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The Author 2007. Published by Oxford University Press on behalf of the Medical Council on Alcohol.
D2 dopamine receptor gene haplotypes and their influence on alcohol and tobacco consumption magnitude in alcohol-dependent individuals
1 Psychiatric Hospital of Ludwig-Maximilians-University Munich, Nußbaumstr. 7, 80336 Munich
2 Department of Psychiatry, Martin-Luther University, Halle Julius-Kühn-Str. 7, 06097 Halle, Germany
3 Private Hospital Meiringen, P.O. Box 612, CH3860 Meiringen
* Author to whom correspondence should be addressed at: Department of Psychiatry, Martin-Luther University, Halle, Julius-Kühn-Str. 7, 06097 Halle, Germany. Tel: 0345-557-4595; Fax: 0345-557-3500; E-mail: ulrich.preuss{at}medizin.uni-halle.de
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Introduction: Alcohol dependence and habitual smoking frequently co-occur and possibly mutually influence each other. Both have been related to alterations of dopaminergic neurotransmission. The aim of this analysis of the Munich Gene Data Bank for Alcoholism(MGBA) was to re-evaluate the potential relation between D2 receptor and dopamine transporter gene haplotypes and quantity-related phenotypes of alcohol consumption (average daily alcohol intake before admission for treatment) and smoking (average units smoked per day). Methods: A total of 333 inpatients (265 males) were enrolled in the study, all of who met the ICD10 diagnosis of alcohol dependence. Mild and strong quantity drinkers and smokers were separated into groups by median split. A number of genetic markers were chosen across D2 dopamine receptor gene (–141 Ins/Del, Taq1B, Taq1D, Ser311Cys; rs1079594 (intron 7); Taq1A) and dopamine transporter (40bp variable number of tandem repeat; rs2617605 (intron 2); rs37022 (intron 7); rs40184 (intron 14)). Genotyping was performed using PCR. Results: Strong drinkers reported significantly higher amounts of smoking and vice versa. While no association was detected for dopamine transporter genetic variants, a number of D2 receptor gene single nucleotide polymorphisms were related to both smoking- and drinking-related behaviours. Subsequent analysis of D2 receptor gene haplotypes revealed that two common haplotypes had a significant association with quantitative phenotypes of regular drinking (Ins-C-G-C-A1) and smoking (Ins-T-G-A-A2). Discussion: The finding of an association between common D2 dopamine receptor gene haplotypes with the quantity of drinking and smoking corroborates with results from previous studies suggesting a relationship between the dopamine system and alcohol and substance use disorders. Furthermore, it makes D2 dopamine receptor a candidate gene significantly influencing both alcohol and nicotine dependence.
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In humans, the consumption of alcohol and cigarette smoking were suggested to be correlated with each other (Bien and Burge, 1990
; Collins, 1990; Zacny, 1990), and heavy drinkers tend to be heavy smokers. A possible explanation for the observed correlation between ethanol and tobacco consumption is that ethanol potentiates the pleasurable or behaviour reinforcing effects associated with nicotine use. Behavioural reinforcement and locomotor stimulation evoked by either nicotine or ethanol are both associated with the release of dopamine from mesolimbic dopaminergic terminals located in the nucleus accumbens (Samson et al., 1992; Phillips and Shen, 1996; Balfour et al., 1998; Koob et al., 1998). In support of this notion, the ethanol induced enhancement of locomotor activity and dopamine release is antagonized by the nicotinic channel blocker mecamylamine in animal models (Blomqvist et al., 1997). Both alcohol dependence and smoking are complex behaviours that are influenced by environmental as well as genetic factors. Various types of research, including studies of identical and fraternal twins, adoptees, and families with multiple alcoholic members have provided evidence for a strong genetic component in the development of alcohol and nicotine dependence.
