Methods and materials for determining pain sensitivity and predicting and treating related disorders

• US 20100132058A1
• Filed: 07/25/2005
• Published: 05/27/2010
• Est. Priority Date: 07/23/2004
• Status: Abandoned Application

• Current Assignee: University of South Carolina
• Original Assignee: University of South Carolina
• Inventors: Slade, Gary, Diatchenko, Luda B., Neeley, Andrea Gail, Maixner, William
• Application Number:
  US11/632,141
• Publication Number:
  US 20100132058A1
• Time in Patent Office: Days
• US Class Current: 800/9
• CPC Class Codes: C12N 15/1137 against enzymes viral enzymes C12N15/1131; receptors C12N15/1138
• CPC Class Codes: C12N 15/1138 against receptors or cell surface proteins
• CPC Class Codes: C12N 2310/14 interfering N.A.
• CPC Class Codes: C12Q 1/6881 for tissue or cell typing, e.g. human leukocyte antigen [HLA] probes
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/106 Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers
• CPC Class Codes: C12Q 2600/158 Expression markers
• CPC Class Codes: C12Q 2600/172 Haplotypes
• CPC Class Codes: C12Y 201/01006 Catechol O-methyltransferase (2.1.1.6)
• CPC Class Codes: G16B 20/00 ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
• CPC Class Codes: G16B 20/20 Allele or variant detection, e.g. single nucleotide polymorphism [SNP] detection
• CPC Class Codes: G16B 20/40 Population genetics; Linkage disequilibrium
• CPC Class Codes: G16B 20/50 Mutagenesis
• CPC Class Codes: Y02A 90/10 Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation

Abstract

Methods of treating somatosensory disorders and modulating production of proinflammatory cytokines by administering to a subject an effective amount of a COMT modulator, ADRB2 modulator, ADRB3 modulator or combinations thereof are provided. Methods of predicting effective pharmacological therapies for a subject afflicted with a somatosensory disorder by determining a genotype of the subject with regard to a gene selected from the group consisting of COMT, ADRB2, ADRB3, and combinations thereof are further provided. Methods of determining pain responses or pain perception and predicting susceptibility of a subject to develop related disorders, such as somatosensory disorders and somatization, by determining a genotype of the subject with regard to a gene selected from the group consisting of COMT, ADRB2, ADRB3, and combinations thereof are further provided.

Claims

1. A method of treating a somatosensory disorder in a subject, comprising administering to the subject an effective amount of a COMT modulator, an ADRB2 modulator, an ADRB3 modulator, or combinations thereof.

2. The method of claim 1, wherein the somatosensory disorder is selected from the group consisting of chronic pain conditions, fibromyalgia syndrome, tension headache, migraine headache, phantom limb sensations, irritable bowel syndrome, chronic lower back pain, chronic fatigue, multiple chemical sensitivities, temporomandibular joint disorder, post-traumatic stress disorder, chronic idiopathic pelvic pain, Gulf War Syndrome, vulvar vestibulitis, osteoarthritis, rheumatoid arthritis, and angina pectoris.

3. The method of claim 1, wherein the ADRB2 modulator is an ADRB2 antagonist, the ADRB3 modulator is an ADRB3 antagonist, and the COMT modulator is a COMT activator.

4. The method of claim 3, wherein both the ADRB2 antagonist and the ADRB3 antagonist are administered to the subject.

5. The method of claim 1, further comprising determining a genotype of the subject with respect to a gene selected from the group consisting of ADRB2, ADRB3, COMT, and combinations thereof and administering to the subject the effective amount of the COMT modulator, the ADRB2 modulator, the ADRB3 modulator, or combinations thereof based on determined genotype of the subject.

