Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2002-06-11
2004-06-01
Fredman, Jeffrey (Department: 1637)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
73, C536S023100, C536S024300
Reexamination Certificate
active
06743589
ABSTRACT:
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not applicable.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to screening patients to determine their risk for having major depression.
2. Description of the Related Art
A bibliography follows at the end of the Detailed Description of the Invention. The listed references are all incorporated herein by reference.
The lifetime frequency of major depression (MD) is twice as high in women as in men (1). Twin studies have shown a significant genetic contribution to MD in women with heritabilities ranging from 0.33 to 0.45 and higher (2-5), and an important role of stress (6). Some twin studies have suggested a comparible heritability for men and women (4), while others have suggested a greater heritability for women (5). In 1972 and again in 1994, Janowsky (8, 9) reviewed the evidence for a role of cholinergic hypersensitivity in depression. Both REM and non-REM sleep is regulated by cholinergic, serotonergic and noradrenergic neurons in the brain stem (10). The early onset of REM sleep, increased REM density and exaggerated REM response to cholinergic stimulation in depression, is consistent with CNS cholinergic overactivity or muscarinic supersensivity in depression (10). While the HPA axis has been emphasized in the response to stress, recent studies of Kaufer, et al. (11) have identified an important alternative cholinergic pathway. They showed that acute stress resulted in an immediate increase in synaptosomal acetylcholine with neuronal excitability, with a delayed phase response of increased expression of acetylcholineaserase, decreased choline acetyl transferase and vesicular acetylcholine transporter (CHAT) activity and a resulting decrease in neuronal excitability (11, 12). Others have also emphasized the important role of stress in activating muscarinic systems (13).
BRIEF SUMMARY OF THE INVENTION
In one aspect, the present invention relates to a method for screening a patient to determine whether such patient is at increased risk for developing major depression, said method comprising analyzing a sample of said patient's genetic material to determine the patient's genotype with respect to the cholinergic muscarinic receptor 2 (CHRM2) gene, wherein the presence of a T at nucleotide number 1890 in the 3′ UTR of said gene correlates with an increased risk for developing major depression.
In another aspect, the present invention relates to a method for diagnosing major depression in a patient, said method comprising analyzing a sample of a patient's genetic material to determine to determine the patient's genotype with respect to the cholinergic muscarinic receptor 2 (CHRM2) gene, wherein the presence of a T at nucleotide number 1890 in the 3′ UTR of said gene is indicative of the presence of major depression.
In another aspect, the present invention relates to a method for screening a subject to determine whether such subject is a candidate for a therapy using a drug which prevents or treats a disorder associated with the presence of a T at nucleotide number 1890 in the 3′ UTR of the cholinergic muscarinic receptor 2 (CHRM2) gene, said method comprising determining the subject's genotype with respect to such gene, wherein a subject having a T at said nucleotide number is a candidate for such therapy.
In another aspect, the present invention relates to a method for treating a patient having or at increased risk for developing major depression associated with the presence of a T at nucleotide number 1890 in the 3′ UTR of the cholinergic muscarinic receptor 2 (CHRM2) gene, said method comprising administering to said patient an effective amount of a material which diminishes the effect of such gene.
In another aspect, the present invention relates to a method for identifying materials that can be used in the treatment of a patient having or at increased risk for developing a disorder associated with the presence of a T at nucleotide number 1890 in the 3′ UTR of the cholinergic muscarinic receptor 2 (CHRM2) gene, said method comprising determining whether the material is capable of diminishing the effect of such gene.
In another aspect, the present invention relates to a pharmaceutical composition which comprises
a) an effective amount of a material which is capable of diminishing the effect of the cholinergic muscarinic receptor 2 (CHRM2) gene having a T at nucleotide number 1890 in the 3′ UTR; and
b) a pharmaceutically acceptable carrier.
In another aspect, the present invention relates to a kit suitable for screening a subject to determine whether such subject is at increased risk for having or developing a disorder associated with the presence of a T at nucleotide number 1890 in the 3′ UTR of the cholinergic muscarinic receptor 2 (CHRM2) gene, said kit comprising
a) material for determining the subject's genotype with respect to said gene;
b) suitable packaging material; and optionally
c) instructional material for use of said kit.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is based on the observation that subjects, particularly females, having a T at nucleotide number 1890 in the 3′ UTR of the cholinergic muscarinic receptor 2 (CHRM2) gene have an increased risk of having major depression.
