WO2001077363A2 - Haplotypes of the impdh2 gene - Google Patents

Abstract

Novel single nucleotide polymorphisms in the human IMP dehydrogenase 2 (IMPDH2) gene are described. In addition, various genotypes, haplotypes and haplotype pairs for the IMPDH2 gene that exist in the population are described. Compositions and methods for haplotyping and/or genotyping the IMPDH2 gene in an individual are also disclosed. Polynucleotides containing one or more of the IMPDH2 polymorphisms disclosed herein are also described.

Claims

ttcagttact gagaagacct gagattctgt ttcttaaagc agcagcaata gaccaggtgt 3240 acagtgcctc cagcctaccc atgtctctaa gatgtgttgg tgtgatttgg tctygtgcac 3300 tgccaaaggg atcgataagc agagacccca tgcttcagat caagagcctg atgaaagtag 3360 ttcaaagatg cgatgccctt tctcaccatc cctttccaga aatatgaaca gggattcatc 3420 acagaccctg tggtcctcag ccccaaggat cgcgtgcgsg atgtttttga ggccaaggcc 3480 cggcatggtt tctgcggtat cccaatcaca gacacaggcc ggatggggag ccgcttggtg 3540 ggcatcatct cctccaggga cattgatttt ctcaaagagg aggaacatga ctgtttcttg 3600 gaagaggtgg gtgccactgg cagagtagat ccaagctcta gcagcccagg ttgaagacaa 3660 ggggcttctg ttgtctaaga catctctgat agcctcttct ctctgggaaa ggagtgtcaa 3720 accaagtttc tgactccttt attgggttcc tgcatccttc cccaccagag gctttcaaac 3780 tgcccaaatg cttgctagta tcatgctttg ttcttttaaa cccctaaggt aggggcagtg 3840 cttgaggtct gccctgattt tcttgccatt gttcctgtgt tgtcctcctt attccatagt 3900 gtaagagggt gctccactgt gccatgttgt ccttctactc atccctcact caatcatact 3960 gctaagaatt attgggatcc cttgaggaag ggtggtttgg gtgtgatgta tgaacgtggt 4020 ggtccataga acttcacccc tgtaatctca gtactttggg agactgaggc aggcaaatca 4080 tgaggttagg agtttgagac cagcctggcc aacatggtga aaccccgtct ctactaaaaa 4140 tacaaaaaat tagttgggtg tggtggcrcg tgcctctgag ctcagctact tgggaaggaa 4200 agaaaagagt taactggtca tagtcgatga ctggcccttc ttcacatctc ayctcccacg 4260 tagataatga caaagaggga agacttggtg gtagcccctg caggcatcac actgaaggag 4320 gcaaatgaaa ttctgcagcg cagcaagaag ggtaagtcct agagctggga aagggcctgg 4380 aactaatgcc tagggtcctg attcatgtcc tgccctgacc acaggaaagt tgcccattgt 4440 aaatgaagat gatgagcttg tggccatcat tgcccggaca gacctgaaga agaatcggga 4500 ctacccacta gcctccaaag atgccaagaa acagctgctg tgtggggcag ccattggcac 4560 tcatgaggat gacaagtata ggctggactt gctcgcccag gctggtgtgg atgtagtggt 4620 tttggtgagc tgcyacacag gtgggttggg gcaatagggg cagctgccac atcacagtct 4680 gagacttact tcttgtccta ggactcttcc cagggaaatt ccatcttcca gatcaatatg 4740 atcaagtaca tcaaagacaa ataccctaat ctccaagtca ttggaggcaa tggtaaggca 4800 agattgtgcc ctgaaggatg tgtggtggga gtgggtaagc tgggctccca ccttaacctt 4860 cacatgagca ttttcctttc cttcaccata gtggtcactg ctgcccaggc caagaacctc 4920 attgatgcag gtgtggatgc cctgcgggtg ggcatgggaa gtggctccat ctgcattacg 4980 caggaaggta agaatatact ttgatagggc ccacagagac cccagtttca ggccccacat 5040 accttggaac caagcactct tatggggaca atagagccct ccaatagggg caaccctggg 5100 gccaaattgg ctcttggatg ggtgacatgg ctggaagcaa gacaaggtct tgtcatccat 5160 cacctgccac tcccttgcct agcctggcct tcttgctcct gctctgcacc ttctctaaac 5220 tctggtctgt ttgttttatt tagtggctcc caagatccct ccagacataa agtcccacag 5280 ccccaaatgc ccttctacgt cacgggttgc tatagtaagt ccagcccggc ccactgggcc 5340 ggcccagctg cccactgccc ggctgcttgg ttgacgtagc tgtagctccc ggggtttgtg 5400 gtgctgatgg gtgggcaagg caactgatac acagaccatg gtttgggggt gtgtgtctca 5460 agaacatagc tccctctttc cttattctgg ggtatgcctg atagggagga ccttacttcc 5520 ctaggatcag gaccttttct gatcccacat cttctgatca gtaggcatag ttcagggacc 5580 aactcctttg tgtggtcctt gctctcccac acaaccactg cctgctccac acaaccacag 5640 cctgctctcc tacacaacca ctgcccttat cttgcctgag ctgcccacca ttcagggaga 5700 aagggctggg cctgacctca gtgcctctgg ggactaactg cacggtgact cctgccccat 5760 ctgataccag ctggacgggg gctttcccgg ctgctaagac tgcatgtgcc tgaggctgcc 5820 ctgggcactg cacacatgca cgtgcacatg tgggggtgag tagaggtacg cacagctgtt 5880 tgtactattt aaggcagatg tgcagcagcc atcccagaca cgtctgttcc tcagccaagc 5940 tgcagtcctg atgcagatgt agccaaaagc tcctgggtcc taaatatggc cacagggtcc 6000 actgcccgtc cccattaacc ctatccaccc atgtgttcct ccatctcaac agtgctggcc 6060