6. The method of claim 5, wherein determining the genotype of the subject comprises:

(i) identifying at least one haplotype of ADRB2, ADRB3, COMT or combinations thereof;

(ii) identifying at least one polymorphism unique to at least one haplotype of ADRB2, ADRB3, COMT, or combinations thereof;

(iii) identifying at least one polymorphism exhibiting high linkage disequilibrium to at least one polymorphism unique to the at least one ADRB2 haplotype, ADRB3 haplotype, COMT haplotype, or combinations thereof;

or

(iv) identifying at least one polymorphism exhibiting high linkage disequilibrium to at least one ADRB2 haplotype, ADRB3 haplotype, COMT haplotype, or combinations thereof.

7. The method of claim 5, wherein the ADRB2 genotype is selected from the group consisting of Haplotype 1, Haplotype 2, Haplotype 3, and Uncommon;

the ADRB3 genotype is selected from the group consisting of Haplotype 1, Haplotype 2, Haplotype 3, and Uncommon; and

the COMT genotype is selected from the group consisting of low pain sensitive haplotype (LPS), average pain sensitive haplotype (APS), and high pain sensitive haplotype (HPS).

8. The method of claim 7, wherein the determined genotype of the subject with respect to ADRB2 is selected from the group consisting of two copies of Haplotype 2, two copies of Haplotype 3, one copy of both Haplotype 2 and Haplotype 3, and at least one copy of Uncommon and the somatosensory disorder is treated by administering the ADRB2 modulator, the COMT modulator, or combinations thereof to the subject.

9. The method of claim 7, wherein the determined genotype of the subject with respect to ADRB3 is selected from the group consisting of two copies of Haplotype 1, and at least one copy of Uncommon and the somatosensory disorder is treated by administering the ADRB3 modulator, the COMT modulator, or combinations thereof to the subject.

10. The method of claim 7, wherein the determined genotype of the subject with respect to COMT is selected from the group consisting of two copies of APS, two copies of HPS, and one copy of both APS and HPS and the somatosensory disorder is treated by administering the COMT modulator, the ADRB2 modulator, the ADRB3 modulator, or combinations thereof to the subject.

11. A method of predicting susceptibility of a subject to develop a somatosensory disorder, comprising:

(a) determining a genotype of the subject with respect to a gene selected from the group consisting of ADRB2, ADRB3, COMT, and combinations thereof; and

(b) comparing the genotype of the subject with at least one reference genotype associated with susceptibility to develop the somatosensory disorder, wherein the reference genotype is selected from the group consisting of an ADRB2 genotype, an ADRB3 genotype, a COMT genotype, and combinations thereof, whereby susceptibility of the subject to develop the somatosensory disorder is predicted.

12. The method of claim 11, wherein determining the genotype of the subject comprises:

(i) identifying at least one haplotype of ADRB2, ADRB3, COMT or combinations thereof;

(ii) identifying at least one polymorphism unique to at least one haplotype of ADRB2, ADRB3, COMT, or combinations thereof;

(iii) identifying at least one polymorphism exhibiting high linkage disequilibrium to at least one polymorphism unique to at least one ADRB2 haplotype, ADRB3 haplotype, COMT haplotype, or combinations thereof;

or

(iv) identifying at least one polymorphism exhibiting high linkage disequilibrium to at least one ADRB2 haplotype, ADRB3 haplotype, COMT haplotype, or combinations thereof.

13. The method of claim 11, wherein the ADRB2 genotype of the reference genotype is selected from the group consisting of Haplotype 1, Haplotype 2, Haplotype 3, and Uncommon;

the ADRB3 genotype of the reference genotype is selected from the group consisting of Haplotype 1, Haplotype 2, Haplotype 3, and Uncommon; and

the COMT genotype of the reference genotype is selected from the group consisting of low pain sensitive haplotype (LPS), average pain sensitive haplotype (APS), and high pain sensitive haplotype (HPS).

14. The method of claim 13, wherein the determined genotype of the subject with respect to ADRB2 is selected from the group consisting of two copies of Haplotype 1, two copies of Haplotype 2, two copies of Haplotype 3, one copy of both Haplotype 2 and Haplotype 3, and at least one copy of Uncommon and the subject is predicted to be susceptible to develop the somatosensory disorder.

