Gene sequence variations with utility in determining the treatment of disease, in genes relating to drug processing

• US 20010034023A1
• Filed: 12/07/2000
• Published: 10/25/2001
• Est. Priority Date: 04/26/1999
• Status: Abandoned Application

• Current Assignee: Variagenics, Inc. (Arca Biopharma, Inc.)
• Original Assignee: Variagenics, Inc. (Arca Biopharma, Inc.)
• Inventors: Stanton, Vincent P. Jr., Zillmann, Martin
• Application Number:
  US09/733,000
• Publication Number:
  US 20010034023A1
• Time in Patent Office: Days
• US Class Current: 435/6
• CPC Class Codes: C12Q 1/6869 Methods for sequencing
• 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 2600/142 Toxicological screening, e.g. expression profiles which identify toxicity
• 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: 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: Y02A 90/10 Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation

Abstract

Methods for identifying and utilizing variances in genes relating to efficacy and safety of medical therapy and other aspects of medical therapy are described, including methods for selecting an effective treatment.

Claims

1. A method for selecting a treatment for a patient suffering from a disease disorder or condition, comprising

determining whether cells of said patient contain at least one variance in a gene from Tables 1, 3 and 4, wherein the presence or the absence of said variance in said gene is indicative of the effectiveness or safety of said treatment for said disease, disorder, or condition.

2. The method of

claim 1

, wherein said disease, disorder, or condition is selected from the group consisting of drug-induced diseases, disorders, or toxicities consisting of blood dyscrasias, cutaneous toxicities, systemic toxicities, central nervous system toxicities, hepatic toxicities, cardiovascular toxicities, pulmonary toxicities, and renal toxicities.

3. The method of

claim 1

, wherein the presence of said at least one variance is indicative that said treatment will be effective for said patient.

4. The method of

claim 1

, wherein the presence of said variance is indicative that said treatment will be ineffective or contra-indicated for said patient.

5. The method of

claim 1

, wherein said at least one variance comprises a plurality of variances.

6. The method of

claim 5

, wherein said plurality of variances comprise a haplotype or haplotypes.

7. The method of

claim 1

, wherein said selecting a treatment further comprises identifying a compound differentially active in a patient bearing a form of said gene containing said at least one variance.

8. The method of

claim 7

, wherein said compound is a compound listed in a Table herein or that belongs to the same chemical class as a compound listed in said Table.

9. The method of

claim 1

, wherein said selecting a treatment further comprises

eliminating or excluding a treatment, wherein said presence or absence of said at least one variance is indicative that said treatment will be ineffective or contra-indicated.

10. The method of

claim 1

, wherein said treatment comprises a first treatment and a second treatment, said method comprising the steps of:

identifying a said first treatment effective to treat said disease, disorder, or condition; and

identifying a said second treatment which reduces a deleterious effect or promotes efficacy of said first treatment.

11. The method of

claim 1

, wherein said selecting a treatment further comprises selecting a method of administration of a compound effective to treat said disease, disorder or condition, wherein said presence or absence of said at least one variance is indicative of the appropriate method of administration for said compound.

12. The method of

claim 11

, wherein said selecting a method of administration comprises selecting a suitable dosage level or frequency of administration of a compound.

13. The method of

claim 1

, further comprising determining the level of expression of said gene or the level of activity of a protein containing a polypeptide expressed from said gene,

wherein the combination of the determination of the presence or absence of said at least one variance and the determination of the level of activity or the level of expression provides a further indication of the effectiveness of said treatment.

14. The method of

claim 1

, further comprising determining the at least one of sex, age, racial origin, ethnic origin, and geopraphic origin of said patient,

wherein the combination of the determination of the presence or absence of said at least one variance and the determination of the sex, age, racial origin, ethnic origin, and geopraphic origin of said patient provides a further indication of the effectiveness of said treatment.