23 tgtgggcggc cccaagcaac agcagtgtac aaggtgtcag agtatgcacg gcgctttggt 6120 gttccggtca ttgctgatgg aggaatccaa aatgtgggtc atattgcgaa agccttggcc 6180 cttggggcct ccacaggtga ggcagtaccc gtgaaggcca gtgggacccc ctccctagtg 6240 ctgcttaggc tctaacccaa gcactccatc tgtccgcagt catgatgggc tctctcctgg 6300 ctgccaccac tgaggcccct ggtgaatact tcttttccga tgggatccgg ctaaagaaat 6360 atcgcggtat gggttctctc gatgccatgg acaagcacct cagcagccag aacagatatt 6420 tcaggtggga caggcaagcc agttacccca ccctaatcct gcactgacag tctcatctct 6480 gctgtgacct tgccygtgct ctctgcctct ccctgcagtg aagctgacaa aatcaaagtg 6540 gcccagggag tgtctggtgc tgtgcaggac aaagggtcaa tccacaaatt tgtcccttac 6600 ctgattgctg gcatccaaca ctcatgccag gacattggtg ccaagagctt gacccaagtc 6660 cggtgagctt ggggagctgg gacatgggta gaggggctgg tccagggcca gctacccaca 6720 tttgacctct gcccttcttc agagccatga tgtactctgg ggagcttaag tttgagaaga 6780 gaacgtcctc agcccaggtg gaaggtggcg tccatagcct ccattcgtaa gtcaccctgt 6840 ccttggtggg gcctctgcat acctcatgcc tcctttctcc tgccctcacc tcacaggtgg 6900 tccttctgcc tgcaggtatg agaagcggct tttctgaaaa gggatccagc acacctcctc 6960 ggtttttttt tcaataaaag tttagaaaga aaaaagtgat gcctgatctt caacagacag 7020 gtggggctct gtagctgcca ctaccacaga tgcacacaaa aacagcaccc tcatttccag 7080 ggggagcytc agcgcccgag ataaatgtgc tccatggacc tggaagcggg tagttccagg 7140 tccaaaaagt tcctcctgag gctgctcaca aaacagctga ctatagctat agctatggct 7200 cttggggttt cagtctcaca ctgagcatct gactctggct cccaagggtc aaagaacaag 7260 ccctgggact ggcatacaca gggcatcctg ctagcccata gcttggccat ataggaccag 7320 gtcaacacac atatatatcc ctaacttgaa tctctctcgg ccaggcacat tggctcacgt 7380 ctgtatccca gcacttggga ggcaggtgga tcacttaggt caggagttcg agaccatcct 7440 ggccaacatg gtgaaccctt tctctactaa aaatacaaaa attagctggg cgtggtgatg 7500 catacctcta gtcccagcta ctcaggaggc tgaggcagga gaatcactga aacccaggag 7560 gcggaggttg cagtgagctg agactgcgcc actgcactcc accctggcga aagagcaaga 7620 ctcatctcca gaaaaaaaaa aaaaaaaaaa agcccagtgt agtggtaggg gcctctaatt 7680 ccagctactc aggaggctga ggcacgagaa tcgcttgaat ccaggaggtg gaggttgtag 7740 tgggccaaga tcacgccact gcactgcagc ccgggcgaca cgagactcca tctcaaaaaa 7800 agaaaaacaa tcagcgattt tgtgagaaaa gccgttgagg tcctctcaaa tctgcatgtg 7860 agcaagtagg tctacaacag gcaaacatac tgcttccgac ttctgaaaag tcaaggaatc 7920 ctaagtaatc tagatgaaaa agtgactcct tggtttcttc acattcccct ccaagagccc 7980 agtgagccat cagctcctgg ccagcaacac acctgataca aaatgggaga agtgtataaa 8040 ttattatgtt gataagcaag ataagtgcca aagggtagat aagagtgaaa gcattgggaa 8100 gcctggcaga gtgcagtcag caggtcagtt cctggcggtt cattgagcag cttggcccaa 8160 agatgtaagt gaagtccctc ctggtggagg gatgagagca gctccagtta ctcggccttc 8220 atgacacagg aagttgaagg tggcacaggc attgggctgc aaagaaaagg ccagcatcag 8280 cctgtctagc gccaggcctg tgctccccgc agcatgcccc agtcccggga ctcaccgtgt 8340 cctgcacttc cacagcaatg ccccgctgcc tcatggcttg aagcacctgg gactgcagcc 8400 tctcggtccg gtctccagtc cccaccacca cgatctctag ggaagggtgg gtgtggctag 8460 tctacgtctg ttgagaggct gcagtggggg tcgccttctg gggcccagaa cacctctgtt 8520 ctccctcccc ttccccagta cctatccggg gctccagcaa ccagaagagg gaaaagctgt 8580 cttcggtgat gtcctggtgg gatcccacct gtgcagggag gaggcacatt aacacgaaat 8640 ccacgcagcc tctccccatc tccatccatc tgcaggagg gacagaggaa agccaagttt 8700 gcagggacca agcagggtga gggcctgtga ctctgggcct cagtttccac actgcgggcc 8760 aggactcacg ttccactgca ccaccgagtg cgggacagaa gcgcaggggc cgagcacgcg 8820 gtttccgttt atcatgaagc cgcggctgtt gtagctgtcg atgtacttgc ctgagcggcc 8880 tcgcgttgca gcagagagat gcgcgtccgc tgatacagct cgtcatccgc cggcgagagc 8940

