who have a known cardiovascular status, wherein said polymorphic position is selected from the group consisting of positions in the ACE regulatory region (SEQ ID NO:129) numbered 5106, 5349, and 5496; positions in the ACE coding region (SEQ ID NO:130) numbered 375, 582, 731, 1060, 1215, 2193, 2328, 2741, 3132, 3387, 3503, and 3906; positions in the AGT regulatory region (SEQ ID NO: 123) numbered 395, 412, 432, 449, 692, 839, 1007, 1072, 1204, and 1218; positions in the AGT coding region (SEQ ID NO: 124) numbered 273, 620, 803, 912, 997, 1116, and 1174; position 49 in the AGT gene (SEQ ID NO:126); position 1451 in the ACE gene (SEQ ID NO:128); positions in the AT1 regulatory region (SEQ ID NO:131) numbered 1427, 1756, 1853, 2046, 2354, 2355, and 2415; positions in the AT1 coding region (SEQ ID NOS:132-133, which are contiguous) numbered 449, 678, 1167, and 1271; and combinations of any of the foregoing.

37. A method as defined in claim 36, wherein said polymorphic patterns are selected from the group consisting of: ACE 5349 A/T, AGR 1218 A; ACE 5496 C, AGR 1204 A/C; ACE 5496 C/T, AGR 1218 A, AGT 620 C/T; ACE 2193 A, AGR 1204 C, ACE 2328 G; ACE 2193 A, AGR 1204 A/C; ACE 3387 T, AGR 1218 A; ACE 3387 T, AGT 620 C/T; AGR 1204 A/C, AT1 678 C/T; AGR 1204 A/C, AT1 1271 A/C; ACE 1215 C, AGR 1204 A/C; AGR 1204 A/C, AT1 1167 A, ACE 3906 A/G; AGR 1204 A, AGT 620 C, AT1 1271 A, AT1 1167 A, AGR 395 A/T; AGR 1204 A/C, AGT 620 C/T, AT1 1271 A/C, AT1 1167 A, AGR 395 T; AGR 1204 A/C, AGT 620 C/T, AT1 1271 A/C, AT1 1167 A/G, AGR 395 T; AGR 1204 A, AT1 678 C, AT1 1167 A, AGR 395 A/T; AGR 1204 A/C, AT1 678 C/T, AT1 1167 A, AGR 395 T; AGT 620 C/T, AT1 1271 A/C, AT1 1167 A, AGR 395 T; AGT 620 C/T, AT1 1271 A/C, AT1 1167 A/G AGR 395 T; AGT 620 C, AT1 1271 A, AT1 1167 A, AGR 395 A/T; AGT 620 C, AT1 678 A, AT1 1167 A, AGR 395 A/T; AGT 620 C/T, AT1 678 C/T; AT1 1167 A, AGR 395 T; ACE 2193 A, AGR 1218 A, AGT 803 A; ACE 2193 A, AGT 620 C/T; ACE 2328 G, AGT 620 C/T; ACE 3387 T, AGR 1204 A/C; ACE 2193 A, ACE 2328 G, AGR 1204 C; and ACE 2193 A/G, AGR 1072 G/A, AT1 1167 A/C.

38. A method for predicting the response of a human individual having a cardiovascular syndrome to a treatment regimen of said cardiovascular syndrome, which method comprises comparing a polymorphic pattern established in a combination of polymorphic positions within one or more of the ACE, AGT, or AT1 genes of said individual with a polymorphic pattern of the same polymorphic positions of humans who heave a known response to the treatment regimen.

39. A method as defined in claim 23, wherein said polymorphic position is selected from the group consisting of positions in the ACE regulatory region (SEQ ID NO: 129) numbered 5106, 5349, and 5496; positions in the ACE coding region (SEQ ID NO: 130) numbered 375, 582, 731, 1060, 1215, 2193, 2328, 2741, 3132, 3387, 3503, and 3906; positions in the AGT regulatory region (SEQ ID NO: 123) numbered 395, 412, 432, 449, 692, 839, 1007, 1072, 1204, and 1218; positions in the AGT coding region (SEQ ID NO: 124) numbered 273, 620, 803, 912, 997, 1116, and 1174; position 49 in the AGT gene (SEQ ID NO: 126); position 1451 in the ACE gene (SEQ ID NO: 128); positions in the AT1 regulatory region (SEQ ID NO: 131) numbered 1427, 1756, 1853, 2046, 2354, 2355, and 2415; positions in the AT1 coding region (SEQ ID NO: 132-133, which are contiguous) numbered 449, 678, 1167, and 1271; and combinations of any of the foregoing.

40. A method as defined in claim 39, wherein said polymorphic patterns are selected from the group consisting of: ACE 5349 A/T, AGR 1218 A; ACE 5496 C, AGR 1204 A/C; ACE 5496 C/T, AGR 1218 A, AGT 620 C/T; ACE 2193 A, AGR 1204 C, ACE 2328 G; ACE 2193 A, AGR 1204 A/C; ACE 3387 T, AGR 1218 A; ACE 3387 T, AGT 620 C/T; AGR 1204 A/C, AT1 678 C/T; AGR 1204 A/C, AT1 1271 A/C; ACE 1215 C, AGR 1204 A/C, AGR 1204 A/C, AT1 1167 A, ACE 3906 A/G; AGR 1204 A, AGT 620 C, AT1 1271 A, AT1 1167 A, AGR 395 A/T; AGR 1204 A/C, AGT 620 C/T, AT1 1271 A/C, AT1 1167 A, AGR 395 T; AGR 1204 A/C, AGT 620 C/T, AT1 1271 A/C, AT1 1167 A/G, AGR 395 T; AGR 1204 A, AT1 678 C, AT1 1167 A, AGR 395 A/T; AGR 1204 A/C, AT1 678 C/T, AT1 1167 A, AGR 395 T; AGT 620 C/T, AT1 1271 A/C, AT1 1167 A, AGR 395 T; AGT 620 C/T, AT1 1271 A/C, AT1 1167 A/G, AGR 395 T; AGT 620 C, AT1 1271 A, AT1 1167 A, AGR 395 A/T; AGT 620 C, AT1 678 A, AT1 1167 A, AGR 395 A/T; AGT 620 C/T, AT1 678 C/T; AT1 1167 A, AGR 395 T; ACE 2193 A, AGR 1218 A, AGT 803 A; ACE 2193 A, AGT 620 C/T; ACE 2328 G, AGT 620 C/T; ACE 3387 T, AGR 1204 A/C; ACE 2193 A, ACE 2328 G, AGR 1204 C; and ACE 2193 A/G, AGR 1072 G/A, AT1 1167 A/G.

Details for Patent 6,197,505

Applicant Tradename Biologic Ingredient Dosage Form BLA Number Approval Date Patent No. Assignee Estimated Patent Expiration Status Orphan Source
Schering INTRON A interferon alfa-2b VIAL 103132 001 1986-06-04   Try a Free Trial Pyrosequencing AB (Uppsala, SE) 2017-04-04 RX search
Schering INTRON A interferon alfa-2b VIAL 103132 002 1986-06-04   Try a Free Trial Pyrosequencing AB (Uppsala, SE) 2017-04-04 RX search
Schering INTRON A interferon alfa-2b VIAL 103132 003 1986-06-04   Try a Free Trial Pyrosequencing AB (Uppsala, SE) 2017-04-04 RX search
Applicant Tradename Biologic Ingredient Dosage Form BLA Number Approval Date Patent No. Assignee Estimated Patent Expiration Status Orphan Source

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