15. The method of

claim 1

, wherein said disease, disorder, or condition is selected from the group consisting of drug-induced diseases, disorders, or toxicities consisting of blood dyscrasias, cutaneous toxicities, systemic toxicities, central nervous system toxicities, hepatic toxicities, cardiovascular toxicities, pulmonary toxicities, and renal toxicities.

16. The method of

claim 1

, wherein the detection of the presence or absence of said at least one variance comprises amplifying a segment of nucleic acid including at least one of said variances.

17. The method of

claim 16

, wherein said segment of nucleic acid is 500 nucleotides or less in length.

18. The method of

claim 16

, wherein said segment of nucleic acid is 100 nucleotides or less in length.

19. The method of

claim 16

, wherein said segment of nucleic acid is 45 nucleotides or less in length.

20. The method of

claim 16

, wherein said segment includes a plurality of variances.

21. The method of

claim 17

, wherein amplification preferentially occurs from one of the two strands of a chromosome.

22. The method of

claim 17

, wherein said segment of nucleic acid is at least 500 nucleotides in length.

23. The method of

claim 1

, wherein the detection of the presence or absence of said at least one variance comprises contacting nucleic acid comprising a variance site with at least one nucleic acid probe, wherein said at least one probe preferentially hybridizes with a nucleic acid sequence including said variance site and containing a complementary base at said variance site under selective hybridization conditions.

24. The method of

claim 1

, wherein the detection of the presence or absence of said at least one variance comprises sequencing at least one nucleic acid sequence.

25. The method of

claim 1

, wherein the detection of the presence or absence of said at least one variance comprises mass spectrometric determination of at least one nucleic acid sequence.

26. The method of

claim 1

, wherein the detection of the presence or absence of said at least one variance comprises determining the haplotype of a plurality of variances in a gene.

27. A method for selecting a method of treatment, comprising

comparing at least one variance in at least one gene from Tables 1, 3 and 4 in a patient suffering from a disease or condition with a list of variances in said at least one gene indicative of the effectiveness of at least one method of treatment.

28. The method of

claim 27

, wherein said list comprises at least 5 variances.

29. The method of

claim 27

, wherein said at least one variance comprises a plurality of variances.

30. The method of

claim 27

, wherein said list of variances comprises a plurality of variances.

31. The method of

claim 27

, wherein at least one said method of treatment comprises the administration of a compound effective against said disease or condition to a patient.

32. The method of

claim 31

, wherein said compound is selected from the group consisting of agonists, antagonists, blockers, partial agonists, partial antagonists, inhibitors, activators, modulators, negative antagonists, inverse agonists, mimetics, or factors that elicit pharmacological activity on a gene product of at least one gene or gene pathway listed in Table 1.

33. The method of

claim 27

, wherein the presence or absence of at least one variance or haplotype in said gene is indicative that said treatment will be effective in said patient.

34. The method of

claim 27

, wherein the presence or absence of at least one variance in said gene is indicative that said treatment will be ineffective or contra-indicated.

35. The method of

claim 27

, wherein said treatment is a first treatment and the presence or absence of at least one variance in said gene is indicative that a second treatment will be beneficial to reduce a deleterious effect or promotes efficacy of said first treatment.

36. The method of

claim 27

, wherein said at least one method of treatment is a plurality of methods of treatment.

37. The method of

claim 36

, wherein said selecting comprises determining whether any of said plurality of methods of treatment will be more effective than at least one other of said plurality of methods of treatment.

38. The method of

claim 27

, wherein said disease is from the group consisting of drug-induced diseases, disorders, or toxicities consisting of blood dyscrasias, cutaneous toxicities, systemic toxicities, central nervous system toxicities, hepatic toxicities, cardiovascular toxicities, pulmonary toxicities, and renal toxicities.

39. A method for selecting a method of administration of to a patient suffering from a condition or disease for a compound or compounds effective to treat said condition or disease, comprising

determining whether at least one variance in a gene from Tables 1, 3 and 4 is present or absent in cells of said patient, wherein said presence or absence of said at least one variance is indicative of an appropriate method of administration for said compound.

