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Genetic Influences on Smoking: Candidate Genes
Abstract
Twin studies consistently indicate important genetic influences on multiple aspects of smoking behavior, including both initiation and cessation; however, knowledge regarding the role of specific genes is extremely limited. Habit-forming actions of nicotine appear to be triggered primarily at nicotinic receptors on the cell bodies of dopaminergic neurons in the mesolimbic "reward" system of the brain, a region implicated in addiction to other substances including cocaine, opiates, and alcohol. Important aspects of the dopaminergic pathway include synthesis of dopamine in dopaminergic neurons, release of dopamine by presynaptic neurons, receptor activation of postsynaptic neurons, dopamine re-uptake by presynaptic neurons, and metabolism of released dopamine. Research examining the role of allelic variation in genes involved in these functions is being actively pursued with respect to addictive behavior as well as personality traits and psycho- and neuropathologic conditions and has implications for smoking research. In addition, genetic differences in nicotinic receptors or nicotine metabolism might reasonably be hypothesized to play a role in smoking addiction. A role of dopaminergic or other genes in smoking cessation is of particular potential importance, as research in this area may lead to the identification of subgroups of individuals for whom pharmacologic cessation aids may be most effective.
... Met de beschikbaarheid van 'DNA markers' die het gehele menselijke genoom bestrijken en verbeterde detectiemethoden is het in principe mogelijk geworden om de specifieke genen die verantwoordelijk zijn voor de variatie in nicotineverslaving te vinden. De wetenschappelijke kennis over de specifieke genen die verband houden met nicotineverslaving bevindt zich momenteel echter nog in de kinderschoenen [14,25]. Bij proefdieren zijn inmiddels wel een aantal genen die met verslaving te maken hebben geïdentificeerd [26]. ...
... De ontdekking dat het dopaminesysteem betrokken is bij de belonende effecten van nicotine is richtinggevend geweest bij de speurtocht naar welke genen een rol spelen bij nicotineverslaving. Er zijn meerdere 'dopamine receptor genen' geïdentificeerd [25,31] . De belangstelling heeft zich vooral gericht op het D2 dopamine receptor gen (DRD2). ...
... Bij nicotinegevoelige individuen is een andere benadering noodzakelijk die meer ingrijpt op de genetische predispositie [13]. De ontdekking van specifieke genetische determinanten van nicotineverslaving biedt belangrijke mogelijkheden om groepen rokers te onderscheiden die een verhoogd risico lopen op nicotineverslaving of bij wie bepaalde vormen van farmacotherapie het meest effectief zijn [25,31]. Er zijn snelle en betrouwbare DNA-tests in ontwikkeling De eerste onderzoekingen naar de genetische predispositie van roken werden gedaan in het licht van de discussie over de vraag of het roken van tabak longkanker veroorzaakt. ...
... Although several studies are available on nicotine addiction, it is still unclear how a smoking career develops. In the Netherlands 71% of the adolescents have ever tried a cigarette by age 18 (1) and smoking rates are rising in adolescents. Helping young people to avoid starting to smoke is a widely endorsed goal of public health, but there is uncertainty about how to do this. ...
... Most smokers begin smoking during childhood or adolescence: 89% of daily smokers tried their first cigarette by or at age 18, and 71 % of persons who have ever smoked daily began smoking daily before or by age 18 (2). In the Netherlands 71% of the adolescents have ever tried a cigarette by age 18 (1), which is comparable with data from the USA where 68.8% of all persons have tried a cigarette by age 18 (2). It can be concluded that most smoking careers start in adolescents, but at what age do children actually start to experiment with smoking? ...
... Initial support for a genetic influence on the use of tobacco came from cross-sectional studies in twins and showed a mean heritability of cigarette smoking of 0.53 with a range of 0.28-0.84 (18) (19). This means that between 28% and 84% of the observed variation in current smoking behaviour in the population from which the data were drawn, can be accounted for by genetic factors. ...
This report discusses the current knowledge on nicotine dependence, devoting a special chapter to smoking among youths, given that most smoking careers start in adolescence. The transition period, in which youths go from elementary to high school (ages 13-14), showes to be particularly risky for smoking initiation. The earlier youths start smoking, the more likely they will become dependent, and the more likely they will be heavier cigarette smokers in adult life. Since nicotine seems to be able to cause addiction in a short period of time, the aim should be to prevent children experimenting with cigarettes. Studies have shown that heavy smokers experience less aversive effects during their first smoke than light smokers. 'Light' cigarettes and flavour-enhancing additives could reduce aversive effects during smoking compared to regular cigarettes without such additives. Therefore, prohibiting the use of 'light' cigarettes and the use of flavour-enhancing additives could prevent adolescents from trying a second cigarette and ultimately contribute to preventing addiction among youths. In dit rapport wordt de huidige kennis op het gebied van nicotineverslaving bediscussieerd. Er is een speciaal hoofdstuk gewijd aan roken onder jongeren, omdat de meeste rokers op jeugdige leeftijd beginnen met roken. De overgangsjaren van basisschool naar middelbare school (13 tot en met 14 jaar oud) blijken een hoog-risico periode te zijn voor het beginnen met roken. Hoe eerder een kind begint met roken hoe waarschijnlijker het is dat hij of zij verslaafd raakt. Daarnaast correleert vroeg starten met veel roken op latere leeftijd. Omdat nicotine in staat lijkt te zijn om verslaving te veroorzaken in een korte tijdsperiode, is het belangrijk om te voorkomen dat kinderen met sigaretten gaan experimenteren. Studies hebben aangetoond dat zware rokers minder aversieve effecten hebben ervaren tijdens het roken van hun eerste sigaret dan lichte rokers. 'Light' sigaretten en smaakverbeterende additieven kunnen waarschijnlijk aversieve effecten verminderen tijdes het roken vergeleken met gewone sigaretten zonder zulke additieven. Daarom kan het verbieden van 'light' sigaretten en het verbieden van smaakverbeterende additieven, bijdragen aan het voorkomen dat kinderen een tweede sigaret proberen en zo uiteindelijk bijdragen aan het voorkomen van verslaving onder de jeugd.
... The MCLS is of particular relevance to addictive behaviours because it plays a central role in incentive, preparatory or acquisition aspects of reward-based behaviours (Corrigall et al. 1992;Rossing 1998;Comings & Blum 2000). The general hypothesis is that any source of genetic variation that acts to reduce MCLS function has potential to create an endogenous reward deficit that requires compensatory action-biological or behavioural. ...
... Our results show that carriers of 7R+ alleles report higher tobacco, cannabis and binge-drinking behaviour in young adulthood than non-carriers. These findings are consistent with previous reports (Shields et al. 1998;Laucht et al. 2007;McGeary et al. 2007) and with a reward deficit hypothesis in which compromised MCLS function motivates use of dopamine-stimulating agents, such as common drugs of abuse (Corrigall et al. 1992;Rossing 1998;Comings & Blum 2000). Results are also consistent with the idea of a generic neurobehavioural disposition to drug addiction for which 7R+ may play a role. ...
