Pleiotropic effect of the TPH A779C polymorphism on nicotine dependence and personality.код для вставкиСкачать
American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 134B:20 – 24 (2005) Pleiotropic Effect of the TPH A779C Polymorphism on Nicotine Dependence and Personality M. Reuter* and J. Hennig Department of Psychology, Center of Psychobiology and Behavioral Medicine, University of Giessen, Giessen, Germany Recent studies from molecular genetics have suggested an association between the tryptophan hydroxylase 1 (TPH1) gene and nicotine addiction indicating a dysfunction of the serotonergic (5-HT) system in smoking behavior. In a sample of 252 healthy subjects, a significant association between variations observed in nicotine dependence and the heterozygous AC-genotype of the TPH A779C polymorphism could be demonstrated. Moreover, the heterozygous genotype was significantly associated with a personality trait of neurotic aggression (indirect hostility, negativism), as measured by the Buss–Durkee-HostilityInventory (BDHI). The positive heterosis effects with respect to nicotine addiction and personality support the idea that the TPH1 gene exerts pleiotropic effects. ß 2005 Wiley-Liss, Inc. KEY WORDS: TPH1 A779C polymorphism; 5-HT; nicotine addiction; personality; pleiotropic effect INTRODUCTION Studies from behavioral genetics reveal the high heritability of smoking behavior, ranging from 47% to 76% [Heath et al., 1995; Hughes et al., 1997], which is at least as high as the heritability of alcohol dependence [Hughes et al., 1997]. Candidate genes that contribute to the phenotype of nicotine dependence were polymorphisms in cytochrome P450 genes, which are involved in nicotine metabolism, and genes relevant for the metabolism of dopamine (DA) because DA was assumed to be the final common pathway of reward (for a review see Spanagel and Weiss, 1999). Several authors also reported associations between polymorphisms in genes of the serotonergic system (5-HT system) and smoking behavior. The 5-HT system is involved in many physiological and psychological processes including sleep, appetite, mood, aggression, and sexual behavior. The link to nicotine dependence comes from evidence that nicotine increases 5-HT in the central nervous system and that central 5-HT levels decrease during nicotine withdrawal [Ribeiro et al., 1993; Mihailescu et al., 2002]. Based on these findings, the hypothesis has put forward that mood and appetite disturbances during nicotine withdrawal are mediated through a reduced activity of the 5-HT system [Ribeiro et al., 1993]. *Correspondence to: Dr. M. Reuter, Department of Psychology, Justus-Liebig-University of Giessen, Otto-Behaghel-Str. 10F, D-35394 Giessen, Germany. E-mail: [email protected] Received 2 August 2004; Accepted 20 October 2004 DOI 10.1002/ajmg.b.30153 ß 2005 Wiley-Liss, Inc. Lerman et al.  reported an association between the A779C single nucleotide polymorphism (SNP) of the tryptophan hydroxylase 1 (TPH1) gene and smoking behavior. However, only the age of smoking initiation differed significantly between groups defined by genotypes, with lowest age at smoking initiation in carriers of the AA genotype and highest age in carriers of the CC genotype. Other smoking related variables were not linked to the TPH1 polymorphism, including (a) the degree of nicotine dependence measured by the Fagerstrom Test of Nicotine Dependence (FTND) [Heatherton et al., 1991], (b) smoking status, (c) quitting history, and (d) current smoking rate. In another study, Sullivan et al.  reported associations for the A779C SNP and for another marker in the seventh intron of the TPH gene [i.e., the C218A SNP] and smoking initiation but not progression to nicotine dependence. In order to evaluate an association with smoking initiation, frequencies of genotypes, alleles, and haplotypes of the two loci of the TPH1 gene, that could be demonstrated to be in strong linkage disequilibrium [Nielsen et al., 1997; Kunugi et al., 1999; Marshall et al., 1999], were compared between lifetime nonsmokers and smokers (regular smokers with low and high scores on the Fagerstrom Tolerance Questionnaire (FTQ) [Fagerstrom, 