40. The method of

claim 39

, wherein said at least one variance is a plurality of variances.

41. The method of

claim 39

, wherein said selecting a method of administration comprises selecting a dosage level or frequency or frequency of administration of said compound.

42. The method of

claim 39

, wherein said compound is selected from the group consisting of agonists, antagonists, blockers, partial agonists, partial antagonists, inhibitors, activators, modulators, negative antagonists, inverse agonists, mimetics, or factors that elicit pharmacological activity on a gene product of at least one gene or gene pathway listed in Table 1.

43. The method of

claim 39

, wherein said disease is from the group consisting of drug-induced diseases, disorders, or toxicities consisting of blood dyscrasias, cutaneous toxicities, systemic toxicities, central nervous system toxicities, hepatic toxicities, cardiovascular toxicities, pulmonary toxicities, and renal toxicities.

44. A method for selecting a patient for administration of a method of treatment, comprising

comparing the presence or absence of at least one variance or haplotype in a gene from Tables 1, 3 and 4 in cells of a patient suffering from a disease or condition with a list of variances in said at least one gene, wherein the presence or absence of said at least one variance or haplotype in said cells is indicative that said treatment will be effective, more effective, less effective, ineffective, or contra-indicated in said patient;

and

determining whether said patient will receive said method of treatment based on the presence or absence of said at least one variance in said cells.

45. The method of

claim 44

, wherein said list comprises at least 5 variances.

46. The method of

claim 44

, wherein said method of treatment comprises administration of a compound effective against said disease or condition.

47. The method of

claim 46

, wherein said compound is selected from the group consisting of agonists, antagonists, blockers, partial agonists, partial antagonists, inhibitors, activators, modulators, negative antagonists, inverse agonists, mimetics, or factors that elicit pharmacological activity on a gene product of at least one gene or gene pathway listed in Table 1.

48. A method for identifying the presence or absence of at least one form of a gene from Tables 1, 3 and 4 in cells of an individual, comprising:

determining the presence or absence of at least one variance in said gene in said cells.

49. The method of

claim 48

, wherein said said at least one variance is a plurality of variances.

50. The method of

claim 49

, wherein said plurality of variances comprises a haplotype.

51. The method of

claim 50

, wherein said individual suffers from a disease or condition.

52. The method of

claim 50

, wherein the presence or absence of said at least one variance is indicative of the effectiveness of a therapeutic treatment in a patient having cells containing said at least one variance.

53. The method of

claim 50

, wherein said determining comprises amplifying a segment of nucleic acid including a site of at least one variance.

54. The method of

claim 50

, wherein said determining comprises contacting a nucleic acid sequence containing a variance site corresponding to a said variance with a probe which specifically binds under selective binding conditions to a nucleic acid sequence comprising at least one said variance.

55. The method of

claim 50

, wherein the detection of the presence or absence of said at least one variance comprises sequencing at least one nucleic acid sequence.

56. The method of

claim 50

, wherein the detection of the presence or absence of said at least one variance comprises mass spectrometric determination of at least one nucleic acid sequence.

57. The method of

claim 50

, wherein the detection of the presence or absence of said at least one variance comprises determining the haplotype of a plurality of variances in a gene.

58. A pharmaceutical composition comprising

a compound which has a differential effect in patients having at least one copy of a particular form of an identified gene from Tables 1, 3 and 4;

and

a pharmaceutically acceptable carrier or excipient or diluent,

wherein said composition is preferentially effective to treat a patient with cells comprising a form of said gene comprising at least one variance.

59. The method of

claim 58

, wherein said composition is adapted to be preferentially effective based on the unit dosage, presence of additional active components, complexing of said compound with stabilizing components, or inclusion of components enhancing delivery or slowing excretion of said compound.

60. The composition of

claim 58

, wherein said compound is deleterious to patients having said at least one copy or in patients not having said at least one copy, but not in both.