Based on these findings, the heritability of alcohol dependence has been estimated at 64% (Heath et al., 1997). Similarly, twin studies have supported the role of genetic influence on smoking, suggesting a heritability of 60% for nicotine dependence (True et al., 1997). Because alcohol dependence and habitual smoking frequently co-occur and because genetic factors influence both behaviours, twin studies have examined the extent to which both addictions might share some genetic risk factors. These analyses found evidence of a substantial overlap in genetic factors influencing nicotine and alcohol dependence (i.e. a genetic correlation of 0.68) (True et al., 1999). These data also support a common underlying genetic vulnerability to both alcohol and nicotine dependence.
Studies on monozygotic and dizygotic twins have also reported that heredity influences the uptake of a smoking habit, being a current smoker or ex-smoker and the number of cigarettes smoked. The strongest contribution of heredity seems to be the persistence of smoking: being more dependent and failing to quit (Gorrod and Aislaitner, 1998).
Linkage analyses from several independent studies provide evidence for suggested linkage of smoking behaviour to various chromosomal regions (1, 2, 4, 5, 6, 7, 9, 10, 11, 14, 17, 18 and 21) (Straub et al., 1999; Goode et al., 2003; Li et al., 2003; Saccone et al., 2003). However, almost none of these loci have been replicated yet (Li et al., 2004). Pertaining to the other approach in marker-based genetic studies, the majority of genetic influences on tobacco dependence and related phenotypes are directed at genes involved in regulating the dopaminergic system (reviewed by Lerman and Swan, 2002; Li et al., 2004).
Numerous population-based association studies have been performed to examine the effects of some candidate genes, including dopamine receptors and dopamine, serotonin transporter and nicotinic acetylcholine receptor, on smoking behaviour. However, many of these reports have not yet received independent confirmation. Of these candidate genes, the D2 dopamine receptor gene has been extensively studied in both nicotine and alcohol dependence. Meta-analysis of 12 reported studies showed a significantly higher prevalence of the D2 dopamine receptor A1 allele in smokers than that in non-smokers (P < 0.0001; pooled OR: 1.50; 95% CI: 1.33–1.70) (Li et al., 2004). While there is no unanimous agreement on the functional relevance of D2 dopamine receptor A1 allele, it has been related to a reduced D2 dopamine receptor binding affinity (Noble, 2003) and lower striatal D2 dopamine receptor densities in healthy controls (Jonsson et al., 1999).
Moreover, abnormalities in dopaminergic neurotransmission were suggested to be one of the pathogenic mechanisms of alcoholism and other substance use disorders, like smoking (review by Bowirrat and Oscar–Berman, 2005). Subsequently, numerous studies investigated the relationship between alcohol dependence and genetic variants of candidate genes in the dopamine system, including the D2 dopamine receptor gene, and the dopamine transporter, with conflicting results (Review by Bowirrat and Oscar–Berman, 2005). Including numerous studies on this topic in their study, a meta-analysis indicated that there might be a higher frequency of the D2 dopamine receptor gene A1 allele in alcoholics, in particular, those with heavy alcohol consumption, making this genetic variant a candidate increasing the liability for the development of alcohol dependence (Noble, 1998). Recent work reported an association between the amount of drinking and this polymorphism in social drinkers (Munafo et al., 2005).
Higher dopamine transporter densities among violent type II alcoholics were reported when compared with healthy controls (Tiihonen et al., 1995), and several studies related dopamine transporter variable number of tandem repeats 9 allele to severe alcohol withdrawal (Sander et al., 1997; Schmidt et al., 1998; Gorwood et al., 2003).
Again, studies investigating the relationship between putative functional dopamine transporter 40 bp variable number of tandem repeat variant, for which functional consequences with respect to protein expression (VanNess et al., 2005) have been reported, revealed controversial results. While some studies found an increased liability for smoking in carriers of the 9-repeat variant (Lerman et al., 1999; Sabol et al., 1999), subsequent research reported even a decreased susceptibility (Vandenbergh et al., 2002; Erblich et al., 2004). Other studies compared those who had smoked less then 100 cigarettes in their lifetime to either former or current smokers, and found that carrying at least one copy of the 9 allele decreases risk of smoking almost 50% and is associated with a four-fold higher likelihood of successful smoking cessation (Lerman et al., 1999; Sabol et al., 1999).
