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Serotonin Transporter Gene and Treatment Of (19) TZZ __T (11) EP 2 255 184 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: G01N 33/48 (2006.01) C12Q 1/68 (2006.01) 24.04.2013 Bulletin 2013/17 G01N 33/68 (2006.01) G01N 33/94 (2006.01) A61K 45/06 (2006.01) (21) Application number: 09714591.6 (86) International application number: (22) Date of filing: 27.02.2009 PCT/US2009/035420 (87) International publication number: WO 2009/108837 (03.09.2009 Gazette 2009/36) (54) SEROTONIN TRANSPORTER GENE AND TREATMENT OF ALCOHOLISM SEROTONINTRANSPORTERGEN UND BEHANDLUNG VON ALKOHOLSUCHT GÈNE DU TRANSPORTEUR DE LA SÉROTONINE ET TRAITEMENT DE L’ALCOOLISME (84) Designated Contracting States: • MANNELLI PAOLO ET AL: "Polymorphism in the AT BE BG CH CY CZ DE DK EE ES FI FR GB GR serotonin transporter gene and response to HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL treatment in African American cocaine and PT RO SE SI SK TR alcohol-abusing individuals", ADDICTION BIOLOGY, ABINGDON CARFAX PUBLISHING, (30) Priority: 28.02.2008 US 32263 P ABINGDON, GB, vol. 10, no. 3, 1 September 2005 06.06.2008 US 59301 P (2005-09-01), pages261-268, XP002595912, ISSN: 22.01.2009 US 146440 P 1355-6215, DOI: DOI: 10.1080/13556210500235540 [retrieved on (43) Date of publication of application: 2006-06-09] 01.12.2010 Bulletin 2010/48 • MARY-ANNE ENOCH ET AL: "Genetics of Alcoholism Using Intermediate Phenotypes", (73) Proprietor: UNIVERSITY OF VIRGINIA PATENT ALCOHOLISM: CLINICAL & EXPERIMENTAL FOUNDATION RESEARCH, vol. 27, no. 2, 1 February 2003 Charlottesville, VA 22902 (US) (2003-02-01), pages 169-176, XP55002791, ISSN: 0145-6008, DOI: 10.1097/01.ALC. (72) Inventor: JOHNSON, Bankole A. 0000052702.77807.8C Charlottesville, VA 22902 (US) • YING LIU ET AL: "Association of habitual smoking and drinking with single nucleotide (74) Representative: Lucas, Brian Ronald polymorphism (SNP) in 40 candidate genes: data Lucas & Co. from random population-based Japanese 135 Westhall Road samples", JOURNAL OF HUMAN GENETICS, Warlingham, SPRINGER-VERLAG, TO, vol. 50, no. 2, 1 Surrey CR6 9HJ (GB) February 2005 (2005-02-01), pages 62-68, XP019374275, ISSN: 1435-232X, DOI: DOI: (56) References cited: 10.1007/S10038-004-0221-9 WO-A2-00/50639 WO-A2-2007/095580 • SAMOCHOWIEC J ET AL: "Family-based and US-A1- 2004 167 164 US-A1- 2006 286 594 case-control study of DRD2, DAT, 5HTT, COMT US-A1- 2007 167 423 US-A1- 2007 292 880 genes polymorphisms in alcohol dependence", US-A1- 2008 004 291 NEUROSCIENCE LETTERS, LIMERICK, IE, vol. 410, no. 1, 13 December 2006 (2006-12-13), pages 1-5, XP025023688, ISSN: 0304-3940, DOI: DOI: 10.1016/J.NEULET.2006.05.005 [retrieved on 2006-12-13] Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 255 184 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 255 184 B1 • B. A. JOHNSON ET AL: "Pharmacogenetic • KONISHI ET AL.: ’ADH1 B*1, ADH1C*2, DRD2 (- Approach at the Serotonin Transporter Gene as 141C ins), and 5-HTTLPR are associated with a Method of Reducing the Severity of Alcohol alcoholism in Mexican American men living’ Drinking", AMERICAN JOURNAL OF ALCOHOL CLIN EXP RES. vol. 28, no. 8, 2004, PSYCHIATRY, vol. 168, no. 3, 1 March 2011 LOS ANGELES., pages 1145 - 52 (2011-03-01) , pages 265-275, XP55002502, ISSN: • KAYSEN ET AL.: ’Domestic Violence and Alcohol 0002-953X, DOI: 10.1176/appi.ajp.2010.10050755 Use: Trauma-related Symptoms and Motives for • SENEVIRATNE CHAMINDI ET AL: Drinking.’ ADDICT BEHAV. vol. 32, no. 6, 2007, "Characterization of a functional polymorphism pages 1272 - 1283 in the 3’ UTR of SLC6A4 and its association with • SZILAGYI ET AL.: ’Combined effect of promoter drinking intensity", ALCOHOLISM: CLINICAL polymorphisms in the dopamine D4 receptor and AND EXPERIMENTAL RESEARCH, WILLIAMS the serotonin transporter genes in heroin ANDWILKINGS, BALTIMORE, MD,US, vol. 33, no. dependence.’ NEUROPSYCHOPHARMACOL 2, 1 February 2009 (2009-02-01), pages 332-339, HUNG., [Online] vol. 7, no. 1, 2005, pages 28 - 33 XP002595913, ISSN: 0145-6008, DOI: DOI: Retrieved from the Internet: <URL:http: 10.1111/J.1530-0277.2008.00837.X [retrieved on //www.ncbi.nlm.nih.gov/sites/entr ez> [retrieved 2008-11-20] on 2009-09-23] • CHORBOV ET AL.: ’Relationship of 5-HTTLPR Genotypes and Depression Risk in the Presence Remarks: of Trauma in a Female Twin Sample. ’ AM. J MED Thefile contains technical information submitted after GEN PART B (NEUROPSYCH GENET) vol. 144B, the application was filed and not included in this 2007, pages 830 - 8 specification 2 EP 2 255 184 B1 Description FIELD OF INVENTION 5 [0001] This invention relates generally to the field of diagnosing the susceptibility to addiction-related diseases and disorders and impulse control disorders, particularly alcohol-related