To investigate the combined effect of an exon III variable number tandem repeat in the dopamine receptor gene (DRD4) and insecure attachment style on risk for tobacco, cannabis and alcohol use problems in young adulthood. It was hypothesized that (1) individuals with 5, 6, 7 or 8 repeats (labelled 7R+) would be at increased risk for problematic drug use, and (2) risk for drug use would be further increased in individuals with 7R+ repeats who also have a history of insecure parent–child attachment relations. Data were drawn from the Victorian Adolescent Health Cohort Study, an eight-wave longitudinal study of adolescent and young adult development. DRD4 genotypes were available for 839 participants. Risk attributable to the combined effects of 7R+ genotype and insecure attachments was evaluated within a sufficient causes framework under the assumptions of additive interaction using a two-by-four table format with a common reference group. 7R+ alleles were associated with higher tobacco, cannabis and alcohol use (binging). Insecure attachments were associated with higher tobacco and cannabis use but lower alcohol use. For tobacco, there was evidence of interaction for anxious but not avoidant attachments. For cannabis, there was evidence of interaction for both anxious and avoidant attachments, although the interaction for anxious attachments was more substantial. There is no evidence of interaction for binge drinking. Results are consistent with a generic reward deficit hypothesis of drug addiction for which the 7R+ disposition may play a role. Interaction between 7R+ alleles and attachment insecurity may intensify risk for problematic tobacco and cannabis use.
... Environmental influences on the development of tobacco dependence are well documented, and it has been hypothesised that the overall rates of decline in smoking is a response to social pressures. The biological factors have been little studied, and genetic influences may be particularly strong within the remaining population of smokers [93,94). ...
p> Objectives: 1. Smoking is a major cause of death and often initiates in adolescence. Haploinsufficiency of CYP2A6 in adults is associated with lower cigarette consumption, lower cotinine level and higher quit rates. Other genes are also implicated in smoking behaviour. I explored genotypes of CYP2A6 and other genes in relation to smoking behaviour and cotinine levels in the UK-wide School Heart and Health Study (SHHS). 2. The association between low birthweight and adult disorders have been widely investigated. Environmental factors have been widely investigated but there has been less focus on genetic factors. There is however evidence that GH-CSH influences adult GH level, one year weight, metabolic syndrome traits and bone loss. I focused on major growth genes in relation to birthweight and other metabolic traits in the SHHS cohort. 3. Results from previous studies led to the hypothesis that some ACE D allele phenotypic associations may represent proxy marking of causal factors located in the GH-CSH gene cluster. I tested this hypothesis for cardiac muscle growth response to exercise and ACE level in a British army heart study cohort.
Methods: 1. 1,520 subjects from the SHHS were genotyped for CYP2A6 alleles * 1A, *1B, *2, *4, *5, *9 and *12 to classify predicted nicotine metabolism rate. DBH, MAOA, DRD4 and 5HT2A markers were also studied. 2. Microsatellites CSH1.01 and IGF2 (CA)n were genotyped and analysed in relation to birthweight and other metabolic traits in the SHHS cohort. 3. Combined analyses of ACE I/D and GH-CSH Bgl IIB in relation to exercise induced left ventricular mass (LVM) change and serum ACE activity were investigated in a group of Caucasian males in the UK.
Results: 1. Those predicted to be half normal metabolisers due to haploinsufficiency of CYP2A6 (carriers of one fully inactive allele, i.e. *2, *4, or *5 ) were more likely to be a current smoker at age 18 years. Current versus ever odds ratio was 1.95 (95% C.I. 1.03-3.68). Salivary cotinine levels in current smokers were significantly lower in the ‘normal’ group compared with ‘slow’ or ‘very slow’ group. 2. The CSH1.01 TT genotype in the SHHS boys showed a higher birthweight compared with those D1D1 or D2D2 genotype. There was no evidence for association of the IGF1 (CA)n genotype with birthweight in the SHHS, but boys of 192/192bp genotype did show a leg length 0.65cm greater (p=0.05) than those not homozygous for allele 192bp. 3. A significant association between GH-CSH Bgl IIB and ACE activity was detected but only through its LD with ACE I/D. No association between GH-CSH Bgl IIB and LVM change was found.</p
... GWAS simultaneously analyzes common genetic variants across the entire genome and has have been used since the early 2000s to identify genetic variants contributing to cigarette use phenotypes (26). Gene-finding efforts have identified associations between a variety of cigarette use phenotypes and single nucleotide polymorphisms (SNPs) within neuronal nicotinic acetylcholine receptor genes (nAChRs), the initial physiological targets of nicotine in the central and peripheral nervous system (27)(28)(29), and variable-number-of-tandem-repeats (VNTR) polymorphisms located in dopaminergic genes and serotonin transporter genes (30). ...
Tobacco use remains the leading cause of preventable death in the US, emphasizing the need to understand which genes and environments are involved in the establishment of cigarette use behaviors. However, to date, no comprehensive review of the influence of genes, the environment, and their interaction on cigarette use exists. This narrative review provides a description of gene variants and environmental factors associated with cigarette use, as well as an overview of studies investigating gene–environment interaction (GxE) in cigarette use. GxE studies of cigarette use have been useful in demonstrating that the influence of genes changes as a function of both the phenotype being measured and the environment. However, it is difficult to determine how the effect of genes contributing to different phenotypes of cigarette use changes as a function of the environment. This suggests the need for more studies of GxE, to parse out the effects of genes and the environment across the development of cigarette use phenotypes, which may help to inform potential prevention and intervention efforts aimed at reducing the prevalence of cigarette use.
• Key Messages
• No comprehensive reviews of the influence of genes, the environment, and their interaction on cigarette use exist currently.
• The influence of genes may change as a function of the environment and the phenotype being measured.
• It is difficult to determine how the effect of genes contributing to different phenotypes of cigarette use changes according to environmental context, suggesting the need for more studies of gene–environment interaction related to cigarette use to parse out effects.
... Ezt egy dopaminerg anyag mediálja, melyben a nikotin, nikotinreceptorokhoz kötôdve elôsegíti a dopamin kiáramlását és a neurotranszmissziót (2). A nikotinreceptor aktivitásában vagy a nikotinanyagcserében létrejövô genetikai elváltozások befolyásolhatják a dohányzáshoz történô hozzászokást, és számos ilyen génjelöltet már azonosítottak is (16). Ha ilyen gének résztvesznek a hozzászokásban, lehetôvé válik olyan, nem invazív szûrési eljárások alkalmazása, amilyeneket a molekuláris genetikában más elváltozások kiderítésére már alkalmaznak, így megállapítható lenne, kik azok az emberek, akiknél a gyógyszertani leszoktatás leginkább hatásos lenne. ...