Though it is doubtful that these genetic variants are related to the diagnoses of alcohol- and nicotine-dependence itself, genetic variants of the dopamine system might be associated with drinking- and smoking-related traits like amount of consumption or age at onset. For both traits, a genetic influence in substance dependence has been reported (Koopmans et al., 1999; Saccone et al., 2000). Furthermore, for both alcohol and nicotine, a relationship is reported between greater amount of substance consumed with a higher risk of developing a substance use disorder and to have a more severe course of disease (Drummond, 2000; Edwards, 2004).
Furthermore, previous studies reported that genetic variants of the D2 dopamine receptor gene have been related to stress, anxiety and impulsive behaviours (Gilbert et al., 2004; Bowirrat and Oscar-Berman, 2005; Lawford et al., 2006), and all three syndromes have been related to sensitivity of presynaptic D2 dopamine receptors and an increased risk for alcohol and substance use disorders (ASUD) (Comings and Blum, 2000; Noble, 2000).
The association with substance dependence-related traits might also explain some of the inconsistencies in previous association studies, since the samples investigated were very heterogeneous and might have differed even more in their alcoholism- and nicotine-related traits than by diagnostic entity.
The aim of our analysis of the Munich Gene Bank for Alcoholism (MGBA) was to investigate whether haplotypes of D2 dopamine receptor gene and dopamine transporter are associated with maximum amount of average alcohol consumption 1 week before admission to an addiction treatment ward, and mean daily consumption of nicotine units. In extension to previous studies, candidate gene haplotypes were chosen because association tests based on haplotypes have been suggested to provide greater statistical power than tests based on the underlying single nucleotide polymorphism and genetic variants only (Bader, 2001; Fan and Knapp, 2003).
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Patients
Seven years ago, the MGBA project was initiated (Preuss et al., 2000
, 2001; Soyka et al., 2002). All inpatients were recruited from a ward for treatment of alcohol dependence. All patients were older than 18 years and met ICD10 and DSM-IV criteria for alcohol dependence. Characteristics of alcohol and nicotine dependence were assessed with a structured interview Semi-structured Assessment for the Genetics of Alcoholism (SSAGA) (Bucholz et al., 1994; Hesselbrock et al., 1999). These characteristics included age at onset of alcohol and/or nicotine dependence, average alcohol and nicotine consumption during the last week before admission, maximum quantity of alcohol ever consumed in 24 h, duration of alcohol dependence and smoking, and number of DSM-IV alcohol dependence criteria endorsed. Age at onset of alcohol dependence was assessed computing the mean of retrospectively obtained first alcohol dependence ages at onset criteria as mentioned in DSM-IV by the SSAGA: higher consumption of alcohol than intended, attempts to stop or control alcohol consumption, significant time spent to consume alcohol or recover from alcohol intake, regular withdrawal symptoms during important daily obligations like school or work, reduction of important occupational or private activities because of alcohol intake, continued alcohol consumption despite the occurrence of psychological or physical harm and occurrence of 50% higher tolerance to alcohol effects. Daily alcohol intake data was obtained using the typical daily average alcohol consumption of the last 7 days before admission. Pure alcohol intake was computed in g/day. Duration of alcohol dependence was computed as the difference between current age and age at onset.
Finally, to compare the influence of functional dopamine transporter and D2 receptor gene haplotypes on the inpatient's consumption quantity of alcohol and nicotine, a median split of average alcohol intake during 7 days before admission and mean daily nicotine consumption before admission were conducted. As a result, a group of mild and strong consumers of both maximum quantity of alcohol in 24 h and daily nicotine consumption were generated.
Genotyping
Genomic DNA was extracted from whole blood according to standard procedures.