61. The composition of

claim 58

, wherein said patient suffers from a disease or condition selected from the group consisting of drug-induced diseases, disorders, or toxicities consisting of blood dyscrasias, cutaneous toxicities, systemic toxicities, central nervous system toxicities, hepatic toxicities, cardiovascular toxicities, pulmonary toxicities, and renal toxicities.

62. The pharmaceutical composition of

claim 58

, wherein said composition is subject to a regulatory restriction or recommendation for use of a diagnostic test determining the presence or absence of at least one variance or haplotype in said gene.

63. The pharmaceutical composition of

claim 58

, wherein said pharmaceutical composition is subject to a regulatory limitation or recommendation restricting or recommending restriction of the use of said pharmaceutical composition to patients having at least one copy of a form of a gene comprising at least one variance.

64. The pharmaceutical composition of

claim 58

, wherein said pharmaceutical composition is subject to a regulatory limitation or recommendation indicating said pharmaceutical composition is not to be used in patients having at least one copy of a form of a gene comprising at least one variance.

65. The pharmaceutical composition of

claim 58

, wherein said pharmaceutical composition is packaged, and the packaging includes a label or insert restricting or recommending the restriction of the use of said pharmaceutical composition to patients having at least one copy of a form of a gene comprising at least one variance or haplotype.

66. The pharmaceutical composition of

claim 58

, wherein said pharmaceutical composition is packaged, and said packaging includes a label or insert requiring or recommending the use of a test to determine the presence or absence of at least one variance in cells of a said patient.

67. A nucleic acid probe comprising a nucleic acid sequence 7 to 200 nucleotide bases in length that specifically binds under selective binding conditions to a nucleic acid sequence comprising at least one variance in a gene from Tables 1, 3 and 4, or a sequence complementary thereto or an RNA equivalent.

68. The probe of

claim 67

, wherein said probe comprises a nucleic acid sequence 500 nucleotide bases or fewer in length.

69. The probe of

claim 67

, wherein said nucleic acid sequence is 100 or fewer nucleotide bases in length.

70. The probe of

claim 67

, wherein said nucleic acid sequence is 25 or fewer nucleotide bases in length.

71. The probe of

claim 67

, wherein said probe comprises DNA.

72. The probe of

claim 67

, wherein said probe comprises DNA and at least one nucleic acid analog.

73. The probe of

claim 67

, wherein said probe comprises peptide nucleic acid (PNA).

74. The probe of

claim 67

, further comprising a detectable label.

75. The probe of

claim 74

, wherein said detectable label is a fluorescent label.

76. A method for determining a genotype of an individual, comprising analyzing at least one nucleic acid sequence from cells of said individual using mass spectrometric analysis,

wherein said nucleic acid sequence is a portion of a gene from Tables 1, 3 and 4 or a sequence complementary thereto.

77. The method of

claim 76

, wherein said analyzing a nucleic acid sequence comprises determining the presence or absence of a variance in said gene.

78. The method of

claim 76

, wherein said analyzing a nucleic acid sequence comprises determining the nucleotide sequence of said at least one nucleic acid sequence.

79. The method of

claim 76

, wherein said at least one nucleic acid sequence is 500 nucleotides or less in length.

80. The method of

claim 76

, wherein said at least one nucleic acid sequence comprises at least one variance site in said gene.

81. An isolated, purified or enriched nucleic acid sequence of 15 to 500 nucleotides in length, comprising at least one variance site, wherein said sequence has the base sequence of a portion of an allele of a gene from Tables 1, 3 and 4.

82. The nucleic acid sequence of

claim 81

, wherein said nucleic acid sequence is 15 to 100 nucleotide bases in length.

83. The nucleic acid sequence of

claim 81

, wherein said nucleic acid sequence is 15 to 25 nucleotide bases in length.

84. A method for determining whether a compound has differential effects on cells containing at least one different form of a gene from Tables 1, 3 and 4, comprising:

contacting a first cell and a second cell with said compound, wherein said first cell and said second cell differ in the presence or absence of at least one variance in said gene; and

determining whether the responses of said first cell and said second cell to said compound differ, wherein the difference in said response is due to the presence or absence of said at least one variance.