Mai világunkban a dohányzás jelenti a legkönnyebben megelôzhetô betegség-és halálokot. A fejlett országokban 1950 és 2000 között bekövetkezett 260 millió fér-fi halálából, számítások szerint, mintegy 50 millióé tulajdonítható a dohányzás-nak. Az orális és kraniofaciális régióban a dohányzás a szájpadhasadék elôfordu-lásával, parodontális betegségekkel, a fogak elvesztésével, számos lágyrész-elváltozással, közöttük a szájüregi rákkal függ össze. Becslések szerint az ajak-, garat-és szájûri rákot 92%-ban a dohányzás okozza. Kevés tanulmány foglalkozik a dohányzás elleni számos próbálkozás hatásosságával, de tapasztalat szerint álta-lában a törvényi beavatkozások, mint a dohány adójának emelése, a hirdetés megtiltása, sokkal hatásosabbak, míg a nyomtatott oktatási anyagok, a leszokta-tásra alakított csoportok járnak a legkevesebb eredménnyel. Minden esetben az egészségügyi dolgozóktól származó tanácsok, esetleg beavatkozások a nem-törvé-nyi eljárások közül a leghatásosabbak. Számos ilyen jellegû professzionális eljá-rást írtak le, közöttük gyógyszeres, magatartásbeli és csoportos tanácsadásokat. A fogászatban dolgozóknak egyedülálló lehetôségük van betegeik dohányzási szo-kásainak befolyásolására. Ennek haszna a fogorvos vagy a fogászati asszisztens részére azonnal nyilvánvaló, a szájszag, a festékes fogak, a rossz szájhigiéné vagy a látható szájüregi betegségek alapján. A fogászatban dolgozókat számos írásos vezérfonal segíti betegeik tanáccsal való ellátásában. Magyar Onkológia 45:123-128, 2001 Tobacco represents the single most preventable cause of disease and death in the world today. Of 260 million male deaths in the developed world between 1950 and 2000, it is estimated that 50 million will be due to smoking. In the oral and craniofacial region tobacco use has been associated with the occurrence of cleft palate, periodontal disease and tooth loss, and a variety of soft tissue lesions including oral cancer. For example, smoking is estimated to account for 92% of cancers of the lip, oral cavity and pharynx. Few studies have examined the relative efficiency of the many different approaches to tobacco control but, in general, legis-lative approaches such as increasing tobacco taxes and prohibiting advertising are most effective and those based on printed educational materials and cessation groups, the least effective. In all cases, advice or intervention by health care professionals ranked among the most effective non-legislative approaches to control. A very wide range of professionally-based interventions have been descri-bed, including pharmacologic interventions, behavioral approaches and group counseling. The dental profession has a unique opportunity to influence tobacco use by their patients. Its use is almost always immediately evident to the dentist or dental assistant in terms of odor, staining, poor oral hygiene or obvious oral disease. There is also a tendency for the length of personal contact with the dentist to be greater than with a physician. Guidelines are now available that provide the dental professional with advice on the best approaches to tobacco control with their patients. Squier C. The hierarchy of approaches to tobacco control. Hungarian Oncology 45:123-128, 2001 A "Rizikótényezôk a szájüregi daganatok kialakulásában" c. symposiumon elhangzott elôadás, Semmelweis Egyetem, Budapest, 2001. március 23-24.
... 31 These specific DA projections play an important role in motivational behaviour and are thought to underpin the incentive, preparatory or acquisition aspects of reward based behaviours. [32][33][34] Reward deficit due to compromised function of the mesolimbic DA pathway has been associated with addiction disorders and may play a key role in ahedonia (the inability to experience pleasure), which is a diagnostic feature of depression. 20,23 Biosynthesis of DA for MCLS neurotransmission takes place in the ventral tegmental area and relies on neuronal uptake of the amino acid precursor tyrosine, which is hydroxylated into dihydroxy-l-phenylalanine (DOPA) by tyrosine hydroxylase (TH). ...
Genetic risk for depressive disorders is poor-ly understood despite consistent suggestions of a high heritable component. Most genetic stud-ies have focused on risk associated with single variants, a strategy which has so far only yield-ed small (often non-replicable) risks for depres-sive disorders. In this paper we argue that more substantial risks are likely to emerge from genetic variants acting in synergy within and across larger neurobiological systems (poly-genic risk factors). We show how knowledge of major integrated neurobiological systems pro-vides a robust basis for defining and testing the-oretically defensible polygenic risk factors. We do this by describing the architecture of the overall stress response. Maladaptation via impaired stress responsiveness is central to the aetiology of depression and anxiety and pro-vides a framework for a systems biology approach to candidate gene selection. We pro-pose principles for identifying genes and gene networks within the neurosystems involved in the stress response and for defining polygenic risk factors based on the neurobiology of stress-related behaviour. We conclude that knowledge of the neurobiology of the stress response sys-tem is likely to play a central role in future efforts to improve genetic prediction of depres-sion and related disorders.
... Important functions of the dopaminergic system are the activation of postsynaptic receptor neurons (i.e., dopamine receptors) and dopamine reuptake by presynaptic neurons (i.e., dopamine transporters). Candidate genes involved in dopaminergic neurotransmission are the dopamine receptor D2 and D4 and the dopamine transporter gene DAT1 [12]. Review studies and meta-analyses on the direct relation of dopaminergic system on smoking initiation showed mixed results. ...
Although environmental smoking (i.e., paternal and maternal smoking, sibling smoking, and peer smoking) is one of the most important factors for explaining adolescent smoking behavior, not all adolescents are similarly affected. The extent to which individuals are vulnerable to smoking in their environment might depend on genetic factors. The aim of this study was to examine the interplay between environmental smoking and genes encoding components of the dopaminergic system (i.e., dopamine receptor D2, D4, and dopamine transporter DAT1) in adolescent smoking onset. Data from two longitudinal studies were used. Study 1 consisted of 991 non-smoking early adolescents (mean age = 12.52, SD = .57) whereas study 2 consisted of 365 non-smoking middle to late adolescents (mean age = 14.16, SD = 1.07) who were followed for 16 and 48 months, respectively. Logistic regression analyses were conducted using Mplus. In study 1, we found positive associations between parents' and friends' smoking at the first measurement and smoking status 16 months later. In study 2 we found a positive association between friends' smoking and smoking onset 48 months later. Neither study demonstrated any interaction effects of the DRD2, DRD4, or DAT1 genotypes. In conclusion, the effects of environmental smoking on smoking onset are similar for adolescent carriers and non-carriers of these specific genes related to the dopaminergic system.
... Welche Gene etwa sind involviert in das Rauchverhalten? In welcher Weise beeinflussen die Gene, ob jemand mit dem Rauchen beginnt, dabei bleibt, aufhört, wieder rückfällig wird (Omenn 2000, Rossing 1998)? ...