Dopamine transporter gene
Polymerase chain reaction (PCR) was used to amplify the 40-base pair variable number of tandem repeat genetic variants located in the 3'-UTR of the dopamine transporter gene as described elsewhere (Sano et al., 1993). PCR products were subjected to electrophoresis in 2.5% agarose gels containing ethidium bromide. The numeric designation of each allele refers to the number of repeats it contains.
The single nucleotide polymorphisms rs2617605 (C/T; intron 2), rs37022 (A/T; intron 7) and rs40184 (C/T; intron 14) were genotyped applying the TaqMan technology (Assay-on-Demand) on an ABI7000 system (Applied Biosystems, Foster City, CA, USA) with the following assay-IDs: rs2617605 (C_15898456_10), rs37022 (C_3284821_20), and rs40184 (C_2960969_10). The standard PCR reaction was carried out using a TaqMan Universal PCR Master Mix reagent kit in a 10 µl volume according to the manufacturer's instructions.
Dopamine D2 receptor gene The single nucleotide polymorphisms rs1079597 (C/T; intron 1; ‘Taq B’), rs1800498 (A/G; intron 2; ‘Taq D’) and rs1079594 (A/C; intron 7) were amplified and detected using the TaqMan technology as described above with the following ‘Assay-on-Demand’-IDs: rs1800498 (C_2601166_10), and rs1079594 (C_10722_10). Probes and primers for single nucleotide polymorphism rs1079597 were designed by the ‘Assay-on-Design’-service of Applied Biosystems.
The genotyping methods for the single nucleotide polymorphisms rs1800497 (A/G; ‘Taq A’) and rs1799732 (141 C Ins/Del; 5'-UTR) were taken from Grandy et al. (1993), Arinami et al. (1997) and Breen et al. (1999).
Reference sequences and single nucleotide polymorphism rs-numbers were obtained from the National Centre for Biotechnology Information (NCBI) database (http://www.ncbi.nlm.nih.gov/). All laboratory procedures were carried out blind to case control status.
Statistics
All continuous data were tested for normal distribution by Kolmogorov–Smirnov non-parametrical tests. HWD was analyzed for each sample (smokers and drinkers). The relationship between continuous parameters like age and alcohol dependence criteria such as age at onset, duration of alcohol dependence and daily alcohol intake in mild and strong drinkers and smokers were computed using Student's t-test.
The relationship between the D2 dopamine receptor gene and dopamine transporter genotypes and dichotomized characteristics of nicotine and alcohol dependence were tested using 
2 tests. To permit comparisons between the different associations found, independently of the sample size, odds ratios (OR) were computed with 95% confidence intervals (CI) comparing allele frequency and disease-related traits.
As recently recommended by Wigginton et al. (2005), the Hardy–Weinberg disequilibrium (HWD) was verified using the exact test (Guo and Thompson, 1992), which was calculated by the FINETTI software from the GENESTAT web page (http://ihg.gsf.de/cgi-bin/hw/hwa1.pl). Computations of D2 dopamine receptor gene and dopamine transporter single nucleotide polymorphism linkage disequilibrium matrices and estimation of haplotype frequencies across groups were conducted using THESIAS (Version 3.1) (Tregouet et al., 2002).
A two-tailed a-significance level of P = 0.05 was defined to be statistically significant. Due to the experimental character of this analysis, correction of significance levels was not used.
Ethical standards
A signed written informed consent was obtained from patients and controls after complete and extensive description of the study. The Ethics Committee of the Ludwig–Maximilians University of Munich approved of the study.
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Sample characteristics
Three hundred thirty three alcohol dependent and habitual smoking subjects (265 males) were enrolled in the study, of whom N = 106 were mild, N = 227 were strong smokers, whereas N = 191 were strong drinkers and N = 142 mild. Strong smokers had a significantly higher mean and maximal daily alcohol intake. Vice versa, strong drinkers had a significantly higher amount of daily nicotine consumption. Further sample characteristics across the groups are presented in Table 1.