15. The method of claim 13, wherein the determined genotype of the subject with respect to ADRB3 is selected from the group consisting of two copies of Haplotype 1, and at least one copy of Uncommon and the subject is predicted to be susceptible to develop the somatosensory disorder.

16. The method of claim 13, wherein the determined genotype of the subject with respect to COMT is selected from the group consisting of two copies of APS, two copies of HPS, and one copy of both APS and HPS and the subject is predicted to be susceptible to develop the somatosensory disorder.

17. The method of claim 17, wherein the somatosensory disorder is selected from the group consisting of chronic pain conditions, fibromyalgia syndrome, tension headache, migraine headache, phantom limb sensations, irritable bowel syndrome, chronic lower back pain, chronic fatigue, multiple chemical sensitivities, temporomandibular joint disorder, post-traumatic stress disorder, chronic idiopathic pelvic pain, Gulf War Syndrome, vulvar vestibulitis, osteoarthritis, rheumatoid arthritis, and angina pectoris.

18. A method of predicting a pain response in a subject, comprising:

(a) determining a genotype of the subject with respect to a gene selected from the group consisting of ADRB2, ADRB3, COMT, and combinations thereof; and

(b) comparing the genotype of the subject with at least one reference genotype associated with pain response variability, wherein the reference genotype is selected from the group consisting of an ADRB2 genotype, an ADRB3 genotype, a COMT genotype, and combinations thereof, whereby pain response in the subject is predicted.

19. The method of claim 18, wherein determining the genotype of the subject comprises:

(i) identifying at least one haplotype of ADRB2, ADRB3, COMT or combinations thereof;

(ii) identifying at least one polymorphism unique to at least one haplotype of ADRB2, ADRB3, COMT, or combinations thereof;

(iii) identifying at least one polymorphism exhibiting high linkage disequilibrium to at least one polymorphism unique to at least one ADRB2 haplotype, ADRB3 haplotype, COMT haplotype, or combinations thereof;

or

(iv) identifying at least one polymorphism exhibiting high linkage disequilibrium to at least one ADRB2 haplotype, ADRB3 haplotype, COMT haplotype, or combinations thereof.

20. The method of claim 18, wherein the ADRB2 genotype of the reference genotype is selected from the group consisting of Haplotype 1, Haplotype 2, and Haplotype 3;

the ADRB3 genotype of the reference genotype is selected from the group consisting of Haplotype 1, Haplotype 2, and Haplotype 3; and

the COMT genotype of the reference genotype is selected from the group consisting of low pain sensitive haplotype (LPS), average pain sensitive haplotype (APS), and high pain sensitive haplotype (HPS).

21. The method of claim 20, wherein the determined genotype of the subject with respect to ADRB2 is only one copy of Haplotype 1, and the subject is predicted to have a decreased sensitivity to pain as compared to a population norm.

22. The method of claim 20, wherein the determined genotype of the subject with respect to ADRB3 is selected from the group consisting of at least one copy of Haplotype 2 and at least one copy of Haplotype 3 and the subject is predicted to have decreased sensitivity to pain as compared to a population norm.

23. The method of claim 20, wherein the determined genotype of the subject with respect to COMT is selected from the group consisting of two copies of APS, two copies of HPS, and one copy of both APS and HPS and the subject is predicted to have an increased sensitivity to pain as compared to a population norm.

24. A method of predicting somatization in a subject, comprising:

(a) determining a genotype of the subject with respect to a gene selected from the group consisting of ADRB2, ADRB3, COMT, and combinations thereof; and

(b) comparing the genotype of the subject with at least one reference genotype associated with somatization, wherein the reference genotype is selected from the group consisting of an ADRB2 genotype, an ADRB3 genotype, a COMT genotype, and combinations thereof.

