Alcohol and Alcoholism Advance Access originally published online on June 14, 2008
Alcohol and Alcoholism 2008 43(5):516-522; doi:10.1093/alcalc/agn048
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Association Between the Stin2 VNTR Polymorphism of the Serotonin Transporter Gene and Treatment Outcome in Alcohol-Dependent Patients
1 Department of Psychiatry, University of Oviedo CIBERSAM, Oviedo, Spain
2 Unidad Asistencial "As Burgas," Orense, Spain
3 Laboratory of Molecular Genetics, Central Hospital of Asturias, Oviedo, Spain
* Corresponding author: Centro Asistencial "As Burgas", Curros Enríquez, 7, 1° local-B, 32004 Ourense, Spain. E-mail: Gerardo.florez.menendez{at}sergas.es
Received 12 November 2007; first review notified 17 December 2007; in revised form 20 May 2008; accepted 23 May 2008
 |
ABSTRACT |
|---|
 TOP ABSTRACT IntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Aims: The aim of this study was to investigate the potential association between functional polymorphisms of dopaminergic [dopamine receptor D2 (DRD2), dopamine receptor D3 (DRD3) and dopamine transporter (SLC6A3)] and serotonergic [serotonin 2A receptor (HTR2A) and serotonin transporter (SLC6A4)] genes and treatment outcome in alcohol-dependent patients. Methods: A total of 90 Spanish Caucasian alcohol-dependent outpatients (ICD-10 criteria) were enrolled in the study. The association between genotypes and drinking outcomes was measured over 6 months of treatment. Biomarkers of alcohol consumption, as well as alcohol consumption and its consequences, craving, disability and quality of life, were assessed. Based on those measures, we created a composite secondary measure to globally assess treatment outcome in alcoholism. Results: No association was found between DRD2, DRD3, SLC6A3 or HTR2A gene variants and treatment outcome. However, SLC6A4 STin2 12/12 carriers showed poor 6-month time point treatment outcome [32.8% in the good outcome group versus 64.0% in the poor outcome group,
2 (df) = 7.20 (1), corrected P = 0.042, OR (95% CI) = 0.27 (0.10–0.72)]. Nevertheless, independent analysis of each treatment group reveals that the excess of 12/12 carriers in the poor outcome group was only found in the naltrexone-treated group [24.1% versus 64.7% 2 (df) = 7.41 (1), corrected P = 0.042, OR (95% CI) = 0.17 (0.05–0.64)]. In the whole sample, the L-10 repeats haplotype (5-HTTLPR-STin2 VNTR) is associated with good outcome (LRT = 3.88, df = 1, P = 0.049). Conclusions: Our findings suggest that functional polymorphism of the SLC6A4 gene may have an influence on treatment outcome in alcohol-dependent patients. |
Introduction |
|---|
|
TOPABSTRACTIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Alcohol dependence is a common health problem, with an estimated 6.5% lifetime prevalence in the general population (Kessler et al., 2005
). Alcohol dependence is a genetically influenced disorder (Kendler et al., 2003) as shown in studies that indicate that there is a higher concordance rate, nearly 2 to 1, for monozygotic twins when compared with like-sex dizygotic twins (Kaprio et al., 1987). Genetic influences account for 
50–60% of the population variance in alcohol dependence (McGue, 1999), but this influence is almost certainly due to the combined effects of several genes, each exerting a small individual effect and interacting with other genes and with the environment (Edenberg and Foround, 2006). Candidate genes have been identified among genes that regulate neurotransmission (Worst and Vrana, 2005). In these genes, the study of single nucleotide polymorphisms (SNPs) has shown that the inheritance of different SNPs can increase or decrease the risk of alcoholism (Hesselbrock et al., 2005).
Abnormality in dopaminergic neurotransmission seems to be one of the pathogenic mechanisms of alcoholism (Bowirrat and Oscar-Berman, 2005). Dopamine activity in mesolimbic regions is associated with the reinforcing effects of drugs (Volkow et al., 2004). Several studies suggest that when an individual has a hypodopaminergic trait, he or she is predisposed to increased the release of dopamine by taking substances such as alcohol, creating a high-risk scenario for developing alcohol dependence (Addolorato et al., 2005a and 2005b). A functional polymorphism of the dopamine receptor D2 (DRD2) gene involving the insertion (Ins)/deletion (Del) of a cytosine (–141C Ins/Del, rs1799732) is related to receptor density. The deletion variant is associated with lower promoter activity (Arinami et al., 1997). The –141C Ins/Del polymorphism has been related to alcoholism in several studies (Konishi et al., 2004; Luo et al., 2005) but not in others (Sander et al., 1999; Chen et al., 2001; Wiesbeck et al., 2006).
A functional polymorphism of the dopamine receptor D3 (DRD3) gene involving having a serine (Ser) or a glycine (Gly) (A-206G, Ser9Gly, rs6280) is related to dopamine-binding affinity (Lundstrom and Turpin, 1996). This polymorphism has been indirectly related to alcoholism in a P300 potential study (Mulert et al., 2006), although there is another study that found no direct association (Wiesbeck et al., 2006).