85. The method of

claim 84

, wherein said at least one variance comprises a haplotype.

86. The method of

claim 84

, wherein at least one of said first cell and said second cell are contacted in vivo.

87. The method of

claim 85

, wherein at least one of said first cell and said second cell are contacted in vitro.

88. The method of

claim 87

, wherein at least one of said first cell and said second cell is contacted in vivo in a plurality of patients suffering from a disease or condition.

89. A method of treating a patient suffering from a condition or disease, comprising:

a) determining whether cells of said patient contain a form of a gene from Tables 1, 3 and 4 which comprises at least one variance, wherein the presence or absence of said at least one variance is indicative that a treatment will be effective in said patient; and

b) administering said treatment to said patient.

90. The method of

claim 89

, wherein said gene is listed in Table 1 or is a gene in a pathway listed in Table 1 herein.

91. The method of

claim 89

, wherein said disease or condition is selected from the group consisting of drug-induced diseases, disorders, or toxicities consisting of blood dyscrasias, cutaneous toxicities, systemic toxicities, central nervous system toxicities, hepatic toxicities, cardiovascular toxicities, pulmonary toxicities, and renal toxicities.

92. The method of

claim 89

, wherein said at least one variance is a plurality of variances.

93. The method of

claim 89

, wherein the presence of said at least one variance is indicative that said treatment will be effective in said patient.

94. The method of

claim 93

, wherein said treatment comprises the administration of a compound preferentially active for said condition or disease in a said patient having said at least one variance in said gene.

95. The method of

claim 94

, wherein said compound is selected from the group consisting of agonists, antagonists, blockers, partial agonists, partial antagonists, inhibitors, activators, modulators, negative antagonists, inverse agonists, mimetics, or factors that elicit pharmacological activity on a gene product of at least one gene or gene pathway listed in Table 1.

96. The method of

claim 89

, wherein the presence of said at least one variance in said gene is indicative of an appropriate dosage or frequency of administration of a compound in said treatment.

97. A method of treating a patient suffering from a disease or condition, comprising:

a) comparing the presence or absence of at least one variance in a gene from Tables 1, 3 and 4 in cells of a patient suffering from said disease or condition with a list of variances in said gene indicative of the effectiveness of at least one method of treatment;

b) selecting a method of treatment from said at least one method of treatment, wherein the presence or absence of at least one of said at least one variance is indicative that said method of treatment will be effective in said patient; and

c) administering said method of treatment to said patient.

98. The method of

claim 97

, wherein said at least one gene comprises a gene listed in Table 1 or comprises a gene in a pathway listed in Table 1 herein.

99. The method of

claim 97

, wherein said condition or disease is a condition or disease listed in the Detailed Description, Examples, or Tables herein.

100. The method of

claim 97

, further comprising determining the presence or absence of said at least one variance in cells of said patient.

101. The method of

claim 97

, wherein said at least one variance comprises a plurality of variances.

102. The method of

claim 97

, wherein said list of variances comprises a plurality of variances.

103. The method of

claim 102

, wherein said plurality of variances comprises a haplotype or haplotypes.

104. The method of

claim 97

, wherein said method of treatment comprises the administration of a compound effective against said disease or condition.

105. The method of

claim 97

, wherein said treatment is a first treatment and the presence or absence of at least one variance in said gene is indicative that a second treatment will be beneficial to reduce a deleterious effect or promotes efficacy of said first treatment.

106. The method of

claim 97

, wherein said at least one method of treatment is a plurality of methods of treatment.

107. The method of

claim 97

, wherein said disease or condition is selected from the group consisting of drug-induced diseases, disorders, or toxicities consisting of blood dyscrasias, cutaneous toxicities, systemic toxicities, central nervous system toxicities, hepatic toxicities, cardiovascular toxicities, pulmonary toxicities, and renal toxicities.