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Results of genotyping
Allele and genotype frequencies are demonstrated in Table 2. While not significantly associated with smoking- and drinking-related phenotypes, one D2 dopamine receptor gene single nucleotide polymorphism (rs1801028; D2 dopamine receptor gene Ser311Cys) genotype frequency significantly deviated from HWD, and was excluded from subsequent analyses. All other D2 dopamine receptor gene and dopamine transporter genetic variants did not significantly differ from expected HWD genotype frequencies. While no significant relationships were found for dopamine transporter single nucleotide polymorphisms, univariate statistical comparisons revealed significant associations for the D2 dopamine receptor genes rs1079597 and rs1079594 single nucleotide polymorphisms with smoking intensity and the D2 dopamine receptor genes rs1079597, rs1079594 and rs1800497 single nucleotide polymorphisms with average alcohol intake.
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All other single nucleotide polymorphism's allele distributions of the D2 dopamine receptor gene were similar between smoking and drinking groups.
No subsequent haplotype analysis was performed for dopamine transporter polymorphisms.
Linkage disequilibrium between single nucleotide polymorphism markers within the D2 receptor and dopamine transporter genes
The linkage disequilibrium between the D2 dopamine receptor gene single nucleotide polymorphism markers for drinkers and smokers are presented in Table 3a and b. The LD matrices between mild and strong drinkers and smokers did not differ significantly. While a high degree of linkage disequilibrium was detected for the habitual smokers, with the exception of Taq B with DRD-141 Ins/Del and Taq1D with Taq1A, the drinker's group additionally had a low LD for –141 Ins/Del and all other D2 dopamine receptor gene single nucleotide polymorphisms (see Table 3a and b).
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Identification of common haplotypes
Using THESIAS 3.1 software, best estimates for the generation of D2 dopamine receptor gene 5 marker haplotypes were computed. The three most common haplotypes for smokers and drinkers were identified (Ins-T-A-A-A2 (haplotype 1); Ins-T-G-A-A2 (haplotype 2); Ins-C-G-C-A1 (haplotype 3), shown in Table 4). These three haplotypes were present in 85% of all drinking subjects and 84% of all smokers (see Table 4).
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As also demonstrated in Table 4, the amount of drinking was associated with haplotype 3, which was detected with a higher frequency in strong drinkers, whereas a higher frequency of haplotype 2 was associated with more nicotine units.
Since a significant difference of male and female frequency across drinking and smoking groups were found in this sample (see Table 1), a separate analysis of haplotypes on smoking and drinking behaviour was conducted. Comparing the distribution of the three haplotypes between males and females, only haplotype 1 (Ins-T-A-A-A2) was significantly more often present in males compared to females (2: 4.27; df: 1; p: 0.045), while haplotype 2 and 3 frequencies did not differ between the genders. However, this haplotype was not associated with drinking or smoking behaviour in previous analysis.
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Discussion |
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The most important findings of these analyses of the MGBA, are that two common D2 dopamine receptor gene haplotypes are associated with quantity of smoking and drinking in a sample of alcoholics who were habitual smokers.
However, in contrast to previous research (Lerman et al., 1999; Sabol et al., 1999; Bierut et al., 2000a), an association between dopamine transporter genetic variants and smoking- and drinking-related behaviour could not be detected in this sample. This does not disprove that genetic variants of the dopamine transporter exert an influence on the development of alcohol and nicotine dependence, but the effect of dopamine transporter on the two disorders might be due to factors other than quantity of intake.