A functional polymorphism of the dopamine transporter (DAT1, SLC6A3) gene—a 40 base pair (bp) variable number of tandem repeats (VNTR) ranging from 3 to 11 copies of the repeated sequence—exerts a regulatory influence on gene function, modifying SLC6A3 density and binding affinity (Van Dyck et al., 2005; VanNess et al., 2005). This polymorphism has been related to alcoholism in several studies (Schmidt et al., 1998; Samochowiec et al., 2006) but not in others (Franke et al., 1999; Chen et al., 2001).
Serotonergic neurotransmission plays a critical role in impulse control (Ciccocioppo 1999). Genetic variations in the serotoninergic system that alter its activity can contribute to behavioural disinhibition and loss of control over alcohol intake (Addolorato et al., 2005b). Two polymorphisms (T102C or rs6313 and A-1438G or rs6311) of the serotonin 2A receptor (HTR2A) gene have been described as being in complete linkage disequilibrium in different populations (Spurlock et al., 1998; Kouzmenko et al., 1999; Arranz et al., 2000; Kusumi et al., 2002; Bray et al., 2004; Mata et al., 2004; Saiz et al., 2007). Recent findings suggest that the A-1438G polymorphism might have functional effects on expression of this receptor in the brain (Parsons et al., 2004). These polymorphisms have been related to alcoholism in some studies (Preuss et al., 2001; Hill et al., 2002) but not in others (Fehr et al., 2001).
The SLC6A4 gene codes the serotonin transporter (SERT). A functional polymorphism of this gene, known as 5-HTTLPR involving a 44 bp insertion (L allele) and deletion (S allele), has been described. This polymorphism affects transcriptional activity and transporter density (the S allele is associated with a nearly 50% reduction in SLC6A4 availability) (Heinz et al., 2000; Hariri et al., 2005). The S allele has been significantly associated with alcohol dependence, with the greatest effect observed among individuals with a comorbid psychiatric condition, early onset or more severe alcoholism (Feinn et al., 2005). Not all studies have found evidence of this association (Dick et al., 2007; Bleich et al., 2007), with the latest publications presenting a complex interaction between transporter activity mediated by the polymorphism and drinking history (Johnson et al., 2008). Another functional polymorphism of this gene (STin2 VNTR)—a 17 bp VNTR with four different alleles that correspond to the number of tandem repeats (12, 10, 9 or 7)—has been described. This polymorphic VNTR region acts as a transcriptional regulator (MacKenzie and Quinn, 1999). In spite of the importance of the serotonin system in impulse control, this functional polymorphism has not yet been studied in relation to alcoholism.
In this study, we endeavoured to clarify the role of the dopamine and serotonin systems on treatment outcome in alcoholism. We hypothesized that genetic variants of the DRD2 (–141C Ins/Del), DRD3 (Ser9Gly), SLC6A3 (VNTR), HTR2A (A-1438G and T102C) and SLC6A4 (5-HTTLPR and STin2 VNTR) genes would be related to treatment outcome in alcohol-dependent patients.
|
Patients and Methods |
|---|
|
TOPABSTRACTIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Patients
A total of 90 unrelated outpatients with alcohol dependence [mean age (SD) = 46.03 (8.43) years; males: 86.66%] from Ourense (Galicia, Northern Spain) were enrolled in the study. Diagnosis was determined by experienced psychiatrists using the ICD-10 criteria (World Health Organization, 1992
). The ICD-10 criteria are the mandatory criteria in the Spanish National Health System. Severity of the addiction was determined using the EuropASI (Kokkevi and Hartgers, 1995) (only actively drinkers with an alcohol intake of at least 210 g per week for men and 140 g per week for women during the past month were enrolled in the study). All individuals were of Caucasian Spanish origin. Patients with a current diagnosis of dependence or abuse of other substances except nicotine, a current psychiatric diagnosis other than personality disorders, evidence of severe neurologic or physical disorders, mental retardation, pregnancy or breast feeding, or not having a significant other to provide alcohol-related information to the researchers were excluded from the study.
Written informed consent was obtained from all patients enrolled in the study. The study was conducted in accordance with worldwide Good Clinical Practice (GCP) standards and conformed to acceptable ethical standards as outlined by local requirements and the Declaration of Helsinki (World Medical Association, 1989).
Patients were assessed three times during the study period (baseline, after 3 months of treatment and after 6 months of treatment) using the Spanish versions of the following instruments: EuropASI (Kokkevi and Hartgers, 1995), Obsessive Compulsive Drinking Scale (OCDS) (Anton et al., 1995), Fagerström Test for Nicotine Dependence (Fagerström, 1978), International Personality Disorder Examination (IPDE) (Loranger et al., 1994) (baseline assessment only), Readiness to Change Questionnaire (RCQ) (baseline assessment only) (Rollnick et al., 1992), WHO Psychiatric Disability Assessment Schedule (WHO/DAS) (Janca et al., 1996) and European Quality of Life Questionnaire (EQ-5D) (EuroQoL Group, 1990). The baseline and 6-month assessments also included blood tests to measure the following parameters (Allen and Litten, 2001; Allen et al., 2001): gamma-glutamyltransferase (GGT), serum aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), mean corpuscular volume (MCV) and AST/ALT ratio. Alcohol intake was assessed at each treatment session in a self-reported way. Both the patient and the significant other were interviewed; the higher intake level reported was used.