25. The method of claim 24, wherein determining the genotype of the subject comprises:

(i) identifying at least one haplotype of ADRB2, ADRB3, COMT or combinations thereof;

(ii) identifying at least one polymorphism unique to at least one haplotype of ADRB2, ADRB3, COMT, or combinations thereof;

(iii) identifying at least one polymorphism exhibiting high linkage disequilibrium to at least one polymorphism unique to at least one ADRB2 haplotype, ADRB3 haplotype, COMT haplotype, or combinations thereof;

or

(iv) identifying at least one polymorphism exhibiting high linkage disequilibrium to at least one ADRB2 haplotype, ADRB3 haplotype, COMT haplotype, or combinations thereof.

26. The method of claim 24, wherein the ADRB2 genotype of the reference genotype is selected from the group consisting of Haplotype 1, Haplotype 2, Haplotype 3;

the ADRB3 genotype of the reference genotype is selected from the group consisting of Haplotype 1, Haplotype 2, Haplotype 3; and

the COMT genotype of the reference genotype is selected from the group consisting of low pain sensitive haplotype (LPS), average pain sensitive haplotype (APS), and high pain sensitive haplotype (HPS).

27. The method of claim 26, wherein the determined genotype of the subject with respect to ADRB2 is two copies of Haplotype 2, and the subject is predicted to have increased somatization as compared to a population norm.

28. The method of claim 26, wherein the determined genotype of the subject with respect to ADRB3 is at least one copy of Haplotype 3, and the subject is predicted to have a decreased somatization as compared to a population norm.

29. The method of claim 26, wherein the determined genotype of the subject with respect to COMT is selected from the group consisting of two copies of APS, two copies of HPS, and one copy of both APS and HPS and the subject is predicted to have an increased somatization as compared to a population norm.

30. A method of selecting a therapy for a subject having a somatosensory disorder, comprising:

(a) determining a genotype of the subject with respect to a gene selected from the group consisting of ADRB2, ADRB3, COMT, and combinations thereof; and

(b) selecting a therapy based on the determined genotype of the subject.

31. The method of claim 30, wherein determining the genotype of the subject comprises:

(i) identifying at least one haplotype of ADRB2, ADRB3, COMT or combinations thereof;

(ii) identifying at least one polymorphism unique to at least one haplotype of ADRB2, ADRB3, COMT, or combinations thereof;

(iii) identifying at least one polymorphism exhibiting high linkage disequilibrium to at least one polymorphism unique to at least one ADRB2 haplotype, ADRB3 haplotype, COMT haplotype, or combinations thereof;

or

(iv) identifying at least one polymorphism exhibiting high linkage disequilibrium to at least one ADRB2 haplotype, ADRB3 haplotype, COMT haplotype, or combinations thereof.

32. The method of claim 30, wherein the ADRB2 genotype of the reference genotype is selected from the group consisting of Haplotype 1, Haplotype 2, Haplotype 3, and Uncommon;

the ADRB3 genotype of the reference genotype is selected from the group consisting of Haplotype 1, Haplotype 2, Haplotype 3, and Uncommon; and

the COMT genotype of the reference genotype is selected from the group consisting of low pain sensitive haplotype (LPS), average pain sensitive haplotype (APS), and high pain sensitive haplotype (HPS).

33. The method of claim 32, wherein the therapy is selected from the group consisting of a pharmacological therapy, a behavioral therapy, a psychotherapy, a surgical therapy, and combinations thereof.

34. The method of claim 33, wherein the therapy is a pharmacological therapy comprising administering to the subject an effective amount of an ADRB2 modulator, an ADRB3 modulator, a COMT modulator, or combinations thereof.

35. The method of claim 34, wherein the determined genotype of the subject with respect to ADRB2 is selected from the group consisting of two copies of Haplotype 2, two copies of Haplotype 3, one copy of both Haplotype 2 and Haplotype 3, and an effective amount of an ADRB2 modulator, a COMT modulator, or combinations thereof is selected as a therapy.