24 atgccctcgc cgcggggccc tgcggaggga aagggtcagg ggcgcggggc cgggccgggc 9000 agcccagagg ccggaaggtg ctgggctggc agtcgccggc taggggctgg atggtcgagg 9060 gcgcggggtc caagctcacc agggaagctc aacgggcgga cagcgcagcg agggtcgcgc 9120 tcggtacaag ctacgtagcg cgagagcggt ggccatggct gaccaagcgc ggcgaagtcg 9180 tcaccggcgc cgttagtccc cgggttggga gggcctgcgg agcctgaccc agcgtggctg 9240 cagcgccccc tgcgtcccgg agggcaccgc acagctcgac cggcccagca ggcgagtgtc 9300 ctcagtatta ggaggccgag ttccccgact ccggcgcagc tccagtgtca gcacctgccg 9360 ccctccccgc cccggccctt gcccatagtc ccgggggagt ggaacacctg gcagcgtggc 9420 caccctcagg gcgttgcctg cgagccgcgg cctgcccccg ggctctcagc tattaagccg 9480 cgctcccggg gcgggcgacc gcccacctgg tcgcgtcccg aacacctggc caggcggtgg 9540 gtgccagact tctagcccct aattccagcc tttggggctt cgggcaccgt gggcggggca 9600 gccggctcaa gtttctccgg ctagacgcgg aagcacgccc cgccctaacc gtcacccgcg 9660 cgaccgttgg ctctcgcagc gcgcggagag gggcgtggcc gagcgtggat tggcttctcg 9720 ggttctctag gggcgtggcc aggtggtttc tccttaaaat ggctccaagt ctgcaggcag 9780 ccagagcaag cggaagggca agctgtgata gtgtttgggt ggctgttcgg ctggcccaga 9840 ccaggccgaa ccggaccaga cttgagtaga agcgcgtgga gcatcacctt gtcctcgttc 9900 actctgctcg cgtcctggga gtcccccgtc ccccgtcttg atccaagtca agggcctact 9960 ggcgcgagag tcgctggccc cgacgcgggg tttgggcatc tgcgcacgcc ggctctgtcg 10020 tggcctcagg ggaacattgt gctttgccta ccgcggggcc gggcgagcgg gaagctcggc 10080 acagtgggag cctggtggtg ggtctcctgg ggccggtcgc aatgggtttc cgggggtccg 10140 cggctgctct gtggaccctt cggcccctgg tgctccgggc gctggcagcg tcaccggaca 10200 aaggccaccg agcgcggggg tgtccccgag gtggacgcgc gggtttactt cctctccgcg 10260 cccacgggcg cgcttccctc ctgacggatt ccgaagcccg ccccaccacc gtcaccgcac 10320 cagtggccca ggcttcgtgg gaccaacagg gctaatcctg ccccacggat ctaatccgga 10380 tcgggacccg gtcccagggg aggcccccac ctccccttct attgttctgt ggcccaggtg 10440 agcgtcttgt tccctctaga ctccgtttca caacctactc ccgggtcttc ctcctgggac 10500 tggggatggg cgggttctga tgtggcccca gggcgagtga cctgggggca ggagctc 10557