1978]. A possible association between the TPH1 markers and the progression to nicotine dependence was tested by comparing frequencies of genotypes, alleles, and haplotypes between smokers with low or high FTQ scores. With respect to smoking initiation, there were highly significant differences in genotype, allele, and haplotype frequencies between lifetime nonsmokers and regular smokers. The A-allele and the A-haplotype were more prevalent in smokers than in nonsmokers. Although, the findings of Sullivan et al.  and Lerman et al.  did not yield identical results, they nonetheless revealed both a significant association between the A-allele of the C779A polymorphism and variables relevant for smoking behavior. Because both TPH1 markers (C218A and C779A) are located in a noncoding region and because no exon skipping or alternative splicing have been reported, it is assumed that these polymorphisms are not etiological mutations but may be in linkage disequilibrium with an as yet unidentified polymorphism in the TPH gene [Han et al., 1999; Rotondo et al., 1999]. Recently, Walther et al.  identified a second TPH isoform-referred to as TPH2— in mice which is predominatly expressed in the brain stem, while the classical TPH gene—now called TPH1—is expressed in the gut, pineal gland, spleen, and thymus. The authors also identified a TPH2 homolog on human chromosome 12 [GenBank: AY098914]. Also SNPs on TPH2 have now been detected [e.g., Harvey et al., 2004] but unfortunately after the completion of the present study, so that this promising candidate gene could not be considered. Beside nicotine addiction, the TPH1-gene has been found to be related to impulsive-aggressive personality traits [Rujescu et al., 2002; Hennig et al., 2004], as well as behaviors including suicide which reflects an extreme form of auto-aggression [Nielsen et al., 1994; Mann et al., 1997; Abbar et al., 2001; Souery et al., 2001]. Findings from molecular genetics support prior results from neurochemical studies indicating that aggression as well as impulsivity is marked by a dysfunctional Nicotine Dependence and Personality serotonergic system [e.g., Asberg and Traskman, 1981; Brown and Linnoila, 1990]. Moreover, there is strong evidence from the literature that impulsivity [Reuter et al., 2002a] as well as unsocialized-aggressive behaviors [Zuckerman, 1993], are related to drug addiction. In sum, these findings suggest a pleiotropic effect of the TPH1 gene: i.e., the TPH1 gene exerts a number of influences, affecting, at least, two different phenotypes, nicotine addiction and personality. The aim of the present study was twofold. First, to further investigate the role of the 5-HT system on nicotine dependence and smoking related behaviors. This was done by attempting to replicate the results by Sullivan et al.  and Lerman et al.  who reported an association between the THP1 polymorphism C779A and smoking behavior. Both research groups claimed the necessity of a replication study. The second aim was to look for an association of the TPH1 gene with the personality trait of aggressiveness with the aim of detecting a drug-prone personality trait. MATERIALS AND METHODS Sample The sample of the genetic association study consisted of unrelated subjects (N ¼ 252) of the Giessen Gene Brain Behavior Project (125 men and 127 women, age: M ¼ 25.43, SD ¼ 5.71) of whom 108 were smokers and 144 were nonsmokers. All participants were Caucasian students of German ancestry without any history of psychopathology or drug abuse (except of nicotine) who voluntarily participated in the study after having been informed about the aims of the study and after having given their written informed consent. There was no selective dropout because everyone asked agreed to participate. For a subgroup of subjects (N ¼ 200), questionnaire measures of the personality trait aggression-hostility were available. The study was approved by the ethics committee of the German Psychologist Association. As the 5-HT system seems to be involved in cognitive processes [e.g., Richter-Levin and Segal, 1996; for a review see Buhot, 1997; Nathan et al., 2000], by using the homogenous group of university students the risk of confounding the results with intellectual ability was reduced. 