Nach dem zweiten Weltkrieg war es um die medizinische Genetik nach den Erfahrungen mit der Verbindung zwischen Genetik und eugenischer Bewegung erst einmal still geworden. In der Folgezeit kam es zu enormen Fortschritten auf dem Gebiet der Molekularbiologie. Mei-lensteine waren die Entdeckung der Doppelhelixstruktur der DNA 1953 und die Entschlüsse-lung des genetischen Codes Ende der 60iger Jahre. Im Jahr 1973 gelang es zum ersten Mal, die Erbsubstanz von Labororganismen zu verändern und Ende der 70iger Jahre war man dann auch in der Lage, mit der Erbsubstanz des Menschen zu experimentieren: Die Neue Genetik entstand als Zweig der Biotechnologie. In den 70er Jahren expandierte die Molekularbiologie technisch, institutionell, kulturell und ökonomisch. Mit dem Beginn des Human Genome Projektes Mitte der 80er Jahre erhielt die genetische Forschung einen gewaltigen Zustrom an Geld und Energie. Ziel dieses größten Projektes in der Geschichte der Biowissenschaften ist, die Abfolge der ca. 3 Milliarden che-mischen Buchstaben des Genoms zu dokumentieren und die Funktion der etwa 30.000 bis 40.000 menschlichen Gene aufzuklären. Auf der aktuellen biomedizinischen Forschungsagen-da steht die Frage nach den genetischen Ursachen häufiger Krankheiten - u. a. Herzkrankheit, Krebs, Diabetes und psychische Krankheiten. Die Medien und Fachpublikationen sind voll von neuen Assoziationen zwischen Genen und dieser oder jener Krankheit sowie enthusiastischen Verkündigungen, wonach die molekulare Genetik die Gesundheitssicherung revolutionieren werde. Um zu einer realistischen Einschät-zung zu gelangen und der gesundheitswissenschaftlichen Diskussion zur Neuen Genetik sachkundig folgen zu können, muss man die Produkte der modernen Genomforschung zu-nächst einmal verstehen. Der vorliegende Text will dazu einen Beitrag leisten: Grundzüge, Grundgedanken und zentrale Befunde der Genomforschung und der genetisch-epidemiologi-schen Ursachenforschung werden mit Bezug auf Public Health präsentiert. Dabei werden Konzepte der maßgeschneiderten Therapie und Prävention, also auf die genetische Konstitution eines Individuums zugeschnittene Interventionen (etwa lebenslange prophylaktische Medikation oder Regimes zur Änderung des Lebensstils) dargestellt und ihre schon heute ab-sehbaren Begrenzungen - begründet in der Komplexität des multifaktoriellen Krankheitsge-schehens - herausgearbeitet. --
... This DBH 5′-Ins/Del polymorphism was not related to susceptibility to smoking in schizophrenia or other smoking behavior, such as the age of smoking onset. Other polymorphisms that affect smoking initiation may include acetylcholine (Greenbaum et al., 2006), serotonin , tryptophan (Sullivan et al., 2001) and dopamine (Rossing, 1998;Sullivan et al., 2001). For example, among male Japanese a polymorphism of MAO-A influenced nicotine dependence and smoking initiation, but not severity of smoking (Ito et al., 2003). ...
Recent evidence suggests that a dopamine beta-hydroxylase (DBH) polymorphism may play a role in determining an individual's predisposition to developing nicotine dependence. The mechanism for such an association may reflect nicotine's mediation of drug reward in the brain through actions on dopamine, a key mediator of drug reward. Because schizophrenia patients have usually high rates of nicotine use, they are a model group to study such an association. In this study, we hypothesized that the functional polymorphism of DBH (DβH5'-Ins/Del) was associated with smoking in patients with schizophrenia. This polymorphism was genotyped in 636 chronic male schizophrenia (smoker/nonsmoker=490/146) and 396 male controls (smoker/nonsmoker=231/165) using a case-control design. The cigarettes smoked per day (CPD) and smoking behaviors were evaluated by clinician-administered questionnaires and the Fagerstrom Test for Nicotine Dependence (FTND). The results showed no significant differences in DBH 5'-Ins/Del genotype and allele distributions between the patients and healthy controls or between smokers and nonsmokers in either patients or healthy controls alone. However, schizophrenic smokers with the Del allele smoked fewer cigarettes each day and had lower FTND score than those with Ins/Ins genotype. These results suggest that the DBH 5'-Ins/Del polymorphism may influence smoking severity among schizophrenic smokers.
... An extensive review of cancer genes divided into contributing to cancer risk and connected with cancer progression was written by Vogelstein and Kinzler (2004). An impact of genetic factor on health effects of tobacco smoking was also discussed more specifically in relation to head and neck cancer (Badawy et al., 2008;Rossing, 1998). As such specific genes as BRCA1 or APC involved in breast and colon cancer, respectively, were not discovered in head and neck cancer, an attention was paid on so-called "lowpenetration" genes, mainly those involved in carcinogens processing. ...
... The mesocorticolimbic system (MCLS) of the midbrain is a dopamine-mediated pathway involved in the incentive, preparatory, or acquisition aspects of reward (Comings & Blum, 2000). The MCLS has long been regarded the primary site of action of drugs of abuse (Corrigall, Franklin, Coen, & Clarke, 1992;Rossing, 1998). Nicotine increases dopamine activity within the MCLS (Vandenbergh et al., 2007). ...
Neurotic psychopathology has been extensively examined as a risk factor for nicotine dependence (ND). Genetic stratification may partially explain variability in risk estimates. Genetic variants that compromise dopaminergic neurotransmission may motivate exposure to dopamine-stimulating agents, including nicotine. The 7-repeat allele of a Variable Number Tandem Repeat (VNTR) polymorphism in DRD4 (and evolutionary derivatives 5, 6, and 8 repeats; 7R+) is associated with reduced dopamine receptor function. The purpose of this study was to examine association between both smoking initiation (SI) and progression to ND by young adulthood and (a) history of neuroticism during adolescence, (b) DRD4 7R+, and (c) interaction between neuroticism and DRD4 7R+.
Participants were drawn from the Victorian Adolescent Health Cohort Study, a longitudinal study of the health and well-being of young Australians across 8 waves (14-24 years). Neuroticism was measured at Waves 3 and 6 (mean 15.9 and 17.4 years). SI was defined as any smoking at any wave. ND was measured at Wave 8 (mean 24.1 years). Genotype data for the DRD4 VNTR were available for 839 participants.
While adolescent neuroticism was associated with SI, evidence for association with progression to ND was weak. However, there was evidence of interaction between neuroticism and DRD4 7R+: The odds of progression to ND among those with a history of neuroticism were more than 3.5-fold higher among 7R+ carriers.
Without considering stratification by 7R+, the association between progression to ND and neuroticism would have been assumed barely significant. However, among those carrying DRD4 7R+, risk of progression was considerably intensified.
... Use of tobacco products, cigarettes and smokeless tobacco continues to be a major health problem in the United States and the world. Socio-economic and genetic factors may contribute to this problem [1,3,4]. It has been reported that an estimated 3 million deaths occur worldwide due to tobacco use [2]. ...
Cigarette smoking is known to be a major risk factor for pancreatic cancer and pancreatitis is believed to be a predisposed condition for pancreatic cancer. As of this date, there is no established experimental animal model to conduct detailed studies on these two deadly diseases. Our aim is to establish a rodent model by which we can systematically study the pathogenesis of pancreatitis and pancreatic cancer.
Adult Male Sprague Dawley rats were exposed to graded doses of nicotine by various routes for periods of three to 16 weeks. Blood samples were measured for hormonal and metabolic parameters. The pancreas was evaluated for histopathological changes and its function was assessed in isolated pancreatic acini upon stimulation with cholecystokinin (CCK) or carbachol (Cch). The pancreatic tissue was evaluated further for oncogene expression.
Body weight, food and fluid intakes, plasma glucose and insulin levels were significantly reduced in animals with nicotine exposure when compared to control. However, CCK and gastrin levels in the blood were significantly elevated. Pancreatic function was decreased significantly with no alteration in CCK receptor binding. Pancreatic histology revealed vacuolation, swelling, cellular pyknosis and karyorrhexis. Mutant oncogene, H-ras, was overexpressed in nicotine-treated pancreatic tissue.
The results suggest that alterations in metabolic, hormonal and pathologic parameters following nicotine-treatment appear consistent with diagnostic criteria of human pancreatitis. It is proposed that rats could be considered as a potential animal model to study the pathogenesis of pancreatitis.
