CDK5 genetic markers associated with galantamine response

Abstract

Haplotypes in the CDK5 gene associated with cognitive response to galantamine treatment are disclosed. Compositions and methods for detecting and using these CDK5 haplotypes in a variety of clinical applications are disclosed. Such applications include articles of manufacture comprising galantamine or derivatives thereof that are approved for treating patients having one of these CDK5 haplotypes, methods and kits for predicting the response of an individual to galantamine based upon his/her haplotype profile, and methods for treating Alzheimer's patients based upon their haplotype profile.

1 .- 28 . (canceled) 
     
     
         29 . A kit for determining whether an individual has a response marker I, a response marker II, or a response marker III, the kit comprising a set of one or more oligonucleotides designed for identifying at least one of the alleles at each polymorphic site (PS) in a set of one or more PSs, wherein the set of one or more PSs comprises: (a) PS3 and PS4; (b) PS2, PS3, and PS4; (c) a set of one or more PSs in a linked haplotype for any of haplotypes (1)-(2) in Table 1; or (d) a set of one or more PSs in a substitute haplotype for any of haplotypes (1)-(2) in Table 1, wherein the enumerated PSs in sets (a)-(b) correspond to the following nucleotide positions in SEQ ID NO:1: PS2, 3892; PS3, 4808; and PS4, 5284. 
     
     
         30 . The kit of  claim 29 , wherein the kit comprises a set of one or more oligonucleotides designed for identifying at least one of the alleles at each PS in a set of one or more PSs, wherein the set of one or more PSs is any of: (a) PS3 and PS4; (b) PS2, PS3, and PS4; (c) a set of one or more PSs in a linked haplotype for any of haplotypes (1)-(2) in Table 1; and (d) a set of one or more PSs in a substitute haplotype for any of haplotypes (1)-(2) in Table 1, wherein the enumerated PSs in sets (a)-(b) correspond to the following nucleotide positions in SEQ ID NO:1: PS2, 3892; PS3, 4808; and PS4, 5284. 
     
     
         31 . The kit of  claim 29 , wherein the set of one or more oligonucleotides is designed for identifying both alleles at each PS in the set of one or more PSs. 
     
     
         32 . The kit of  claim 29 , wherein the set of one or more PSs is (a), (c), or (d), wherein if the set is (c), then the linked haplotype is a linked haplotype for haplotype (1) in Table 1, and wherein if the set is (d), then the substitute haplotype is a substitute haplotype for haplotype (1) in Table 1. 
     
     
         33 . The kit of  claim 32 , wherein the set of one or more PSs is (a). 
     
     
         34 . The kit of  claim 29 , wherein the individual is Caucasian. 
     
     
         35 . The kit of  claim 29 , which further comprises a manual with instructions for (a) performing one or more reactions on a human nucleic acid sample to identify the allele or alleles present in the individual at each PS in the set of one or more PSs, and (b) determining if the individual has a response marker I, a response marker II, or a response marker III based on the identified allele or alleles. 
     
     
         36 . The kit of  claim 29 , wherein the linkage disequilibrium between the linked haplotype and at least one of haplotypes (1)-(2) in Table 1 has a delta squared value selected from the group consisting of at least 0.75, at least 0.80, at least 0.85, at least 0.90, at least 0.95, and 1.0. 
     
     
         37 . The kit of  claim 29 , wherein the set of one or more PSs is (a) or (c), wherein if the set is (c), then the linked haplotype is a linked haplotype for haplotype (1) in Table 1 and the linkage disequilibrium between the linked haplotype and haplotype (1) in Table 1 has a delta squared value of at least 0.95. 
     
     
         38 . The kit of  claim 29 , wherein the linkage disequilibrium between the allele at a substituting PS in the substitute haplotype and the allele at a substituted PS in any of haplotypes (1)-(2) in Table 1 has a delta squared value selected from the group consisting of at least 0.75, at least 0.80, at least 0.85, at least 0.90, at least 0.95, and 1.0. 
     
     
         39 . The kit of  claim 29 , wherein the set of one or more PSs is (a) or (d), wherein if the set is (d), then the substitute haplotype is a substitute haplotype for haplotype (1) in Table 1 and the linkage disequilibrium between the allele at a substituting PS in the substitute haplotype and the allele at a substituted PS in haplotype (1) in Table 1 has a delta squared value of at least 0.95. 
     
     
         40 . The kit of  claim 29 , wherein at least one oligonucleotide in the set of one or more oligonucleotides is an allele-specific oligonucleotide (ASO) probe comprising a nucleotide sequence, wherein the sequence is any of SEQ ID NOS:2-4 and their complements. 
     
     
         41 . The kit of  claim 40 , wherein the set of one or more PSs is (a) and the at least one oligonucleotide in the set of one or more oligonucleotides is a first ASO probe, a second ASO probe, a third ASO probe, and a fourth ASO probe, wherein the first ASO probe comprises a nucleotide sequence, wherein the sequence is SEQ ID NO:3 or its complement, wherein R in SEQ ID NO:3 is G, and wherein the second ASO probe comprises a nucleotide sequence, wherein the sequence is SEQ ID NO:3 or its complement, wherein R in SEQ ID NO:3 is A, wherein the third ASO probe comprises a nucleotide sequence, wherein the sequence is SEQ ID NO:4 or its complement, wherein K in SEQ ID NO:4 is G, wherein the fourth ASO probe comprises a nucleotide sequence, wherein the sequence is SEQ ID NO:4 or its complement, wherein K in SEQ ID NO:4 is T. 
     
     
         42 . The kit of  claim 29 , wherein at least one oligonucleotide in the set of one or more oligonucleotides is a primer-extension oligonucleotide comprising a nucleotide sequence, wherein the sequence is any of SEQ ID NOS:5-16. 
     
     
         43 . The kit of  claim 42 , wherein the set of one or more PSs is (a) and the at least one oligonucleotide in the set of one or more oligonucleotides is a first primer-extension oligonucleotide and a second primer-extension oligonucleotide, wherein the first primer extension oligonucleotide comprises a nucleotide sequence, wherein the sequence is any of SEQ ID NO:12 and SEQ ID NO:15, and wherein the second primer-extension oligonucleotide comprises a nucleotide sequence, wherein the sequence is any of SEQ ID NO:13 and SEQ ID NO:16. 
     
     
         44 .- 76 . (canceled)