The present invention entails the determination of the subject's genotype with respect to the CHRM2 gene. That gene is located on chromosome 7q31-q35. See reference (23) and the references cited therein, the contents of which are incorporated herein by reference. The relevant portion of the sequence is as follows (the T nucleotide at position 1890 is indicated in bold type): acatgggaat taggcaggta gacacagtaa tcatgcaggg gaagggagat 50 ttgggagaaa ataatgtggt ttaaaaggag aaacaacatt atgtatttta 100 aaccaatgtt tatattatgt ttgttaattt tattctattt ccttgcaggt 150 ttaaatgttt atttgctact tggctactga ttagagaacg caaaatgaat 200 aactcaacaa actcctctaa caatagcctg gctcttacaa gtccttataa 250 gacatttgaa gtggtgttta ttgtcctggt ggctggatcc ctcagtttgg 300 tgaccattat cgggaacatc ctagtcatgg tttccattaa agtcaaccgc 350 cacctccaga ccgtcaacaa ttacttttta ttcagcttgg cctgtgctga 400 ccttatcata ggtgttttct ccatgaactt gtacaccctc tacactgtga 450 ttggttactg gcctttggga cctgtggtgt gtgacctttg gctagccctg 500 gactatgtgg tcagcaatgc ctcagttatg aatctgctca tcatcagctt 550 tgacaggtac ttctgtgtca caaaacctct gacctaccca gtcaagcgga 600 ccacaaaaat ggcaggtatg atgattgcag ctgcctgggt cctctctttc 650 atcctctggg ctccagccat tctcttctgg cagttcattg taggggtgag 700 aactgtggag gatggggagt gctacattca gtttttttcc aatgctgctg 750 tcacctttgg tacggctatt gcagccttct atttgccagt gatcatcatg 800 actgtgctat attggcacat atcccgagcc agcaagagca ggataaagaa 850 ggacaagaag gagcctgttg ccaaccaaga ccccgtttct ccaagtctgg 900 tacaaggaag gatagtgaag ccaaacaata acaacatgcc cagcagtgac 950 gatggcctgg agcacaacaa aatccagaat ggcaaagccc ccagggatcc 1000 tgtgactgaa aactgtgttc agggagagga gaaggagagc tccaatgact 1050 ccacctcagt cagtgctgtt gcctctaata tgagagatga tgaaataacc 1100 caggatgaaa acacagtttc cacttccctg ggccattcca aagatgagaa 1150 ctctaagcaa acatgcatca gaattggcac caagacccca aaaagtgact 1200 catgtacccc aactaatacc accgtggagg tagtggggtc ttcaggtcag 1250 aatggagatg aaaagcagaa tattgtagcc cgcaagattg tgaagatgac 1300 taagcagcct gcaaaaaaga agcctcctcc ttcccgggaa aagaaagtca 1350 ccaggacaat cttggctatt ctgttggctt tcatcatcac ttgggcccca 1400 tacaatgtca tggtgctcat taacaccttt tgtgcacctt gcatccccaa 1450 cactgtgtgg acaattggtt actggctttg ttacatcaac agcactatca 1500 accctgcctg ctatgcactt tgcaatgcca ccttcaagaa gacctttaaa 1550 caccttctca tgtgtcatta taagaacata ggcgctacaa ggtaaaatat 1600 ctttgaaaaa gatagaaggt gggcaagggg agcttgagaa gaataaaagg 1650 gataaacgag ctcctagttt taaaatctct gccattgcac tttatagtct 1700 gattacaaaa cgtgcaattc aggagcccag cagtgacaca cttatcacgc 1750 ctaggctcca gtttgcaaaa attgcacctt ataaactgtc agtattagga 1800 gcaatgagac aatgaaagaa acatgttggg atcgtggatt taagaaacta 1850 tacactgttt ctcataatct cttgaagaag ggcttctgat tctacaattt 1900 tatcagtctc tgcacaagag gaataacctt gttccttttt tgttactttt 1950 gttgttgttg ttctcatgtg tccttaagag aagg
Comings David E.
MacMurray James P.
City of Hope
Fredman Jeffrey
Rothwell Figg Ernst & Manbeck
Strzelecka Teresa
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