... A number of other candidate genes besides these also deserve consideration. 39,40 The strategy of our research program on smoking and nicotine is to use the positional and candidate gene approaches synergistically, and to collaborate with other groups that have complementary resources and methods. The goal is to identify those genes that contribute most to susceptibility, to use this knowledge as a tool to identify and characterize in greater detail the important environmental variables, and then to explore the interactions between genes and environment. ...
Cigarette smoking is associated with considerable morbidity, mortality, and public health costs. Genetic factors influence both smoking initiation and nicotine dependence, but none of the genes involved have been identified. A genome scan using 451 markers was conducted to identify chromosomal regions linked to nicotine dependence in a collection of 130 families containing 343 genotyped individuals (308 nicotine-dependent) from Christchurch, New Zealand. By pairwise analysis, the best result was with marker D2S1326 which gave a lod score under heterogeneity (H-LOD) of 2.63 (P=0.0012) and a nonparametric linkage (NPL, Zall) score of 2.65 (P=0.0011). To identify regions that warranted further study, rather than comparing the pairwise scores from the scan to theoretical thresholds, we compared them to an empirical baseline, found here to be H-LOD scores of 0.5 and Zall scores of 1.0. We also found a number of large (31-88 cM) regions where many (8-16) consecutive markers yielded small but positive Zall scores. Selected regions of chromosomes 2, 4, 10, 16, 17 and 18 were investigated further by additional genotyping of the Christchurch sample and an independent sample from Richmond, Virginia (91 families with 264 genotyped individuals, 211 nicotine-dependent). Multipoint nonparametric analysis showed the following maximums for the Christchurch sample: Chr. 2 (Zlr=2.61, P=0.005), Chr. 4 (Zlr=1.36, P=0.09), Chr. 10 (Zlr=2.43, P=0.008), Chr. 16 (Zlr=0.85, P=0.19), Chr. 17 (Zlr=1.64, P=0.05), Chr. 18 (Zlr=1.54, P=0.06). Analysis of the Richmond sample showed the following maximums: Chr. 2 (Zlr=1.00, P=0.15), Chr. 4 (Zlr=0.39, P=0.34), Chr. 10 (Zlr=1.21, P=0.11), Chr. 16 (Zlr=1.11, P=0.13), Chr. 17 (Zlr=1.60, P=0.05), Chr. 18 (Zlr=1.33, P=0.09). It is probable that the small samples used here provided only limited power to detect linkage. It may have been difficult therefore to detect genes of small effect, or those that are influencing risk in only a small proportion of the families. When simply judged against the usual standards of linkage significance, none of the individual regions yielded strong evidence in either sample. Some or all of the most positive results in the genome scan of the Christchurch sample, therefore, could be due to chance. However, the presence in the Christchurch scan of multiple large regions containing many consecutive positive markers, coupled with the relatively positive results in these same regions in the Richmond sample, suggests that some of these regions may contain genes influencing nicotine dependence and therefore deserve further study.
... The three shared loci among the EVRNVR and PKYRS tests is similar to that expected by chance, also suggesting that PKYRS regression analysis does not have power to detect loci modifying smoking history. However, the chromosome 5 marker D5S1354, identified as a quantitative trait locus for smoking history [Duggirala et al., this issue], and the "smoking" candidate gene DBH [Rossing, 1998], are two of the three shared loci. ...
Using the Collaborative Study on the Genetics of Alcoholism (COGA) data, we performed a sib-pair linkage analysis of two smoking-related traits and one alcoholism phenotype. The first trait, EVRNVR, was a dichotomous one we constructed based on epidemiological definitions of smoking. The second trait, PKYRS, used the quantitative pack-year history provided, and the third trait was the COGA alcoholism classification, ALDX1. There was some evidence for linkage of the EVRNVR trait to regions-on chromosomes 6, 9, and 14. Smaller numbers of loci provided nominal evidence for linkage to PKYRS, although some candidate gene regions were identified. The number of loci identified using EVRNVR suggests that a threshold-based phenotype may better identify loci affecting smoking history. Approximately one-third of the loci that showed evidence for linkage to EVRNVR at a nominal significance level (p < 0.01) also showed evidence for linkage to ALDX1. Some of these regions may represent loci increasing vulnerability to both smoking and alcoholism.
... It is not unreasonable to hypothesise that genetic polymorphisms may influence an individual's smoking behaviour. Candidate polymorphic genes include those involved in dopamine biosynthesis and metabolism, dopamine receptors, nicotinic acetylcholinergic receptors and enzymes involved in nicotine metabolism (Rossing, 1998). Variation in genes that encode enzymes responsible for chemical metabolism generally result from point mutations or small deletions/insertions that may lead to alterations in function of the enzyme (Kalow and Grant, 1995). ...
Large interindividual differences occur in human nicotine disposition, and it has been proposed that genetic polymorphisms in nicotine metabolism may be a major determinant of an individual's smoking behaviour. Hepatic cytochrome P4502A6 (CYP2A6) catalyses the major route of nicotine metabolism: C-oxidation to cotinine, followed by hydroxylation to trans-3'-hydroxycotinine. Nicotine and cotinine both undergo N-oxidation and pyridine N-glucuronidation. Nicotine N-1-oxide formation is catalysed by hepatic flavin-containing monooxygenase form 3 (FMO3), but the enzyme(s) required for cotinine N-1'-oxide formation has not been identified. trans-3'-Hydroxycotinine is conjugated by O-glucuronidation. The uridine diphosphate-glucuronosyltransferase (UGT) enzyme(s) required for N- and O-glucuronidation have not been identified. CYP2A6 is highly polymorphic resulting in functional differences in nicotine C-oxidation both in vitro and in vivo; however, population studies fail to consistently and conclusively demonstrate any associations between variant CYP2A6 alleles encoding for either reduced or enhanced enzyme activity with self-reported smoking behaviour. The functional consequences of FMO3 and UGT polymorphisms on nicotine disposition have not been investigated, but are unlikely to significantly affect smoking behaviour. Therefore, current evidence does not support the hypothesis that genetic polymorphisms associated with nicotine metabolism are a major determinant of an individual's smoking behaviour and exposure to tobacco smoke.
Genetic factors have clearly been shown to be related to susceptibility of lung cancer, particularly pulmonary adenocarcinoma. Genetic polymorphisms have been identified that have the potential to increase lung cancer risk. These genetic polymorphisms involve genes that are associated primarily with the metabolism of tobacco smoke carcinogens and the suppression of mutations induced by those carcinogens. Tobacco-associated versus nontobacco-associated lung cancers, gender differences, and geographic differences continue to be confounding factors in the evaluation of the genetic factors involved in lung cancer risk.