36. The method of claim 34, wherein the determined genotype of the subject with respect to ADRB3 is two copies of Haplotype 1, and an effective amount of an ADRB2 modulator, a COMT modulator, or combinations thereof is selected as a therapy.

37. The method of claim 34, wherein the determined genotype of the subject with respect to COMT is selected from the group consisting of two copies of APS, two copies of HPS, and one copy of both APS and HPS and an effective amount of an ADRB2 modulator, an ADRB3 modulator, a COMT modulator, or combinations thereof is selected as a therapy.

38. The method of claim 34, wherein the ADRB2 modulator is an ADRB2 antagonist, the ADRB3 modulator is an ADRB3 antagonist, and the COMT modulator is a COMT activator.

39. The method of claim 38, wherein both the ADRB2 antagonist and the ADRB3 antagonist are selected.

40. The method of claim 30, wherein the somatosensory disorder is selected from the group consisting of chronic pain conditions, fibromyalgia syndrome, tension headache, migraine headache, phantom limb sensations, irritable bowel syndrome, chronic lower back pain, chronic fatigue, multiple chemical sensitivities, temporomandibular joint disorder, post-traumatic stress disorder, chronic idiopathic pelvic pain, Gulf War Syndrome, vulvar vestibulitis, osteoarthritis, rheumatoid arthritis, and angina pectoris.

41. A method of classifying a somatosensory disorder afflicting a subject, comprising:

(a) determining a genotype of the subject with respect to a gene selected from the group consisting of ADRB2, ADRB3, COMT, and combinations thereof; and

(b) classifying the somatosensory disorder into a genetic subclass somatosensory disorder based on the determined genotype of the subject.

42. The method of claim 41, wherein determining the genotype of the subject comprises:

(i) identifying at least one haplotype of ADRB2, ADRB3, COMT or combinations thereof;

(ii) identifying at least one polymorphism unique to at least one haplotype of ADRB2, ADRB3, COMT, or combinations thereof;

(iii) identifying at least one polymorphism exhibiting high linkage disequilibrium to at least one polymorphism unique to at least one ADRB2 haplotype, ADRB3 haplotype, COMT haplotype, or combinations thereof;

or

(iv) identifying at least one polymorphism exhibiting high linkage disequilibrium to at least one ADRB2 haplotype, ADRB3 haplotype, COMT haplotype, or combinations thereof.

43. The method of claim 41, wherein the ADRB2 genotype is selected from the group consisting of Haplotype 1, Haplotype 2, Haplotype 3, and Uncommon;

the ADRB3 genotype is selected from the group consisting of Haplotype 1, Haplotype 2, Haplotype 3, and Uncommon; and

the COMT genotype is selected from the group consisting of low pain sensitive haplotype (LPS), average pain sensitive haplotype (APS), and high pain sensitive haplotype (HPS).

44. The method of claim 41, wherein classifying the somatosensory disorder into the genetic subclass somatosensory disorder is utilized to select an effective therapy for use in treating the genetic subclass somatosensory disorder.

45. A method of modulating production of proinflammatory cytokines in a subject, comprising administering to the subject an effective amount of a COMT modulator, an ADRB2 modulator, an ADRB3 modulator, or combinations thereof.

46. The method of claim 45, wherein the proinflammatory cytokines are selected from the group consisting of IL-6, IL-1α

, IL-1β

, TNF-α

, and combinations thereof.

47. The method of claim 45, wherein modulating production of proinflammatory cytokines comprises inhibiting production of proinflammatory cytokines.

48. The method of claim 45, wherein the ADRB2 modulator is an ADRB2 antagonist, the ADRB3 modulator is an ADRB3 antagonist, and the COMT modulator is a COMT activator.

49. The method of claim 48, wherein both the ADRB2 antagonist and the ADRB3 antagonist are administered to the subject.

50. The method of claim 45, further comprising determining a genotype of the subject with respect to a gene selected from the group consisting of ADRB2, ADRB3, COMT, and combinations thereof and administering to the subject the effective amount of the COMT modulator, the ADRB2 modulator, the ADRB3 modulator, or combinations thereof based on the determined genotype of the subject.