21 Genetic Analyses DNA was extracted from buccal cells to avoid a selective exclusion of subjects with blood and injection phobia. Purification of genomic DNA was performed with a standard commercial extraction kit (High Pure PCR Template Preparation Kit; Roche Diagnostics, Mannheim, Germany). Genotyping of the TPH A779C polymorphism was performed by real-time PCR using fluorescence melting curve detection analysis by means of the Light Cycler System (Roche Diagnostics). By means of the melting curve analyses SNPs could be detected without conducting gel electrophoresis and ensuing sequencing after amplification. The primers and hybridization probes used (TIB MOLBIOL, Berlin, Germany) and the PCR protocols were as follows: forward primer: 50 -CTTATATGTGTGAGTCTGAGTGG-30 ; reverse primer: 50 -GGACATGACCTAAGAGTTCATGGCA-30 ; acceptor hybridization probe: 50 -LCRed640-CACGCTGCAGTGCTTAACATACGTTTATAA-phosphate-30 ; donor hybridization probe: 50 -CTGAAAGAGAGGTACAAGTT-fluorescein-30 . The PCR run comprised 55 cycles of denaturation (958C, 0 sec, ramp rate 208C per sec), annealing (608C, 10 sec, ramp rate 208C per sec) and extension (728C, 10 sec, ramp rate 208C per sec) which followed an incubation period of 10 min to activate the FastStart Taq DNA Polymerase of the reaction mix (Light Cycler FastStart DNA Master Hybridization Probes, Roche Diagnostics). After amplification, a melting curve was generated by keeping the reaction time at 408C for 2 min and then heating slowly to 958C with a ramp rate of 0.28C per sec. The fluorescence signal was plotted against temperature to yield the respective melting points (Tm) of the two alleles. Tm for the A allele was 51.478C (SEM ¼ 0.07) and 56.998C (SEM ¼ 0.06) for the C allele. Statistics Analyses of variance tested for possible associations between the TPH1-gene and smoking/personality. Due to the fact that the distribution of FTND scores is nonnormal and variancehomogeneity is not warranted, in addition nonparametric Kruskal–Wallis-H-tests were also performed. RESULTS Measures of Nicotine Addiction The degree of nicotine dependence was measured by the Fagerstrom Test of Nicotine Dependence (FTND) [Heatherton et al., 1991]. Dependent variables comprised: the total FTND score (FTND); the smoking categories suggested for the FTND (FTND-CAT: 0, nonsmoker; 1–2, weak dependence; 3–5, medium dependence; 6–7, strong dependence; 8–10, very strong dependence) [Fagerstrom and Schneider, 1989]; an aggregation of the FTND categories (FTND-adjCAT) which separates nonsmokers (FTND ¼ 0) from light smokers (FTND ¼ 1 or FTND ¼ 2) and addicted smokers (FTND > 2); and finally the categorical item 4 of the FTND assessing the average daily cigarettes consumed (0, nonsmokers; 1–10, 1; 11–20, 2; 21–30, 3; >30, 4). Measures of Impulsivity-Aggressiveness The personality trait of aggression-hostility was measured by applying the Buss–Durkee-Hostility-Inventory (BDHI) Buss and Durkee , which is one of the most frequently used clinical instrument for the assessment of aggression related behaviors. The questionnaire consists of eight subscales, assault, indirect hostility, irritability, negativism, resentment, suspicion, verbal hostility, and guilt. The distributions of genotype and allele frequencies of the TPH A779C polymorphism are shown in Table I. The genotype distribution was in Hardy–Weinberg equilibrium (TPH1: w2 ¼ 0.01, df ¼ 1, P ¼ 0.904). With respect to the TPH1 SNP, the proportion of the less common A-allele was 38.10% and of the more common C allele 61.90%. Results of the ANOVAs and the Kruskal–Wallis-H tests yielded significant associations between the TPH A779C SNP and all indicators of progression to nicotine addiction. Mean FTND raw scores, mean FTND categories, mean aggregated FTND categories, and mean cigarettes smoked per day were highest in subjects with the AC genotype (see Table II). There was neither a main effect for gender nor an interaction of genotype gender. TABLE I. Genotype and Allele Frequencies of the TPH A779C Polymorphism (N ¼ 252) TPH A779C AA AC CC A-allele C-allele 36 (14.28%) 120 (47.62%) 96 (38.10%) 192 (38.10%) 312 (61.90%) 22 Reuter and Hennig TABLE II. Associations Between the Degree of Nicotine Dependence and the TPH A779C Polymorphism FTND AA AC CC FTND-CAT AA AC CC FTND-adjCAT AA AC CC Cig/day AA AC CC N M SEM ANOVA Kruskall–Wallis-H-test 36 120 96 0.64 1.73 0.98 0.25 0.24 0.20 F ¼ 4.68, df ¼ 2,249, P ¼ 0.010 w2 ¼ 8.01, df ¼ 2, P ¼ 0.018 36 120 96 0.39 0.88 0.56 0.13 0.11 0.10 F ¼ 4.16, df ¼ 2,249, P ¼ 0.017 w2 ¼ 7.49, df ¼ 2, P ¼ 0.024 36 120 96 0.33 0.72 0.48 0.11 0.08 0.08 F ¼ 4.35, df ¼ 2,249, P ¼ 0.014 w2 ¼ 7.67, df ¼ 2, P ¼ 0.022 36 120 96 0.39 0.79 0.52 0.128 F ¼ 3.45, df ¼ 2,249, P ¼ 0.033 0.096 0.092 w2 ¼ 6.61, df ¼ 2, P ¼ 0.037 FTND, Fagerstrom Test of Nicotine Dependence (FTND) [Heatherton et al., 1991]. FTND-CAT [smoking categories suggested for the FTND; Fagerstrom and Schneider, 1989]: 0, nonsmoker; 1–2, weak dependence; 3–5, medium dependence; 6–7, strong dependence; 8–10, very strong dependence. FTND-adjCAT (aggregation of the FTND categories): separating nonsmokers (FTND ¼ 0) from light smokers (FTND ¼ 1 or FTND ¼ 2) and addicted smokers (FTND > 2). Cig/day (FTND item 4: average daily cigarettes consumed): 0, nonsmokers; 1–10, 1; 11–20, 2; 21–30, 3; >30, 4. With respect to personality, two subscales indirect hostility and negativism were significantly associated with the TPH1 gene (see Table III). For both subscales, mean aggressionhostility scores were highest in the heterozygous AC group and lowest in the CC group. There were no significant interaction effects genotype gender observable but a single significant gender effect for the irritability scale, showing higher irritability scores for women than men (men: M ¼ 4.84, women: 5.76, F(1,199) ¼ 5.42, P ¼ 0.021). In addition, two-factorial analyses of variance were calculated with the factors genotype and BDHI subscales after dichotomizing the personality measures, but no significant interaction effects were observed. DISCUSSION Previous studies demonstrate that nicotine consumption by smoking leads to an increase in 5-HT levels, and given the fact that 5-HT plays a crucial role in the regulation of mood and impulsivity, it was hypothesized that the serotonergic system is also involved in nicotine dependence. It was proposed that candidate genes for nicotine dependence should be investigated to elucidate the biological basis of smoking behavior and smoking abuse. Moreover, a dysfunctional 5-HT system has been demonstrated to be a prominent biological factor influencing personality traits related to aggression. These findings indicate a pleiotropic effect of the 5-HT system by influencing nicotine addiction as well as specific personality traits. TABLE III. Significant Associations Between the BDHI Subscales and the TPH A779C Polymorphism M SEM F df P 36 120 96 5.28 5.50 4.64 0.41 0.19 0.22 4.38 2,197 0.014 36 120 96 2.75 2.89 2.35 0.29 0.15 0.16 3.10 2,197 0.047 N Indirect hostility AA AC CC Negativism AA AC CC The present study investigated one of the most prominent SNPs of the serotonergic system, TPH A779C for such a pleiotropic effect. TPH plays a crucial role in 5-HT biosynthesis and therefore regulates the availability of 5-HT. With respect to the TPH1 polymorphism, previous findings that found associations with smoking related behaviors and nicotine addiction could be corroborated. The dilemma is that all three studies who investigated the role of the TPH1 gene on nicotine addiction, the study of Sullivan et al. , Lerman et al. , and our own study, differ with respect to the relative importance of the respective genotypes/alleles or the relevance of the TPH1 gene for different indicators of nicotine addiction. Sullivan et al.  found that the A-allele is significantly more prevalent in smokers than in nonsmokers, whereas Lerman et al.  could not find an association between the A-allele and smoking initiation. But Lerman et al.  reported a negative linear relationship between the number of A-alleles and the age of smoking initiation. Both studies did not find an association between the A779C polymorphism and progression to nicotine dependence. However, our own results found that the heterozygous