Although tobacco smoke, with its numerous carcinogens and procarcinogens, is strongly linked to lung cancer risk, many people have similar tobacco smoke and other environmental exposures and do not develop lung cancer. Also, the histologic types occurring in never-smokers differs from those occurring in smokers. People are thought to have different susceptibilities to cancer risk factors, including lung cancer risk factors; and a genetic basis for differing cancer risk factor susceptibilities has been proposed based on to the observation that different susceptibilities appear to be inherited based on aggregation of cancers within families. The concept of inherited susceptibilities explains why some people with little or no tobacco smoke exposure develop lung cancer. Further, genetic differences, gene-environment interactions, and risk factors could help explain why some people develop lung cancer with little or no smoke exposure, or at younger ages; why some heavy smokers do not develop lung cancer; and why some lung cancer patients have strong family histories of cancer. Studies of genetic factors associated with tobacco-related lung cancer risk have identified several genetic polymorphisms as potentially increasing lung cancer risk. These genetic polymorphisms involve genes that are associated primarily with the metabolism of tobacco smoke carcinogens and the suppression of mutations induced by those carcinogens. Tobacco-associated vs. nontobacco-associated lung cancers, gender differences, and geographic differences are all confounding factors in the evaluation of the genetic factors involved in lung cancer risk. There is much that remains to be discovered, and studies such as these must continue in order to further elucidate the relationship between genetic polymorphisms and lung cancer risk, and how such relationships may be used to prevent lung cancer, affect treatment responses, and improve clinical outcomes.
This chapter is devoted to the pharmacological actions of nicotine relevant for its dependence liability. As most, if not all, of the central actions of nicotine might, in principle, concur to its dependence liability, a chapter on this topic would have required a review of the whole psychopharmacology of nicotine, a task far beyond the limits of this chapter. However, some aspects of nicotine psychopharmacology, such as its effects on cognition, learning and performance, as well as the genetics of its central actions are covered in specific chapters of this volume. Therefore, these topics will be discussed when necessary but will not be specifically reviewed in this chapter.
The goal of this chapter is to introduce the reader to the world of tobacco smoking, the role of nicotine in inducing a nicotine addiction, as well as to be confident with some tools in measuring nicotine dependence and motivation to quit.
Moreover, it will serve to give an update overview about genetic risk factors for smoking behavior going in depth with molecular and biological aspects and to describe the role of genetic determinants in initiation and cessation of cigarette smoking.
Since the mid-20th century, the scientific community has substantially improved its understanding of the worldwide tobacco epidemic. Although significant progress has been made, the sheer enormity and scope of the global problem put it on track to take a billion lives this century. Curbing the epidemic will require maximizing the impact of proven tools as well as the development of new, breakthrough methods to help interrupt the spread of nicotine addiction and reduce the downstream morbidity.
Members of the Tobacco Action Committee of the American Thoracic Society queried bibliographic databases, including Medline, Embase, and the Cochrane Collaborative, to identify primary sources and reviews relevant to the epidemic. Exploded search terms were used to identify evidence, including tobacco, addiction, smoking, cigarettes, nicotine, and smoking cessation. Evidence was consolidated into three thematic areas: (1) determinants of risk, (2) maternal-fetal exposure, and (3) current tobacco users. Expert panel consensus regarding current gaps in understanding and recommendations for future research priorities was generated through iterative discussion.
Although much has been accomplished, significant gaps in understanding remain. Implementation often lags well behind insight. This report identifies a number of investigative opportunities for significantly reducing the toll of tobacco use, including: (1) the need for novel, nonlinear models of population-based disease control; (2) refinement of "real-world" models of clinical intervention in trial design; and (3) understanding of mechanisms by which intrauterine smoke exposure may lead to persistent, tobacco-related chronic disease.
In the coming era of tobacco research, pooled talent from multiple disciplines will be required to further illuminate the complex social, environmental and biological codeterminants of tobacco dependence.
The chapter presents a study on the characterization of multiple sites of action of ibogaine. This chapter describes findings that indicate support for the use of ibogaine, its metabolite, and/or ibogaine-related compounds in the treatment of addiction, based on their ability to target relevant multiple neurotransmitter sites appropriate for the drug of abuse examined. Because of the multiple components of reward systems, a “dirty” drug like ibogaine that affects multiple neurotransmitter systems should not be excluded from consideration. Indeed, it is a likely positive attribute. Based on radioligand binding and other in vivo/in vitro studies, and several behavioral assays, to characterize its effects, ibogaine has been reported to have affinities to at least the dopamine and serotonin transporters, and to the glutamatergic (NMDA), sigma, kappa- and mu-opioid, and nicotinic acetylcholine receptors. Cocaine also binds and inhibits the uptake of serotonin and norepinephrine, with equal potency. “Knockout” models of rodents missing dopamine reuptake transport still self-administer cocaine. Psychostimulants act predominantly to elevate brain dopamine, either by their ability to release dopamine, as is the case for amphetamine, or by blockade of the reuptake transporter, as in the case of cocaine.
Although nicotine dependence is one of the primary reasons why smokers cannot quit smoking, nicotine cannot explain all of the psychopharmacological effects of tobacco smoke. Accumulating evidence points to potent inhibition of monoamine oxidase (MAO) which metabolizes neurotransmitters relating to additive behaviour. We have therefore investigated the association between smoking behaviour and MAO (MAO-A variable number of tandem repeat in the promoter region and MAO-B A644G) polymorphisms. The genotypes were examined in 504 Japanese outpatients (217 men and 287 women) who visited Aichi Cancer Centre Hospital. The age-adjusted odds ratios (aORs) were estimated by a logistic model. Among males, we did not find a significant association of the smoking habit with either of the MAO polymorphisms. The median Fargastrom test for nicotine dependence (FTND) score among male current smokers was significantly higher with than without the MAO-A 4-repeat allele (5.8 and 4.7, respectively). The aOR of FTND ≥ 6 versus FTND < 6 was 2.72 (95% confidence interval 1.13-6.50) for males with the 4-repeat allele. Among females, the aOR of being current smokers compared to never smokers was 0.49 (0.26-0.93) for individuals with the 4-repeat allele. Our results indicate that the polymorphisms of MAO influence the smoking habit for female, as well as the nicotine dependence and smoking initiation for male smokers. These findings among male smokers support the view that MAO affects a smokers' requirement for nicotine and may explain why some people are predisposed to tobacco addiction and why some individuals find it difficult to stop smoking.
Nachdem im Trendbericht des letzten Jahres ausgewhlte Beispiele aus Bereichen der Umweltchemie besprochen wurden,1) sollen in diesem Jahr Ergebnisse aus Ökotoxikologie and Humantoxikologie behandelt werden. Zunchst werden einige Arbeiten aus den Bereichen der Entsorgungsverfahren und neue Entwicklungen bei Spurenstoffen vorgestellt. Da das Gebiet der nachhaltigen Chemie immer mehr in den Brennpunkt des Interesses rückt, werden auch neue umweltfreundliche Synthesen und Produkte ausführlich diskutiert.
Several types of evidence, including experiments with mice that lack the nicotinic acetylcholine receptor β2-subunit gene (CHRNB2), have suggested that a β2-containing nicotinic receptor is necessary for at least some of the reinforcing properties of nicotine. However, sequence variations in CHRNB2 have not been reported, and its role in influencing human smoking behavior and nicotine dependence is not known. We screened most of the introns and exons and found five novel single nucleotide polymorphisms (SNPs). We tested four of these SNPs in three large, carefully selected samples: nonsmokers (n = 317) and regular smokers low levels of nicotine dependence (ND, n = 238), or smokers with high-ND (n = 317). None of the four polymorphisms we tested, nor their estimated haplotypes, were associated with smoking initiation or progression to nicotine dependence. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:646–653, 2000. © 2000 Wiley-Liss, Inc.