Treatment was randomized when patients entered the study; half were treated with naltrexone (dosage: 50 mg tablet once daily with no further escalation) and the other half with topiramate (dosage: treatment was started with a 50 mg tablet once daily and was increased by 50 mg every 4 days until a daily dose of 200 mg was reached. If patients reported cravings or alcohol intake, topiramate was increased in the same way, 50 mg per day every 4 days, up to 300 mg per day and, if that dose was not sufficient to control alcohol intake or cravings, up to 400 mg per day. Both treatments have shown their efficacy in the treatment of alcohol dependence (Johnson et al., 2003, 2007; Srisurapanont and Jarusuraisin, 2005).
Genotype characterization
Genomic DNA was extracted from peripheral white blood cells obtained from each participant, according to standard protocols (Miller et al., 1988). Gene polymorphisms were identified according to previously published methods (Lannfelt et al., 1992; Vandenbergh et al., 1992; Arinami et al., 1997; Martinez-Barrondo et al., 2005) (Table 1).
|
Outcome measurement
Good outcome was defined not only as improved results on the aforesaid instruments, but a composite outcome measure was also used (Anton et al., 2006
). This measure comprised the following groups (Babor et al., 1994; Cisler and Zweben, 1999; Stout, 2003): (i) Abstinence: no alcohol intake reported during the previous 3 months. No problems reported (problems were defined as a score of 4 or more on any of the EuropASI scales). (ii) Moderate drinking without problems: reported drinking was <40 g of ethanol per day for men and <30 for women, with no >2 days on which heavier drinking was reported. No problems reported. (iii) Moderate drinking with problems: same as the previous, but problems were reported. (iv) Heavy drinking without problems: reported drinking was greater than moderate drinking on three or more occasions per quarter. No problems reported. (v) Heavy drinking with problems: same as the previous, but problems were reported. Groups (i) and (ii) were considered good outcome, and Groups (iii), (iv), (v) and dropouts were considered poor outcome. Dropouts were defined in the following way: patients who stopped coming to appointments for at least 1 month.
Statistical analysis
The data were analysed on an intent-to-treat basis including all patients. Dropouts were assumed to have resumed heavy drinking on the day after their last contact.
Observed frequencies were compared with those expected according to the Hardy–Weinberg equilibrium through a Chi-square (2) test. The composite outcome measure was evaluated in two different ways: first, abstinence versus the rest (including patients taking disulfiram and dropouts), and then good outcome (abstinence and moderate drinking without problems) versus the poor outcome group (including patients taking disulfiram and dropouts). Comparisons between the groups (genotypes) were calculated using the 2 test. Odds ratios (ORs) and their confidence intervals (CI) were also calculated. SPSS version (13.0) was used for the statistical analyses. The Genecounting program (Curtis and Knight, 2003) was used to compare estimated haplotype frequencies between groups and to test for differences with a likelihood ratio test (LRT), as well as to calculate the pairwise linkage disequilibrium (LD) between pairs of markers. A Bonferroni correction coefficient of 6 (six genetic markers were finally included in the study) was applied to P values to control for multiple comparisons. Assuming that the frequency of the minor alleles was 35% in a healthy Caucasian population, the minimum statistical power, when analysing differences between the outcome groups, was 75% to detect a relative risk of 3.5 with a significance of 5% (two-tailed test).
|
Results |
|---|
|
TOPABSTRACTIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Baseline demographic, clinical and alcohol-related characteristics of the sample are presented in Table 2. The total number of samples analysed differed among polymorphisms because of sample depletion or repeated assay failure. The entire group showed the Hardy–Weinberg equilibrium for the analysed genetic variability. A-1438G and T102C polymorphisms were in complete LD [R values (Cramer's V) = 1.00, P = 0] in our population; because of this situation, statistical analyses were performed only on the A-1438G polymorphism. Some degree of LD was found between 5-HTTLPR and STin2 VNTR polymorphisms [R values (Cramer's V) = 0.247, P = 0.07363], but LD was not complete enough to warrant not genotyping both polymorphisms.
|
The genotype distribution for all the studied polymorphisms is summarized in Table 3. The subsamples grouped according to the genotype did not differ in demographic, clinical or alcohol-related characteristics (data not shown).