The other finding supports the influence of the D2 dopamine receptor gene and its genetic variants on alcohol and nicotine dependence-related traits, and might be one of the potential candidate gene variants influencing both the risk for alcohol and nicotine dependence. The results of this study corroborate with both associations of D2 dopamine receptor gene variants with smoking behaviour (Noble et al., 1994; Comings et al., 1996; Spitz et al., 1998) and alcohol dependence (review by Bowirrat and Oscar-Berman, 2005; recently Berggren et al., 2006). They might also, in part, explain the conflicting results from numerous association studies on the D2 dopamine receptor gene with alcohol and substance use disorders (ASUD). While two different quantity and not diagnosis related phenotypes were used in this study (average daily alcohol intake, average quantity of daily smoking) for association analyses, compared to previous research, these latter phenotypes might be closer to the biological substrate of drinking behaviour. Since these quantity-related phenotypes were proposed to be related to severity of ASUD (Drummond, 2000; Edwards, 2004), and if genetic variations of the D2 dopamine receptor gene were related to the quantity rather than diagnosis related phenotypes, variations in the magnitude of alcohol consumption in patients with alcohol dependence in previous studies might have led to conflicting results when genetic variations are compared with diagnoses and not with a related phenotype.
Undoubtedly, the relationship between the dopamine system and ASUD is complex. Previous studies proposed an abnormality of dopaminergic neurotransmission to be one of the pathogenic mechanisms of alcohol and nicotine dependence (review by Bowirrat and Oscar–Berman, 2005). Beside a direct association with alcohol and nicotine dependence, the D2 dopamine receptor gene A1 allele's role in alcoholism has also been associated with sensitivity to stress (a major environmental factor in vulnerability to alcoholism) (Kreek and Koob, 1998) and disinhibitory behaviour (Comings et al., 1996; Lu et al., 2001). As a result, behavioural disinhibition might also lead to an increase of alcohol or nicotine consumption which are both risk factors for developing an ASUD. A set of impulsive and compulsive behaviour are also part of the proposed Reward Deficiency Syndrome (RDS), which suggested inefficiency in the acquired (or unnatural) reward system (Comings and Blum, 2000). RDS also encompasses the acquired need to escape or avoid the negative effect created by repeated cycles of alcohol and substance abuse and dependence because of an altered response of the dopamine system, including the D2 dopamine receptor gene (Bowirrat and Oscar–Berman, 2005). These hypotheses are supported by neuroimaging studies (Volkow et al., 2001) which revealed that acute and chronic drug consumption have different effects on proteins involved in dopamine synaptic transmission. Whereas acute drug administration increases dopamine neurotransmission, chronic drug consumption results in a marked decrease of D2 dopamine receptor density in the striatum and in dopamine activity. This decrease might persist months after detoxification and is associated with deregulation of frontal brain regions (Volkow et al., 2002, 2004). Furthermore, a lower receptor D2 dopamine receptor density was also reported from alcohol-dependent individuals in comparison with controls (Volkow et al., 2004) and the authors suggested that a low D2 dopamine receptor availability in alcoholics may reflect a predisposing factor which might be genetically influenced. Overexpression of the D2 dopamine receptor in rats, on the other hand, decreased voluntary alcohol intake significantly (Thanos et al., 2001, 2004, 2005) and high levels of D2 dopamine receptors have been reported to be a protective factor for alcohol dependence (Volkow et al., 2006).
Studies of the potential functional consequences of D2 dopamine receptor gene variants, like Taq1A or –141 Ins/Del, which were also investigated in this study, however, are controversial. A number of positive (Thompson et al., 1997; Pohjalainen et al., 1998; Jonsson et al., 1999; Ritchie and Noble, 2003) and negative results (Laruelle et al., 1998; Pohjalainen et al., 1999) were reported doubting the strong effects of single nucleotide polymorphisms and derived haplotypes on dopaminegic neurotransmission. Furthermore, no functional haplotype of the D2 dopamine receptor gene has been identified yet. Thus, the potential functional relevance of the two common haplotypes reported from this study remains to be investigated, since they contain both potentially functional relevant polymorphisms (–141 Ins/Del and Taq1A) or at least markers for non-identified functional dopamine receptor gene variants (Ritchie and Noble, 2003).