An inverse association between cigarette smoking and idiopathic Parkinson's disease has been reported in several retrospective studies, but prospective evidence is available only for men. We assessed the association between the incidence of Parkinson's disease and smoking in two large prospective cohort studies comprising men and women. New cases of Parkinson's disease were identified in the Nurses' Health Study for 1976–1996, and in the Health Professionals Follow-up Study for 1986–1996. Smoking history was assessed at baseline and updated on subsequent biennial questionnaires. In women, the age-adjusted rate ratios (95% confidence intervals) for Parkinson's disease relative to never-smokers were 0.7 (0.5, 1.0) for past smokers, and 0.4 (0.2, 0.7) for current smokers. In men, the age-adjusted rate ratios for Parkinson's disease relative to never-smokers were 0.5 (0.4, 0.7) for past smokers, and 0.3 (0.1, 0.8) for current smokers. In both cohorts, the strength of the association decreased with time since quitting (among past smokers), increased with number of cigarettes per day (among current smokers), and increased with pack-years of smoking. These prospective findings confirm that an inverse association between smoking and the incidence of Parkinson's disease exists in both men and women.
Several drugs of abuse, including nicotine, are thought to exert their reinforcing effects through actions on the mesolimbic dopamine system. Animal and human studies suggest that chronic administration of addictive drugs may lead to impaired dopamine neurotransmission in the nucleus accumbens. We measured D1 receptor density in 11 smokers and 18 nonsmokers using positron emission tomography and the D1 receptor ligand [11C]SCH 23390. Ten of the smokers were scanned twice, once after overnight abstinence from cigarettes, and once while smoking at their usual rate, to account for possible acute effects of cigarette smoking on D1 receptor binding. In addition, eight control subjects were scanned twice to assess the reproducibility of the method. We used compartmental modeling to measure [11C]SCH 23390 binding potential, a measure of D1 receptor density. There were no differences in binding between abstinent and nonabstinent scans in smokers or in the two scans in controls. However, there was a significant reduction in [11C]SCH 23390 binding potential in smokers compared to nonsmokers in the striatum, most prominently in the ventral striatum. This suggests that there is a reduction in dopamine D1 receptor density in the ventral striatum of human cigarette smokers relative to nonsmokers, which implies that the postsynaptic mesolimbic dopamine system may be chronically underactive in smokers, either as an antecedent or consequence of addiction to cigarettes. Such a hypodopaminergic state may play an important role in sustaining nicotine-seeking behavior. Alternatively, an inherited reduction in dopamine receptors in the striatum may be associated with an increased risk of addictive behavior. Synapse 42:48–53, 2001. © 2001 Wiley-Liss, Inc.
Recent attention is focused on understanding the genetic basis for individual susceptibility to the development of chronic disease. An emphasis is concentrated on establishing an association between inheritance of polymorphic chemical metabolizing genes and development of environmental cancer (e.g., lung cancer among cigarette smokers). The early reports of such associations have been very encouraging. However, some reported positive associations were not substantiated in subsequent studies using larger sample sizes and different ethnic populations. In this review, some confounding factors that contribute to the discrepancies are presented (e.g., ethnic-dependent distribution of variant gene alleles, differential expression of metabolizing genes, and inadequate study design). It is possible that the precision of the association can be improved if the mentioned investigations are complemented with concurrent studies of biological activities/effects. The usefulness of integrating metabolic susceptibility with biomarker measurement for understanding the development of lung cancers is presented. The importance of using adequate sample size and experimental design is emphasized. Development of a reliable approach for prediction of environmental disease not only will provide fundamental information regarding the genetic basis of human disease but will be useful for reducing disease burden in the population and for advancing patient care. Environ. Mol. Mutagen. 37:215–225, 2001. © 2001 Wiley-Liss, Inc.
Despite greater negative environmental influences such as lower socioeconomic status, less parental education, more single-parent households and urban dwelling, African Americans are less likely to begin smoking than European Americans. The goal of the current investigation was to examine the proportion of genetic and environmental influences on smoking in a sample of adult African-American twins.
Birth records from North Carolina Register of Deeds Offices were used to identify participants for the Carolina African-American Twin Study of Aging (CAATSA). Participants completed an in-person interview that included measures of health status, cognition and psychosocial measures.
Data for the analysis come from 200 pairs of same-sex twins (97 identical pairs and 113 fraternal), with a mean age = 46.9 years (SD = 13.9) and 38% of the sample being men.
Compared to previous research on smoking, our estimates are very similar with genetics, accounting for about 60% of the individual variance in current smoking. We did find that there was a significant amount of genetic variance in pack years but no shared environmental influences.
Similarity in proportions of genetic influences lead to larger questions about the genes involved in smoking among African Americans working in the same manner as in Caucasians or other groups. Additionally, this same question holds for the environmental variance. It is perhaps most likely that while the proportions of environmental variance are similar between groups that the actual source of variance (e.g., poverty, urban rural context, socioeconomic status, attitudes of family and friends) may differ when comparing ethnic groups.
Lung cancer is a highly environmental disease, but cancer researchers have long been interested in investigating genetic susceptibility to lung cancer. This paper is a historical review and provides updated perspectives on lung cancer susceptibility research. The recent introduction of easier genotyping methods and the availability of an almost complete human genome database facilitated the association study to thousands of cases and controls for millions of genetic markers. Discoveries in the field of behavior genetics, that is, the genetic aspects of smoking behavior and nicotine addiction, unexpectedly indicated that polymorphisms in the human central nervous system play an important role in eventually leading to lung cancer. These findings were achieved by using comprehensive approaches, such as a genome, transcriptome, or proteome approach, and the studies were often conducted without a hypothesis. Another-omics approach, the "adductome" or "exposome" approach to how life style information can be integrated into the framework of genetic association studies, has recently emerged. These new paradigms will influence the area of lung cancer risk evaluation in genome cohort studies.
The purpose of this article is to compare the efficacy of two prominent medications utilized in smoking cessation: bupropion and varenicline.
Comprehensive review of the literature on bupropion and varenicline including randomized control trials, government reports, journal reviews, and pharmaceutical inserts.
In all studies comparing varenicline to bupropion and/or placebo, varenicline yielded a greater cessation rate at both 3 and 12 months. Additionally, varenicline 1 mg indicated an increased potential for long-term cessation success when compared with varenicline 0.5 mg. When compared with only placebo, bupropion demonstrated a higher efficacy for cessation both at 3 and 12 months.
Only 6% of the 20 million smokers who attempt to quit will succeed in long term. Clinicians must assess their patient's willingness to quit and educate them about cessation options. Knowing the efficacy of various treatment options for patients will potentially increase their success at quitting smoking. Understanding the treatment options available, allows for clinicians to provide the best possible method for smoking cessation for their patient population.
This study evaluates the relationship of six polymorphisms found in the CHRNA3, DRD2 and COMT genes with nicotine dependence, the ability to quit smoking and the occurrence of withdrawal symptoms after short-term use of nicotine patch in hospitalized patients.