|
After 6 months of treatment no differences in the percent of abstainers in each treatment group were found [52.2% in the naltrexone group versus 54.5% in the topiramate-treated group,
2 (df) = 0.05 (1); P = 0.822]. However, more patients with good outcome were found in the topiramate-treated group [63.0% versus 81.8%, 2 (df) = 3.95 (1); P = 0.047]. The distribution of the genotypes in relation to the outcome groups after 6 months of treatment is presented in Table 4. We observed an apparent excess of the 12/12 genotype of the STin2 VNTR polymorphism in the poor outcome group (moderate drinking with problems, heavy drinking without problems and heavy drinking with problems, plus dropouts) when compared with the good outcome group (abstinence plus moderate drinking without problems) [64.0% versus 32.8%, 2 (df) = 7.56 (2); P = 0.023, not significant after correction for multiple comparisons]. On the other hand, allele 12 was more frequent in the poor outcome group [0.76 versus 0.59, 2 (df) = 4.70 (1); P = 0.030, not significant after Bonferroni correction, OR (95% CI) = 0.45 (0.21–0.93)]. When a dominant model for this polymorphism was applied, no differences in the frequency of allele 12 (12/12 + 12/10) carriers were found between the good and poor outcome groups [84.4% versus 88.0%, respectively; 2 (df) = 0.19 (1), P = 0.663, OR (95% CI) = 0.74 (0.18–2.93)]. However, when a recessive model was applied, we found a higher frequency of 12/12 carriers in the poor outcome group [32.8% versus 64.0%, 2 (df) = 7.20 (1), P = 0.007, significant after Bonferroni correction (P = 0.042), OR (95% CI) = 0.27 (0.10–0.72)]. Nevertheless, when both treatment groups were analysed separately, this significant excess of 12/12 carriers in the poor outcome group was only found in the naltrexone-treated group [24.1% versus 64.7%, 2 (df) = 7.41 (1), P = 0.007, significant after Bonferroni correction (P = 0.042), OR (95% CI) = 0.17 (0.05–0.64)].
|
Haplotype analyses of HTR2A polymorphisms were not performed, as both polymorphisms were in complete LD in our population. With respect to 5-HTT haplotype comparisons between outcome groups, a total of six haplotypes were estimated by Genecounting to have non-zero frequencies. No apparent significant differences were found in the frequencies of these haplotypes between abstainers and the other groups: LRT = 2.30, df = 5, P = 0.806, or between good and poor outcome groups: LRT = 6.12, df = 5, P = 0.295. However, haplotype L-10 repeats are associated with good outcome in the whole sample (LRT = 3.88, df = 1, P = 0.049) (Table 5). No significant differences were found in haplotypic frequencies when both treatment groups were analysed independently.
|
|
Discussion |
|---|
|
TOPABSTRACTIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
In relation to alcohol dependence, the research provides unambiguous evidence that genes and their polymorphisms play an important role in its development (Dick et al., 2006
). However, only a few studies have addressed the question of whether these genes and their polymorphisms contribute to treatment outcome. To the best of our knowledge, this is the first paper investigating the role of HTR2A and SLC6A4 gene polymorphisms in relation to outcome in alcohol dependence. In our study, no association was found for any of the studied polymorphisms when comparing abstainers versus the rest of the patients. However, a positive association was found when good outcome (abstainers plus moderate drinkers without problems) was considered, since our data suggest an excess of 12/12 carriers of the STin2 VNTR polymorphism in the poor outcome group. However, when each group is analysed independently such association is only found in the naltrexone-treated group. On the other hand, in the whole sample, the L-10 repeats haplotype was over-represented in the good-outcome patients. No other associations were found between the studied polymorphisms and treatment outcome.
Our results showed a trend for better outcome after 6 months of treatment in the topiramate-treated group. This result may be consequent with the fact that Cloninger type 1 alcoholics (80% of alcoholics) are suggested to have a dopaminergic defect; they are not benefiting from naltrexone treatment as much as the Cloninger type 2 alcoholics (20% of all alcoholics) (Kiefer et al., 2005, 2008), which do not have such defect in the dopaminergic system (Tupala and Tiihonen, 2004).
Our results agree with prior studies that have not found evidence of a relationship between treatment outcome and DRD2 and DRD3 gene polymorphisms (Heinz et al., 1996; Wiesbeck et al., 2003). In those studies, 97 and 136 alcohol-dependent patients were followed for 6 and 12 months, respectively. At the end of the observation period, no association was found between treatment outcome and DRD2 TaqIA or DRD1 Bsp12686I polymorphisms (Heinz et al., 1996), or for DRD2 –141C Ins/Del or DRD3 Bal I polymorphisms (Wiesbeck et al., 2003). Only one study has checked the role of serotonergic genes in alcohol treatment outcome. Wojnar et al. (2006) found a relationship, after 12 months of treatment, between high suicidality, impulsivity and relapse, and the G/G genotype of the C-1019G 5-HT1A gene polymorphism.