25 HAPLOTYPES OF THE IMPDH2 GENE

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Serial No. 60/196,248 filed April 11, 2000.

FIELD OF THE INVENTION

This invention relates to variation in genes that encode pharmaceutically-important proteins. In particular, this invention provides genetic variants of the human IMP dehydrogenase 2 (IMPDH2) gene and methods for identifying which variant(s) of this gene is are possessed by an individual.

BACKGROUND OF THE INVENTION

Current methods for identifying pharmaceuticals to treat disease often start by identifying, cloning, and expressing an important target protein related to the disease. A determination of whether an agonist or antagonist is needed to produce an effect that may benefit a patient with the disease is then made. Then, vast numbers of compounds are screened against the target protein to find new potential drugs. The desired outcome of this process is a lead compound that is specific for the target, thereby reducing the incidence of the undesired side effects usually caused by activity at non-intended targets. The lead compound identified in this screening process then undergoes further in vitro and in vivo testing to determine its absorption, disposition, metabolism and toxicological profiles. Typically, this testing involves use of cell lines and animal models with limited, if any, genetic diversity.

What this approach fails to consider, however, is that natural genetic variability exists between individuals in any and every population with respect to pharmaceutically-important proteins, including the protein targets of candidate drugs, the enzymes that metabolize these drugs and the proteins whose activity is modulated by such drug targets. Subtle alteration(s) in the primary nucleotide sequence of a gene encoding a pharmaceutically-important protein may be manifested as significant variation in expression, structure and/or function of the protein. Such alterations may explain the relatively high degree of uncertainty inherent in the treatment of individuals with a drug whose design is based upon a single representative example of the target or enzyme(s) involved in metabolizing the drug. For example, it is well-established that some drugs frequently have lower efficacy in some individuals than others, which means such individuals and their physicians must weigh the possible benefit of a larger dosage against a greater risk of side effects. Also, there is significant variation in how well people metabolize drugs and other exogenous chemicals, resulting in substantial interindividual variation in the toxicity and/or efficacy of such exogenous substances (Evans et al., 1999, Science 286:487-491). This variability in efficacy or toxicity of a drug in genetically-diverse patients makes many drugs ineffective or even dangerous in certain groups of the population, leading to the failure of such drugs in clinical trials or their early withdrawal from the