108. A method of treating a patient suffering from a disease or condition, comprising:

a) comparing the presence or absence of at least one variance in a gene from Tables 1, 3 and 4 in cells of a patient suffering from said disease or condition with a list of variances in said gene indicative of the effectiveness of at least one method of treatment;

b) eliminating or excluding a method of treatment from said at least one method of treatment, wherein the presence or absence of at least one of said at least one variance is indicative that said method of treatment will be ineffective or contra-indicated in said patient;

c) selecting an alternative method of treatment effective to treat said cardiovascular or renal disease or condition; and

d) administering said alternative method of treatment to said patient.

109. The method of

claim 108

, further comprising determining the presence or absence of said at least one variance in cells of said patient.

110. The method of

claim 108

, wherein said gene is listed in Table 1 or is a gene in a pathway listed in Table 1 herein.

111. The method of

claim 108

, wherein said disease or condition is a disease or condition listed in the Detailed Description, Examples, or Tables herein.

112. A method for producing a pharmaceutical composition, comprising:

a) identifying a compound which has differential activity against a disease or condition in patients having at least one variance in a gene from Tables 1, 3 and 4;

b) compounding said pharmaceutical composition by combining said compound and a pharmaceutically acceptable carrier or excipient or diluent in a manner adapted to be preferentially effective in patients having said at least one variance.

113. A method for producing a pharmaceutical agent, comprising:

a) identifying a compound which has differential activity against a disease or condition in patients having at least one variance in a gene from Tables 1, 3 and 4; and

b) synthesizing said compound in an amount sufficient to provide a pharmaceutical effect in a patient suffering from said cardiovascular or renal disease or condition.

114. A method for determining whether a variance in a gene from Tables 1, 3 and 4 provides variable patient response to a method of treatment for a disease or condition, comprising:

determining whether the response of a first patient or set of patients suffering from said disease or condition differs from the response of a second patient or set of patients suffering from said disease or condition; and

determining whether the presence or absence of at least one variance in said gene differs between said first patient or set of patient and said second patient or set of patients,

wherein correlation of said presence or absence of at least one variance and the response of said patient to said treatment is indicative that said at least one variance provides variable patient response.

115. The method of

claim 114

, further comprising identifying at least one variance in a said gene.

116. The method of

claim 114

, wherein a plurality of pairwise comparisons of treatment response and the presence or absence of at least one variance are performed for a plurality of patients.

117. The method of

claim 114

, wherein said determining whether the presence or absence of at least one variance in at least one gene comprises comparing the response of at least one patient homozygous for said at least one variance with at least one patient homozygous for the alternative form of said at least one variance.

118. The method of

claim 114

, wherein said determining whether the presence or absence of said at least one variance in at least one gene comprises comparing the response of at least one patient heterozygous for said at least one variance with the response of at least one patient homozygous for said at least one variance.

119. The method of

claim 114

, wherein it is previously known that patient response to said method of treatment is variable.

120. The method of

claim 114

, wherein said disease or condition is a disease or condition listed in the Detailed Description, Examples, or Tables herein.

121. The method of

claim 114

, wherein said disease or condition is selected from the group consisting of drug-induced diseases, disorders, or toxicities consisting of blood dyscrasias, cutaneous toxicities, systemic toxicities, central nervous system toxicities, hepatic toxicities, cardiovascular toxicities, pulmonary toxicities, and renal toxicities.

122. The method of

claim 114

, wherein said method of treatment comprises administration of a compound effective to treat said disease or condition.

123. A method of treating a disease, condition, or a drug-induced disease in a patient, comprising

a) selecting a patient whose cells comprise an allele of a gene from Tables 1, 3 and 4, wherein said allele comprises at least one variance correlated with more effective treatment of said disease or condition;

and

b) altering the level of activity in cells of said patient of a product of said allele, wherein said altering provides a therapeutic effect.

134. The method of

claim 123

, further comprising

determining the patient'"'"'s allele status and selecting those patients having at least one wild type allele of said gene as candidates likely to be affected by a drug-induced disease or condition.