It is important to remark that, in our study, the positive association between the STin2 VNTR polymorphism of the SLC6A4 and treatment outcome was only found when abstainers and moderate drinkers without problems were pooled together and compared with the rest of the patients. This might indicate that abstinence is not closely related to the polymorphisms included in this study and the functional changes they cause in dopaminergic and serotonergic neurotransmission. Abstinence is probably more related to motivational aspects of alcohol consumption, as lengthy follow-up studies seem to indicate (Vaillant, 2003). But when alcohol-dependent patients try moderate drinking, on their own or with the help of medication, the impact of alcohol intake on serotonergic neurotransmission and the risk of not being able to drink in moderation seem to be influenced by the STin2 VNTR polymorphism. This association is supported by the naltrexone literature (Srisurapanont and Jarusuraisin, 2005), which indicates that naltrexone for the treatment of alcohol dependence decreases the risk of alcohol relapse (return to heavy drinking), but no short-term efficacy is found for naltrexone in maintaining abstinence. Research shows that acute alcohol consumption increases dopaminergic and serotonergic activity, and that this increase is greater and has a higher risk of relapse in patients with an overall attenuation of their serotonergic and dopaminergic activity (Ciccocioppo, 1999; Tupala and Tiihonen, 2004; Bowirrat and Oscar-Berman, 2005). Genetic polymorphisms that contribute to this attenuation make this risk even higher. Unfortunately, current genetic research on the functional implications of the STin2 VNTR polymorphism of the SLC6A4 gene is not conclusive. In vitro data suggest that the STin2.12 allele acts as a more potent positive regulator of marker gene expression than the STin2.10 allele when introduced into embryonic stem cells (Fiskerstrand et al., 1999). In vivo data show that the STin2 VNTR polymorphism acts as a transcriptional regulator and has allele-dependent differential enhancer-like properties (STin2.12 seemed to be significantly stronger than the STin2.10 allele) within the rostral hindbrain, where the SLC6A4 gene is known to be transcribed at the embryonic stage of development, which in turn may lead to aberrant serotonin neuron development (MacKenzie and Quinn, 1999). More recently, it has been suggested that individual repeat elements within the STin2 VNTR domain differ in their enhancer activity in an embryonic stem cell model (Lovejoy et al., 2003). On the other hand, Hranilovic et al. (2004) suggest a weak individual influence but a possible combined effect of the 5-HTTLPR and STin2 VNTR polymorphisms on SLC6A4 gene expression. However, in our sample, the haplotype analysis of both polymorphisms reveals differences between the different outcome groups, having the L-10 repeats carriers a better outcome.
Our findings should be interpreted carefully and some methodological limitations should be taken into account. Firstly, it is possible that our study has insufficient statistical power to detect association due to genes of minor effect size. Secondly, the exclusion criteria used in the study configured a group of alcohol-dependent patients with good prognosis (no physical or mental illness, not living alone, not taking other drugs). This should be borne in mind when comparing this study with others. Thirdly, alcohol intake was not collected using a structured interview. Finally, the 6-month duration of the follow-up allows the relationship of these polymorphisms and treatment outcome to be studied during the dishabituation period but not during the relapse prevention phase.
In summary, our findings suggest that functional polymorphism of the SLC6A4 gene may have an influence on treatment outcome in alcohol-dependent patients. Follow-up studies with a larger number of patients are needed in order to confirm or refute the above-mentioned association.
|
References |
|---|
|
TOPABSTRACTIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Addolorato G, Abenavoli L, Leggio L, et al. How many cravings? Pharmacological aspects of craving treatment in alcohol addiction: a review. Neuropsychobiology (2005a) 51:59–66.[CrossRef][Web of Science][Medline]
Addolorato G, Leggio L, Abenavoli L, et al. Neurobiochemical and clinical aspects of craving in alcohol addiction: a review. Addict Behav (2005b) 30:1209–24.[CrossRef][Web of Science][Medline]
Allen JP, Litten RZ. The role of laboratory tests in alcoholism treatment. J Subst Abuse Treat (2001) 20:81–5.[CrossRef][Web of Science][Medline]
Allen JP, Litten RZ, Strid N, et al. The role of biomarkers in alcoholism medication trials. Alcohol Clin Exp Res (2001) 25:1119–25.[CrossRef][Web of Science][Medline]
Anton RF, Moak DH, Latham P. The obsessive compulsive drinking scale: a self-rated instrument for the quantification of thoughts about alcohol and drinking behavior. Alcohol Clin Exp Res (1995) 19:92–9.[CrossRef][Web of Science][Medline]
Anton RF, O’Malley SS, Ciraulo DA, et al. COMBINE Study Research Group. Combined pharmacotherapies and behavioral interventions for alcohol dependence—the COMBINE study: a randomized controlled trial. JAMA (2006) 295:2003–17.
Arinami T, Gao M, Hamaguchi H, et al. A functional polymorphism in the promoter region of the dopamine D2 receptor gene is associated with schizophrenia. Hum Mol Genet (1997) 6:577–82.
Arranz MJ, Munro J, Birkett J, et al. Pharmacogenetic prediction of clozapine response. Lancet (2000) 355:1615–16.[CrossRef][Web of Science][Medline]
Babor TF, Longabaugh R, Zweben A, et al. Issues in the definition and measurement of drinking outcomes in alcoholism treatment research. J Stud Alcohol (1994) 12:101–11.
Bleich S, Bönsch D, Rauh J, et al. Association of the long allele of the 5-HTTLPR polymorphism with compulsive craving in alcohol dependence. Alcohol Alcohol (2007) 42:509–12.