51. The method of claim 50, wherein determining the genotype of the subject comprises:

(i) identifying at least one haplotype of ADRB2, ADRB3, COMT or combinations thereof;

(ii) identifying at least one polymorphism unique to at least one haplotype of ADRB2, ADRB3, COMT, or combinations thereof;

(iii) identifying at least one polymorphism exhibiting high linkage disequilibrium to at least one polymorphism unique to at least one ADRB2 haplotype, ADRB3 haplotype, COMT haplotype, or combinations thereof;

or

(iv) identifying at least one polymorphism exhibiting high linkage disequilibrium to at least one ADRB2 haplotype, ADRB3 haplotype, COMT haplotype, or combinations thereof.

52. The method of claim 50, wherein the ADRB2 genotype of the reference genotype is selected from the group consisting of Haplotype 1, Haplotype 2, Haplotype 3, and Uncommon;

the ADRB3 genotype of the reference genotype is selected from the group consisting of Haplotype 1, Haplotype 2, Haplotype 3, and Uncommon; and

the COMT genotype of the reference genotype is selected from the group consisting of low pain sensitive haplotype (LPS), average pain sensitive haplotype (APS), and high pain sensitive haplotype (HPS).

53. The method of claim 52, wherein the determined genotype of the subject with respect to ADRB2 is selected from the group consisting of two copies of Haplotype 2, two copies of Haplotype 3, one copy of both Haplotype 2 and Haplotype 3, and the production of proinflammatory cytokines in the subject is modulated by administering the ADRB2 modulator, the COMT modulator, or combinations thereof to the subject.

54. The method of claim 52, wherein the determined genotype of the subject with respect to ADRB3 is selected from the group consisting of two copies of Haplotype 1, and the production of proinflammatory cytokines in the subject is modulated by administering the ADRB3 modulator, the COMT modulator, or combinations thereof to the subject.

55. The method of claim 52, wherein the determined genotype of the subject with respect to COMT is selected from the group consisting of two copies of APS, two copies of HPS, and one copy of both APS and HPS and the production of proinflammatory cytokines in the subject is modulated by administering the COMT modulator, the ADRB2 modulator, the ADRB3 modulator, or combinations thereof to the subject.

56. A method of producing a non-human animal model of a human somatosensory disorder, comprising modulating COMT activity, ADRB2 activity, ADRB3 activity, or combinations thereof in the non-human animal model to produce the non-human animal model of the human somatosensory disorder.

57. The method of claim 56, wherein the non-human animal model is a rodent.

58. The method of claim 56, wherein modulating COMT activity in the non-human animal model comprises inhibiting COMT activity in the non-human animal model.

59. The method of claim 58, wherein inhibiting COMT activity comprises administering a COMT inhibitor to the non-human animal model.

60. The method of claim 56, wherein the non-human animal model exhibits an increase in production of proinflammatory cytokines.

61. The method of claim 60, wherein the proinflammatory cytokines are selected from the group consisting of IL-6, IL-1β

, TNF-α

, IL-1α and

combinations thereof.

62. The method of claim 56, wherein the somatosensory disorder is selected from the group consisting of chronic pain disorders, fibromyalgia syndrome, tension headache, migraine headache, phantom limb sensations, irritable bowel syndrome, chronic lower back pain, chronic fatigue, multiple chemical sensitivities, temporomandibular joint disorder, post-traumatic stress disorder, chronic idiopathic pelvic pain, Gulf War Syndrome, vulvar vestibulitis, osteoarthritis, rheumatoid arthritis, and angina pectoris.

63. A non-human animal possessing modulated COMT activity, modulated ADRB2 activity, modulated ADRB3, or combinations thereof, wherein the non-human animal exhibits characteristics of a somatosensory disorder.