124. A method for determining a method of treatment effective to treat a disease or condition in a sub-population of patients, comprising

altering the level of activity of a product of an allele of a gene from Tables 1, 3 and 4;

and

determining whether said alteration provides a differential effect related to reducing or alleviating a disease or condition as compared to at least one alternative allele, wherein the presence of a said differential effect is indicative that said altering the level of activity comprises an effective treatment for said disease or condition in said sub-population.

125. A method for performing a clinical trial or study, comprising

selecting or stratifying subjects using a variance or variances or haplotypes from one or more genes specified in Tables 1, 3 or 4.

126. The method of

claim 125

, wherein differential efficacy, tolerance, or safety of a treatment in a subset of patients who have a particular variance, variances, or haplotype in a gene or genes from Tables 1, 3 and 4, comprising conducting a clinical trial and using a statistical test to assess whether a relationship exists between efficacy, tolerance, or safety with the presence or absence of any of said variances or haplotype in one or more of said genes,

wherein results of said clinical trial or study are indicative whether a higher or lower efficacy, tolerance, or safety of said treatment in said subset of patients is associated with any of said variance or variances or haplotype in one or more of said gene.

127. The method of

claim 125

wherein normal subjects or patients are prospectively stratified by genotype in different genotype-defined groups, including the use of genotype as a enrollment criterion, using a variance, variances or haplotypes from Tables 1, 3 or 4, and subsequently a biological or clinical response variable is compared between the different genotype-defined groups.

128. The method of

claim 125

wherein the normal subjects or patients in a clinical trial or study are stratified by a biological or clinical response variable in different biologically or clinically-defined groups, and subsequently the frequency of a variance, variances or haplotypes from Tables 1, 3 or 4 is measured in the different biologically or clinically defined groups.

129. The method of

claim 127

or 128 where the normal subjects or patients in a clinical trial or study are stratified by at least one demographic characteristic selected from the groups consisting of sex, age, racial origin, ethnic origin, or geographic origin.

130. The method of

claim 125

, wherein said determining comprises assigning said patient to a group to receive said method of treatment or to a control group.

140. The method of

claim 129

, wherein the size of the related and unrelated groups is set in order to achieve a predetermined degree of statistical power.

131. A method for determining whether a variance in a gene provides variable patient response to a method of treatment for a disease or condition, comprising:

determining whether the response of a first patient or set of patients suffering from a disease, condition, or drug-induced disease differs from the response of a second patient or set of patients suffering from said disease or condition;

determining whether the presence or absence of at least one variance in a gene from Tables 1, 3 and 4 differs between said first patient or set of patients and said second patient or set of patients;

wherein correlation of said presence or absence of at least one variance and the response of said patient to said treatment is indicative that said at least one variance provides variable patient response.

132. A method for treating a patient at risk for a disease or diagnosed with a disease or disorder or a drug induced disease, comprising

identifying a said patient and determining the patient'"'"'s genotype allele status for a gene from Tables 1, 3 and 4;

determining a treatment protocol using the patient'"'"'s genotype status to provide a prediction of the efficacy and safety of a therapy in light of said disease or an associated condition.

133. A method for identifying a patient for participation in a clinical trial of a therapy for the treatment of a disease or a drug-associated disease or disorder, comprising

identifying a patient with a disease risk and determining the patient'"'"'s genotype, allele status for an identified gene from Tables 1, 3 and 4.

135. A method for treating a patient at risk for a disease condition, comprising

identifying a patient with a risk for said disease;

determining the genotypic allele status of the patient for at least one gene from Tables 1, 3 and 4; and

converting the genotypic allele status into a treatment protocol that comprises a comparison of the genotypic allele status determination with the allele frequency of a control population, thereby allowing a statistical calculation of the patient'"'"'s risk for having said disease or condition.