Bowirrat A, Oscar-Berman M. Relationship between dopaminergic neurotransmission, alcoholism, and reward deficiency syndrome. Am J Med Genet (Part B: Neuropsychiatr Genet) (2005) 132:29–37.
Bray NJ, Buckland PR, Hall H, et al. The serotonin-2A receptor gene locus does not contain common polymorphism affecting mRNA levels in adult brain. Mol Psychiatry (2004) 9:109–14.[CrossRef][Web of Science][Medline]
Chen WJ, Chen CH, Huang J, et al. Genetic polymorphisms of the promoter region of dopamine D2 receptor and dopamine transporter genes and alcoholism among four aboriginal groups and Han Chinese in Taiwan. Psychiatr Genet (2001) 11:187–95.[CrossRef][Web of Science][Medline]
Ciccocioppo R. The role of serotonin in craving: from basic research to human studies. Alcohol Alcohol (1999) 34:244–53.
Cisler RA, Zweben A. Development of a composite measure for assessing alcohol treatment outcome: operationalization and validation. Alcohol Clin Exp Res (1999) 23:263–71.[CrossRef][Web of Science][Medline]
Curtis D, Knight J. (2003) Genecounting Program. http://www.mds.qmul.ac.uk/statgen/dcurtis.html (8 November 2005, date last accessed).
Dick DM, Rose RJ, Kaprio J. The next challenge for psychiatric genetics: characterizing the risk associated with identified genes. Ann Clin Psychiatry (2006) 18:223–31.[CrossRef][Medline]
Dick DM, Plunkett J, Hamlin D, et al. Association analyses of the serotonin transporter gene with lifetime depression and alcohol dependence in the Collaborative Study on the Genetics of Alcoholism (COGA) sample. Psychiatr Genet (2007) 17:35–8.[CrossRef][Web of Science][Medline]
Edenberg HJ, Foround T. The genetics of alcoholism: identifying specific genes through family studies. Addict Biol (2006) 11:386–96.[CrossRef][Web of Science][Medline]
EuroQoL Group. EuroQoL—a new facility for the measurement of health-related quality of life. Health Policy (1990) 16:199–208.[CrossRef][Web of Science][Medline]
Fagerström KO. Measuring degrees of physical dependence to tobacco smoking with reference to individualization of treatment. Addict Behav (1978) 3:235–41.[CrossRef][Web of Science][Medline]
Fehr C, Schleicher A, Szegedi A, et al. Serotonergic polymorphisms in patients suffering from alcoholism, anxiety disorders and narcolepsy. Prog Neuro-Psychopharmacol Biol Psychiatry (2001) 25:965–982.[CrossRef][Medline]
Feinn R, Nellissery M, Kranzler HR. Meta-analysis of the association of a functional serotonin transporter promoter polymorphism with alcohol dependence. Am J Medical Genet (Part B: Neuropsychiatr Genet) (2005) 133B:79–84.
Fiskerstrand CE, Lovejoy EA, Quinn JP. An intronic polymorphic domain often associated with susceptibility to affective disorders has allele dependent differential enhancer activity in embryonic stem cells. FEBS Lett (1999) 458:171–4.[CrossRef][Web of Science][Medline]
Franke P, Schwab SG, Knapp M, et al. DAT1 gene polymorphism in alcoholism: a family-based association study. Biol Psychiatry (1999) 45:652–4.[CrossRef][Web of Science][Medline]
Hariri AR, Drabant EM, Munoz KE, et al. A susceptibility gene for affective disorders and the response of the human amygdala. Arch Gen Psychiatry (2005) 62:146–152.
Heinz A, Sander T, Harms H, et al. Lack of allelic association of Dopamine D1 and D2 (TaqIA) receptor gene polymorphisms with reduced dopaminergic sensitivity to alcoholism. Alcohol Clin Exp Res (1996) 20:1109–13.[CrossRef][Web of Science][Medline]
Heinz A, Jones DW, Mazzanti C, et al. A relationship between serotonin transporter genotype and in vivo protein expression and alcohol neurotoxicity. Biol Psychiatry (2000) 47:643–9.[CrossRef][Web of Science][Medline]
Hesselbrock V, Higuchi S, Soyka M. Recent developments in the genetics of alcohol-related phenotypes. Alcohol Clin Exp Res (2005) 29:1321–4.[CrossRef][Web of Science][Medline]
Hill EM, Stoltenberg SF, Bullard KH, et al. Antisocial alcoholism and serotonin-related polymorphisms: association tests. Psychiatr Genet (2002) 12:143–53.[CrossRef][Web of Science][Medline]
Hranilovic D, Stefulj J, Schwab S, et al. Serotonin transporter promoter and intron 2 polymorphisms: Relationship between allelic variants and gene expression. Biol Psychiatry (2004) 55:1090–4.[CrossRef][Web of Science][Medline]
Janca A, Kastrup M, Katschnig H, et al. The World Health Organization Short Disability Assessment Schedule (WHO DAS-S): a tool for the assessment of difficulties in selected areas of functioning of patients with mental disorders. Soc Psychiatry Psychiatr Epidemiol (1996) 31:349–54.[CrossRef][Web of Science][Medline]
Johnson BA, Ait-Daoud N, Bowden CL, et al. Oral topiramate for treatment of alcohol dependence: a randomised controlled trial. Lancet (2003) 361:1677–85.[CrossRef][Web of Science][Medline]
Johnson BA, Rosenthal N, Capece JA, et al. Topiramate for treating alcohol dependence: a randomized controlled trial. JAMA (2007) 298:1641–51.