diseases and disorders, as well as monitoring and treating the same. BACKGROUND 10 [0002] Vulnerability to alcohol dependence is heritable, with a rate ranging from 0.52 to 0.64 (Kendler, 2001). Despite this high heritability rate, only one marker allele (alcohol-metabolizing aldehyde dehydrogenase genes) has been iden- tified consistently to be associated with alcoholism (Kranzler et al, 2002). Of the various neurotransmitter systems through which alcohol mediates its effects, the serotonergic system has been shown to play an important role in alcohol preference 15 and consumption (Johnson, 2004). Synaptic serotonergic neurotransmission is terminated when serotonin (5-HT) is transported back into pre- synaptic neurons by 5- HT transporters (5- HTTs) (Talvenheimo and Rudnick, 1980). Therefore, a major part of the functional capacity of the serotonergic system is regulated by the 5- HTT. Heavy episodic drinking is associated with numerous psychiatric and general medical conditions causing a major public health burden (Cargiulo, 2007). Several studies have reported a dose-response relationship between the extent of heavy drinking and the risk 20 of alcohol related morbidity and mortality among heavy drinkers (Makela and Mustonen, 2007; Gastfriend et al., 2007). Consequently, reduction of heavy drinking is used as an indicator of treatment response in clinical trials aimed at treating alcohol dependence. [0003] Of the various neurotransmitter systems through which alcohol mediates its effects, the serotonergic system has been shown to play an important role in alcohol preference and consumption (Johnson, 2004). Synaptic serotonergic 25 neurotransmission is terminated when serotonin (5-HT) is transported back into pre-synaptic neurons by 5-HT trans- porters (5-HTTs) (Talvenheimo and Rudnick, 1980) and the degree of 5- HT reuptake depends on the density of 5- HTTs on presynaptic surface. The selective 5-HT reuptake inhibitors that act directly on 5- HTTs have been shown to reduce alcohol consumption in rats (Gill and Amit, 1989). However, in humans SSRIs have been effective at reducing heavy drinking only among some subtypes of alcoholics, more specifically in type A alcoholics but not in type B alcoholics 30 (Dundon et al., 2004; Pettinati et al., 2000) who are considered to be more biologically predisposed to develop alcohol dependence. Therefore, it is reasonable to propose that allelic variations which alter expression levels of SLC6A4 gene can be expected to have an important effect on drinking intensity. [0004] The human 5-HTT is encoded by a single gene (SLC6A4) mapped on chromosome 17q11.1-q12 (Ramamoorthy et al., 1993). The SLC6A4 gene spans ∼35 kb and has 14 exons. The protein encoded by this gene, the 5-HTT, is a 35 transmembrane protein containing 630 amino acids (Heils et al., 1996). The expression level of SLC6A4 is regulated by at least three mechanisms: transcription regulatory elements in the promoter (Ramamoorthy et al., 1993), differential splicing (Bradley and Blakely, 1997), and the use of different 3’ polyadenylation sites (Battersby et al., 1999). Furthermore, several other polymorphisms that change amino acid sequence (Thr4Ala, Gly56Ala, Glu215Lys, Lys605Asn and Pro612Ser) of 5-HTT have been shown to affect 5-HT uptake function in cell cultures (Prasad et al., 2003). 40 [0005] Although the long (L) and short (S) polymorphism at 5-HTT linked polymorphic region (5-HTTLPR) of SLC6A4 has been extensively studied in the literature, the results are inconclusive. For example, in a meta- analysis of 17 studies, Feinn et al. (2005) showed that S allele was significantly associated with alcohol dependence in subjects with co- occurring serotonergic abnormalities while several other studies reported an association of alcohol dependence with the L allele (Kweon et al., 2005, Hu et al., 2005). On the other hand, numerous studies including the report by our group reveal a 45 differential association between chronic problem-drinking and the density and function of serotonin transporters in al- coholic subjects carrying L and S variants of SLC6A4 (Little et al., 1998, Javors et al., 2005, Johnson et al., 2008). Located in the gene’s transcriptional control region, 5- HTTLPR contains 16 tandem repeats of a 20 to 23 bp (G + C)-rich sequence between bp -1376 and bp-1027. Two common forms of this transcriptional control region have been found: a long 528 bp allele (L) with 16 repeats and a short 484 bp allele (S) with a deletion of 44 bp extending from bp -1255 50 to bp -1212. [0006] Serotonin (5-HT) function has been implicated in the regulation of mood, impulsivity, and alcohol use that includes variation in the age of onset of drinking and onset of alcohol use disorders.
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