Regarding the relationship between quantity of intake and dopaminergic candidate genes, it is worth mentioning that the D2 dopamine receptor gene Taq IA polymorphism has been related to alcohol consumption in male social drinkers in two studies (Hallikainen et al., 2003; Munafo et al., 2005). For both samples, the D2 dopamine receptor gene 1A allele carriers were found to have less alcohol intake, which is quite counter intuitive since many studies associated this allele with a higher risk for alcohol dependence. Otherwise, significant associations of the D2 dopamine receptor gene Taq1A polymorphism but not dopamine transporter genetic variants, and progression of smoking behaviour, including cigarettes smoked in a lifetime, were reported from a recent study in adolescents (Audrain-McGovern et al., 2004). The smoking phenotype in this study resembles the quantity of smoking phenotype under investigation in our study and had similar associations. Quantity of smoking and progression of nicotine dependence, might be both genetically influenced and related, as recently reported (Pergadia et al., 2006).
In comparison to this study, none of these previous studies investigated D2 dopamine receptor gene haplotypes, which might add information to the D2 dopamine receptor genetic variants and increase the power to detect an association with a certain phenotype (Fan and Knapp, 2003). Thus, these common D2 dopamine receptor gene haplotypes might not only be of relevance in subjects with alcohol dependence and habitual smoking. They might influence the quantity of consumption in non-dependent individuals too. Genetic and environmental factors other than these D2 dopamine receptor gene haplotypes might, in addition, play a significant role in the development of alcohol and substance dependence in subjects at risk. Again, more research is needed to clarify the role of these haplotypes and their potential interaction with other genes and their common influence on high quantities of consumption and subsequent alcohol and substance dependence. Even more recent studies on the relationship between the D2 dopamine receptor gene polymorphisms and alcoholism focused on the D2 dopamine receptor gene Taq IA polymorphism alone (Berggren et al., 2006), only a few studies investigated haplotypes of the D2 dopamine receptor gene polymorphisms in relation to alcohol or nicotine dependence. One study reported significant associations of the D2 dopamine receptor gene haplotypes with alcohol dependence (Noble et al., 2000) although this study did not employ descriptive statistics to estimate the most common D2 dopamine receptor gene haplotypes. The other study, investigating an overlapping set of polymorphic D2 dopamine receptor gene markers, did not detect an association with severity of alcohol dependence (Gelernter and Kranzler, 1999). The latter's D2 dopamine receptor gene haplotype also significantly overlapped with those investigated in our analyses (3 of 5 single nucleotide polymorphisms). While similar frequencies were reported in their study for the three most common haplotypes, the phenotype was different although related (severe vs less severe alcoholism), and their sample size was significantly smaller (N = 160 alcohol-dependent individuals). In case–control studies it has been estimated that to detect the role of genes with a small effect size lower than two, which is in the range of the D2 dopamine receptor gene—alcoholism relationship, case—control sets of 300–400 subjects are necessary (Noble, 2003; Berggren et al., 2006). These differences in study design might have resulted in such conflicting results as theirs and ours.
Not surprisingly, alcohol-dependent inpatients had a high rate of habitual smoking in this sample. Almost 90% of these subjects were habitual smokers. Furthermore, strong drinkers had significantly more nicotine units consumed per day and vice versa, strong smokers had a significantly higher maximal and daily alcohol intake. These findings corroborate with previous reports of the mutual influence of smoking and drinking quantities (Bierut et al., 2000b). Smoking in alcohol-dependent individuals has been related to a more severe course of the disease (Anthony and Echeagaray-Wagner, 2000), more cognitive deficits (Glass et al., 2006) and a higher risk of relapse (Hurt and Patten, 2003).
Of course, there are limitations to the study. The sample size of over 300 alcohol-dependent individuals, while larger than that of previous studies, might still be too small to detect all associations between genes and phenotypes. It has to be considered that the sample is still divided into two groups to distinguish between mild and strong consumers. This might have contributed to the non-significance of the association between dopamine transporter polymorphisms with the quantum of smoking and drinking. Finally, quantity-related phenotypes of smoking and drinking are overlapping and mutually influencing but still different. Thus, the common background of the two phenotypes, like behavioural disinhibition, has to be clarified in future research.
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