Johnson BA, Javors MA, Roache JD, et al. Can serotonin transporter genotype predict serotonergic function, chronicity, and severity of drinking? Prog Neuro-Psychopharmacol Biol Psychiatry (2008) 32:209–16.[CrossRef][Medline]
Kaprio J, Koskenvuo M, Langinvainio H, et al. Genetic influences on use and abuse of alcohol: a study of 5638 adult Finnish twin brothers. Alcohol Clin Exp Res (1987) 11:349–56.[CrossRef][Web of Science][Medline]
Kendler KS, Jacobson KC, Prescott CA, et al. Specificity of genetic and environmental risk factors for use and abuse/dependence of cannabis, cocaine, hallucinogens, sedatives, stimulants, and opiates in male twins. Am J Psychiatry (2003) 160:687–95.
Kessler RC, Berglund P, Demler O, et al. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry (2005) 62:593–602.
Kiefer F, Helwig H, Tarnaske T, et al. Pharmacological relapse prevention of alcoholism: clinical predictors of outcome. Eur Addict Res (2005) 11:83–91.[CrossRef][Web of Science][Medline]
Kiefer F, Jiménez-Arriero MA, Klein O, et al. Cloninger's typology and treatment outcome in alcohol-dependent subjects during pharmacotherapy with naltrexone. Addict Biol (2008) 13:124–9.[CrossRef][Web of Science][Medline]
Kokkevi A, Hartgers C. European adaptation of a multidimensional assessment instrument for drug and alcohol dependence. Eur Addict Res (1995) 1:208–10.
Konishi T, Luo HR, Calvillo M, et al. ADH1B*1, ADH1C*2, DRD2 (–141 c Ins), and 5-HTTLPR are associated with alcoholism in Mexican American men living in Los Angeles. Alcohol (2004) 28:1145–52.[Web of Science]
Kouzmenko AP, Scaffidi A, Pereira AM, et al. No correlation between A(-1438)G polymorphism in 5-HT2A receptor gene promoter and the density of frontal cortical 5-HT2A receptors in schizophrenia. Hum Hered (1999) 49:103–5.[CrossRef][Web of Science][Medline]
Kusumi I, Suzuki K, Sasaki Y, et al. Serotonin 5-HT(2A) receptor gene polymorphism, 5-HT(2A) receptor function and personality traits in healthy subjects: a negative study. J Affect Disord (2002) 68:235–41.[CrossRef][Web of Science][Medline]
Lannfelt L, Sokoloff P, Martres MP, et al. Amino-acid substitution in the dopamine D3 receptor as a useful polymorphism for investigating psychiatric disorders. Psychiatr Genet (1992) 2:249–56.
Loranger AW, Sartorius N, Andreoli P, et al. The international personality disorder examination. Arch Gen Psychiatry (1994) 51:215–24.
Lovejoy EA, Scott AC, Fiskerstrand CE, et al. The serotonin transporter intronic VNTR enhancer correlated with a predisposition to affective disorders has distinct regulatory elements within the domain based on the primary DNA sequence of the repeat unit. Eur J Neurosci (2003) 17:417–20.[CrossRef][Web of Science][Medline]
Lundstrom K, Turpin MP. Proposed schizophrenia-related gene polymorphism: Expression of the Ser9Gly mutant human dopamine D3 receptor with the Semliki Forest virus system. Biochem Biophys Res Commun (1996) 225:1068–72.[CrossRef][Web of Science][Medline]
Luo HR, Hou ZF, Wu J, et al. Evolution of the DRD2 gene haplotype and its association with alcoholism in Mexican Americans. Alcohol (2005) 36:117–25.[CrossRef][Web of Science][Medline]
MacKenzie A, Quinn J. A serotonin transporter gene intron 2 polymorphic region, correlated with affective disorders, has allele-dependent differential enhancer-like properties in the mouse embryo. Proc Natl Acad Sci USA (1999) 96:15251–5.
Martinez-Barrondo S, Saiz PA, Morales B, et al. Serotonin gene polymorphisms in patients with panic disorder. Actas Esp Psiqiatr (2005) 33:210–6.
Mata I, Arranz MJ, Patino A, et al. Serotonergic polymorphisms and psychotic disorders in populations from North Spain. Am J Med Genet (Part B: Neuropsychiatr Genet) (2004) 126:88–94.
McGue M. The behavioral genetics of alcoholism. Curr Dir Psychol Sci (1999) 8:109–15.[CrossRef]
Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res (1988) 16:1215.