136. A method for treating a patient at risk for or diagnosed with having a disease or condition, comprising

identifying a said patient;

determining the gene allele load status of the patient for at least one gene from Tables 1, 3 and 4 and converting the gene allele load status into a treatment protocol that includes a comparison of the allele status determinations with the allele frequency of a control population, thereby allowing a statistical calculation of the patient'"'"'s risk for having having said disease or condition.

137. A method for improving the safety of candidate therapies associated with having a disease or condition, comprising

comparing the relative safety of the candidate therapeutic intervention in patients having different alleles in one or more than one of the genes listed in Tables 1, 3 and 4, thereby identifying subsets of patients with differing safety of the candidate therapeutic intervention.

138. A kit for determination of the presence or absence of at least one sequence variance in a gene identified in any of Tables 1, 3, and 4, comprising

at least one probe that preferentially hybridizes with a nucleic acid sequence corresponding to a portion of said gene or at least one primer comprising a nucleic acid sequence corresponding to a portion of said gene or a sequence complementary thereto or both said at least one probe and said at least one primer.

139. A method for determining whether there is a genetic component to intersubject variation in a surrogate treatment response, comprising:

a. administering said treatment to a group of related normal subjects and a group of unrelated normal subjects;

b. measuring a surrogate pharmacodynamic or pharmacokinetic drug response variable in said subjects;

c. performing a statistical test measuring the variation in response in said group of related normal subjects and, separately in said group or unrelated normal subjects; and

d. comparing the magnitude or pattern of variation in response or both between said groups to determine if the responses of said groups are different, using a predetermined statistical measure of difference,

wherein a difference in response between said groups is indicative that there is a genetic component to intersubject variation in said surrogate treatment response.

141. A method for evaluating the combined contribution of two or more variances to a surrogate drug response phenotype in subjects, comprising:

a. genotyping a set of unrelated subjects participating in a clinical trial or study of a compound for two or more variances to identify subjects with specific genotypes, wherein said two or more specific genotypes define two or more genotype-defined groups;

b. administering a drug to subjects with two or more of said specific genotypes;

c. measuring a surrogate pharmacodynamic or pharmacokinetic drug response variable in said subjects;

d. performing statistical tests to measure response in said groups separately, wherein said statistical tests provide a measurement of variation in response with each said group; and

e. comparing the magnitude or pattern of variation in response or both between said groups to determine if said groups are different using a predetermined statistical measure of difference.

142. The method of

claim 141

, wherein said clinical trial or study is a Phase I clinical trial or study.

143. The method of

claim 141

, wherein said specific genotypes are homozygous genotypes for two variances.

144. The method of

claim 141

, wherein the comparison is between groups of subjects differing in three or more variances.

145. A method for providing contract research services to a client, comprising:

a. enrolling subjects in a clinical drug trial or study unit for the purpose of genotyping said subjects in order to assess the contribution of one or more variances or haplotypes to variation in drug response;

b. genotyping said subjects to determine the status of one or more variances in said subjects;

c. administering a compound to said subjects and measuring a surrogate drug response variable;

d. comparing responses between two or more genotype-defined groups of said subjects to determine whether there is a genetic component to the interperson variability in response to said compound; and

e. reporting the results of said clinical drug trial or study unit to a contracting entity.

146. The method of

claim 145

, wherein said clinical drug trial or study unit is a Phase I drug trial or study unit.

147. The method of

claim 145

, wherein at least some of the subjects have disclosed that they are related to each other and said comparing includes comparison of groups of related individuals.

148. The method of

claim 147

, wherein the related individuals are encouraged to participate by compensation in proportion to the number of their relatives participating.

149. A method for recruiting a clinical trial or study population for studies of the influence of one or more variances or haplotypes on drug response, comprising

soliciting subjects to participate in said clinical trial or study;

obtaining consent of said subjects for participation in said clinical trial or study; and

obtaining additional related subjects for participation in said clinical trial by compensating one or more of the related subjects for said participation at a level based on the number of related subjects participating or based on participation of at least a minimum specified number of related subjects.