AC genotype is associated with higher degrees of nicotine dependence as measured by the FTND and this irrespectively of the dependent variable used (FTND raw scores, FTND categories, FTND aggregated categories discriminating nonsmokers from light smokers and addicted smokers, number of cigarettes smoked per day). The result indicating highest prevalence of nicotine addiction in the heterozygous TPH1 group can be interpreted as a phenomenon called heterosis. Molecular heterosis refers to a situation in which the phenotype is greater (positive heterosis) or lesser (negative heterosis) for heterozygotes than for either homozygote [Comings and MacMurray, 2000]. Lee  already had reported a gender-specific molecular heterosis for the DRD2 TAQ IA polymorphism with respect to nicotine addiction. With respect to the TPH1 gene the heterosis effect was not gender-specific. In men as well as in women the AC genotype was associated with higher nicotine addiction. Sullivan et al.  used the FTQ which shares many items with the FTND to assess progression to nicotine dependence. They compared within the group of smokers those with high FTQ scores with those having a low FTQ score with respect to the genotype/allele distributions. Such a transformation to a Nicotine Dependence and Personality lower scale level is always related to a loss of information. This may explain the negative results in the Sullivan et al. study. In our study, we evaluated the FTND raw scores as a dependent variable in an ANOVA approach and therefore maintained the total variance in the dependent variable. Although Lerman et al.  did not find a significant association between the TPH1-gene and progression to nicotine dependence they at least reported highest FTND scores in smokers with the AC genotype which supports our own findings. The method of comparing nonsmokers with smokers yields the risk of contaminating possible associations between a gene loci and smoking behavior by including the group of light smokers into the group of heavy smokers. This may explain why Lerman et al.  did not find any association between the TPH1gene and smoking initiation. Despite of the reported differences across the TPH1-smoking studies, all three studies implicate unequivocally an association of the TPH1-gene on nicotine addiction. The present study revealed pleiotropic effects of the TPH1gene by influencing besides nicotine addiction also the personality trait of aggression-hostility. The two subcomponents of the BDHI, which were associated with the A779C polymorphism reflect the neurotic part of aggressive behavior. By means of a factor analytic approach Hennig et al. [in press] separated two factors of aggression within the BDHI, one factor representing neurotic hostility and one factor representing aggressive hostility. In a group of male nonsmokers aggressive hostility was highest in AA carriers and lowest in CC carriers whereas there was no association between TPH A779C SNP and neurotic hostility in the group of nonsmokers. In our group, we could demonstrate that the AC-genotype is associated with neurotic hostility in a mixed group of smokers and nonsmokers of both genders. This results support previous studies reporting a strong association between the personality trait of neuroticism and smoking behavior [Terracciano and Costa, 1999; Reuter and Netter, 2001]. In sum, the present study yielded further evidence from molecular genetics for the importance of the 5-HT system— especially of the TPH1 gene—for nicotine addiction. The report of a positive heterosis effect for smoking behavior and for the trait of neurotic hostility stresses the importance of pleiotropic effects for behavioral genetics. Pleiotropy can account for phenomena labeled in the addiction research arena as ‘‘drug prone personality’’ by explaining that the same gene contributes to a behavior (smoking) which has been shown to be associated with a certain personality trait (neurotic hostility). Given the fact that the A779C SNP is located on an intron it remains speculative how this gene can influence addictive urges or neurotic hostility. 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