Mulert C, Juckel G, Giegling I, et al. A Ser9Gly polymorphism in the dopamine D3 receptor gene (DRD3) and event-related P300 potentials. Neuropsychopharmacology (2006) 31:1335–44.[Web of Science][Medline]
Parsons MJ, D’Souza UM, Arranz MJ, et al. The –1438A/G polymorphism in the 5-hydroxytryptamine type 2A receptor gene affects promoter activity. Biol Psychiatry (2004) 56:406–10.[CrossRef][Web of Science][Medline]
Preuss UW, Koller G, Bondy B, et al. Impulsive traits and 5-HT2A receptor promoter polymorphism in alcohol dependents: possible association but no influence of personality disorders. Neuropsychobiology (2001) 43:186–91.[CrossRef][Web of Science][Medline]
Rollnick S, Heather N, Gold R, et al. Development of a short ‘readiness to change’ questionnaire for use in brief, opportunistic interventions among excessive drinkers. Br J Addict (1992) 87:743–54.[CrossRef][Web of Science][Medline]
Saiz PA, García-Portilla MP, Arango C, et al. Association study of serotonin 2A receptor (5-HT2A) and serotonin transporter (5-HTT) gene polymorphisms with schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry (2007) 31:741–5.[CrossRef][Medline]
Samochowiec J, Kucharska-Mazur J, Grzywacz A, et al. Family-based and case-control study of DRD2, DAT, 5HTT, COMT genes polymorphisms in alcohol dependence. Neurosci Lett (2006) 410:1–5.[CrossRef][Web of Science][Medline]
Sander T, Ladehoff M, Samochowiec J, et al. Lack of an allelic association between polymorphisms of the dopamine D2 receptor gene and alcohol dependence in the German population. Alcohol Clin Exp Res (1999) 23:578–81.[CrossRef][Web of Science][Medline]
Schmidt LG, Harms H, Kuhn S, et al. Modification of alcohol withdrawal by the A9 allele of the dopamine transporter gene. Am J Psychiatry (1998) 155:474–8.
Spurlock G, Heils A, Holmans P, et al. A family based association study of T102C polymorphism in 5HT2A and schizophrenia plus identification of new polymorphisms in the promoter. Mol Psychiatry (1998) 3:42–9.[CrossRef][Web of Science][Medline]
Srisurapanont M, Jarusuraisin N. Naltrexone for the treatment of alcoholism: a meta-analysis of randomized controlled trials. Int J Neuropsychopharmacol (2005) 8:267–80.[CrossRef][Web of Science][Medline]
Stout RL. Methodological and statistical considerations in measuring alcohol treatment effects. Alcohol Clin Exp Res (2003) 27:1686–91.[CrossRef][Web of Science][Medline]
Tupala E, Tiihonen J. Dopamine and alcoholism: neurobiological basis of ethanol abuse. Prog Neuro-Psychopharmacol Biol Psychiatry (2004) 28:1221–47.[CrossRef][Medline]
Vaillant GE. A 60-year follow-up of alcoholic men. Addiction (2003) 98:1043–51.[CrossRef][Web of Science][Medline]
Vandenbergh DJ, Persico AM, Hawkins AL, et al. Human dopamine transporter gene (DAT1) maps to chromosome 5p15.3 and displays a VNTR. Genomics (1992) 14:1104–06.[CrossRef][Web of Science][Medline]
Van Dyck ChH, Malison RT, Jacobsen LK, et al. Increased dopamine transporter availability associated with the 9-repeat allele of the SLC6A3 gene. J Nucl Med (2005) 46:745–51.
VanNess SH, Owens MJ, Kilts CD. The variable number of tandem repeats element in DAT1 regulates in vitro dopamine transporter density. BMC Genet (2005) 6:55–66.[CrossRef][Medline]
Volkow ND, Fowler JS, Wang GJ. The addicted human brain viewed in the light of imaging studies: brain circuits and treatment strategies. Neuropharmacology (2004) 47:3–13.[CrossRef][Web of Science][Medline]
Wiesbeck GA, Weijers HG, Wodarz N, et al. Dopamine D2 (DAD2) and dopamine D3 (DAD3) receptor gene polymorphisms and treatment outcome in alcohol dependence. J Neural Transm (2003) 110:813–20.[Web of Science][Medline]
Wiesbeck GA, Dursteler-MacFarland KM, Wurst FM, et al. No association of dopamine receptor sensitivity in vivo with genetic predisposition for alcoholism and DRD2/DRD3 gene polymorphisms in alcohol dependence. Addict Biol (2006) 11:72–5.[CrossRef][Web of Science][Medline]
Wojnar M, Brower KJ, Jakubczyk A, et al. Influence of impulsivity, suicidality and serotonin genes on treatment outcomes in alcohol dependence. Psychiatr Pol (2006) 40:985–94.[Medline]
World Medical Association. Declaration of Helsinki, recommendations guiding physicians in biomedical research involving human subjects. (1989) Amended by the 41st World Medical Assembly, Hong Kong.
World Health Organization. (1992) ICD-10, 10th Revision of the International Classification of Diseases. World Health Organization, Madrid.
Worst TJ, Vrana KE. Alcohol and gene expression in the central nervous system. Alcohol Alcohol (2005) 40:63–75.
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||