64. The non-human animal of claim 63, wherein the non-human animal is a genetically modified animal.

65. The method of claim 64, wherein the non-human animal is a transgenic non-human animal that overexpresses ADRB2, ADRB3, or both ADRB2 and ADRB3.

66. The non-human animal of claim 64, wherein the non-human animal is a COMT knockout or knockdown animal.

67. A method of predicting COMT activity, ADRB2 activity, ADRB3 activity or combinations thereof in a subject, comprising:

(a) determining a genotype of the subject with respect to a gene selected from the group consisting of ADRB2, ADRB3, COMT, and combinations thereof; and

(b) comparing the genotype of the subject with at least one reference genotype associated with activity of ADRB2, ADRB3, COMT, and combinations thereof, wherein the reference genotype is selected from the group consisting of an ADRB2 genotype, an ADRB3 genotype, a COMT genotype, and combinations thereof, whereby activity of COMT activity, ADRB2 activity, ADRB3 activity or combinations thereof is predicted.

68. The method of claim 68, wherein determining the genotype of the subject comprises:

(i) identifying at least one haplotype of COMT, ADRB2, ADRB3, or combinations thereof;

(ii) identifying at least one polymorphism unique to the at least one haplotype of COMT, ADRB2, ADRB3, or combinations thereof;

(iii) identifying at least one polymorphism exhibiting high linkage disequilibrium to at least one polymorphism unique to the at least one COMT haplotype, ADRB2 haplotype, ADRB3 haplotype, or combinations thereof;

or

(iv) identifying at least one polymorphism exhibiting high linkage disequilibrium to at least one COMT haplotype, ADRB2 haplotype, ADRB3 haplotype, or combinations thereof.

69. The method of claim 68, wherein the COMT genotype of the reference genotype is selected from the group consisting of low pain sensitive haplotype (LPS), average pain sensitive haplotype (APS), and high pain sensitive haplotype (HPS);

the ADRB2 genotype of the reference genotype is selected from the group consisting of Haplotype 1, Haplotype 2, Haplotype 3, and Uncommon; and

the ADRB3 genotype of the reference genotype is selected from the group consisting of Haplotype 1, Haplotype 2, Haplotype 3, and Uncommon.

70. The method of claim 69, wherein the determined genotype of the subject with respect to COMT is selected from the group consisting of two copies of APS, two copies of HPS, and one copy of both APS and HPS and the subject is predicted to have low COMT activity.

71. The method of claim 69, wherein the determined genotype of the subject with respect to ADRB2 is selected from the group consisting of two copies of Haplotype 1 and the subject is predicted to have low ADRB2 activity.

72. The method of claim 69, wherein the determined genotype of the subject with respect to ADRB2 is selected from the group consisting of two copies of Haplotype 2, two copies of Haplotype 3, and one copy of both Haplotype 2 and Haplotype 3, and the subject is predicted to have high ADRB2 activity.

73. The method of claim 69, wherein the determined genotype of the subject with respect to ADRB2 is selected from the group consisting of two copies of Haplotype 3, and the subject is predicted to have high ADRB2 activity in the resting stage and low ADRB2 activity in response to an agonist

74. The method of claim 73, wherein the agonist is epinephrine.

75. The method of claim 69, wherein the determined genotype of the subject with respect to ADRB3 is selected from the group consisting of at least one copy of Haplotype 2, at least one copy of Haplotype 3 and the subject is predicted to have low ADRB3 activity.

76. The method of claim 71, wherein an effective dosage of a therapeutic compound metabolized by COMT is determined for the subject on the basis of the determined COMT genotype.

77. The method in claim 76 where the therapeutic compound is selected from the group consisting of estrogen, tolcapone, methylphenidate, L-DOPA, antidepressants, clonidine, mirtazapine, and antipsychotics.

78. The method of claim 71, wherein an adverse biological side effect to the subject by a compound metabolized by COMT can be predicted on the basis of the determined COMT genotype.