The study included 233 participants from a double-blind, placebo-controlled trial of nicotine patch substitution with a 6-month follow-up period. Nicotine dependence was assessed by the Fagerström Test for Nicotine Dependence (FTND) questionnaire, withdrawal symptoms by the Minnesota Nicotine Withdrawal Scale questionnaire and smoking cessation by self-reported abstinence at 1 week, 1 month and 6 months after treatment.
After correcting for multiple testing, three polymorphisms in the DRD2 gene (Taq1A, Taq1B and Pro319Pro) were significantly associated with nicotine dependence (p = 0.018, p = 0.048 and p = 0.006, respectively). Using a cutoff point for the FTND score, the CHRNA3 Tyr215Tyr (rs1051730) polymorphism was also associated with nicotine dependence (p = 0.037 and p = 0.074 after correction for multiple testing). No association of any of the studied polymorphisms was observed with either smoking cessation or the occurrence of withdrawal symptoms.
This study confirms the reported association of the CHRNA3 locus with nicotine dependence and shows the involvement of two independent DRD2 polymorphisms in nicotine dependence.
Smoking has been reported to be inversely associated with Parkinson's disease (PD) in many studies, but a recent study in China found that smoking increased the risk of PD. Variants in genes associated with dopamine metabolism found to increase the risk for PD have also been associated with smoking behavior. To investigate the association between smoking and PD in a Chinese population and determine whether the genetic variants of genes involved in dopamine metabolism influence the relationship between smoking and risk for PD. Chinese PD patients were recruited from Xuanwu Hospital. Controls were sampled from community. Detailed information on life-long smoking behavior was collected by face-to-face interview. Genotypes were determined for SLC6A3 VNTR, COMT Val108/158Met and MAO-B intron13 A/G polymorphisms by PCR-RFLP, DHPLC and sequencing. Chi-square and logistic regression model were used in the analysis. 176 PD cases and 354 controls were enrolled in this study. 23.9% cases are smokers, compared to 48.0% in controls. Ever smoking is inversely associated with PD (odds ratio=0.14, 95% CI 0.08-0.26, adjusted for age and gender). None of the above-mentioned genetic polymorphisms was associated with PD risk or smoking. When each variant was included in the logistic regression model, the inverse association between smoking and PD remained the same, and the interactions between smoking and variants were not significant in the model. Our data support a reduction of PD risk associated with smoking in a Chinese population. These variants of genes associated with DA uptake and metabolism do not affect the inverse association between smoking and PD.
Tobacco smoking is a global health problem. The association of a functional common polymorphism in the catechol-o-methyltransferase gene (COMT Val158Met) with smoking behavior has been extensively studied, but with divergent findings. In the present study the frequency of COMT genotypes and alleles was evaluated in 578 male and a smaller group of 79 female unrelated, medication-free Caucasian healthy subjects of Croatian origin. Smokers were classified as subjects smoking <or=10 cigarettes per day, while subjects who never smoked in their life were regarded as nonsmokers. A chi(2)-test with standardized residuals and Bonferroni correction revealed significant (P=0.017) differences in Met/Met, Met/Val or Val/Val genotype frequency between male smokers and nonsmokers. This significant association between COMT Val158Met polymorphism and smoking was not detected in female subjects, due to the small number of women, which represents a limitation of the study. Our results confirmed the significant association between COMT variants and smoking, which was due to the higher frequency of Val/Val homozygotes in male smokers compared to male nonsmokers. These results suggest that carriers of the high activity COMT variant are more prone to develop a higher level of nicotine dependence, or that they release more dopamine than carriers of Met/Met or Met/Val genotypes.
Cigarette smoking is the largest preventable risk factor for morbidity and mortality in developed countries. Dramatic changes in the prevalence of cigarette smoking in the second half of this century in the United States (i.e., a reduction among men and an increase among women) have reduced current smoking levels to approximately one quarter of the adult population and have reduced differences in smoking prevalence and smoking-attributable diseases between the sexes. Current smoking in the United States is positively associated with younger age, lower income, reduced educational achievement, and disadvantaged neighborhood environment. Daily smokers smoke cigarettes to maintain nicotine levels in the brain, primarily to avoid the negative effects of nicotine withdrawal, but also to modulate mood. Regular smokers exhibit higher and lower levels of stress and arousal, respectively, than nonsmokers, as well as higher impulsivity and neuroticism trait values. Nicotine dependence is the single most common psychiatric diagnosis in the United States, and substance abuse, major depression, and anxiety disorders are the most prevalent psychiatric comorbid conditions associated with nicotine dependence. Studies in twins have implicated genetic factors that explain most of the variability in vulnerability to smoking and in persistence of the smoking phenotype. Future research into the causes of smoking must take into account these associated demographics, social factors, comorbid psychiatric conditions, and genetic factors to understand this complex human behavior.
Tobacco smoking continues to be the largest preventable cause of premature morbidity and mortality throughout the world, including chronic respiratory diseases such as asthma and chronic obstructive pulmonary disease. Although most smokers are highly motivated to quit and many smoking cessation therapies are available, cessation rates remain very low. Recent research strongly suggests that variation in genetic background is an important determinant of smoking behaviour and addiction. Since these genetic variants might also influence the response to smoking cessation pharmacotherapies, it is likely that assessment of genetic background could be a promising tool to guide selection of the most effective cessation treatment for an individual smoker. Recently, it has been shown that genetic variants in the dopaminergic system, opioid receptors, the bupropion-metabolising enzyme CYP2B6 and the nicotine-metabolising enzyme CYP2A6 may play an important role in predicting smoking cessation responses to nicotine replacement therapy and bupropion treatment. Despite the progress that has been made, several challenges will still have to be overcome before genetically tailored smoking cessation therapy can be implemented in standard clinical practice.
The Met/Val functional polymorphism of the gene-encoding catechol-O-methyltransferase (COMT) is one of the most widely tested variants for association with different phenotypes of addictive behavior, but replication has been inconsistent for smoking status. We investigated the relationship of this COMT single nucleotide polymorphism with smoking cessation in elderly persons in retrospective and prospective analyses.
The study is embedded in the population-based Rotterdam Study cohort and included 5,115 persons aged 55 years and more. In the retrospective analyses using logistic regression, current smokers who had smoked 10 or more cigarettes daily for 10 or more years were compared with former smokers. In the prospective analyses, we followed 1,195 current smokers up to 12 years and used Cox proportional hazard model to detect the effect of the COMT single nucleotide polymorphism on self-reported incidence of smoking cessation.
The Val/Val genotype of COMT had a consistent association with smoking cessation as compared with the Met/Met+Met/Val genotypes in retrospective [odds ratio=0.79, 95% confidence interval (CI): 0.66-0.96, P=0.02] and prospective analyses (hazard ratio=0.80, 95% CI: 0.63-1.01, P=0.06). In the pooled analyses of prevalent and incident cessation cases that we compared with persisting smokers, the odds ratio was 0.70 (95% CI: 0.55-0.88, P=0.003). No sex difference and no effect of the COMT polymorphism on smoking initiation were observed.
Our results suggest that COMT Met/Val polymorphism is strongly associated with smoking cessation. The Met allele is the risk allele that decreases the likelihood of smoking cessation in men and women.
Using the overlapping criteria of (1) current smoking status and (2) homeostatic accommodation of smoking, the categories of nonsmoker, beginning smoker, smoker, and quitting smoker are structured into a cyclic representation of smoking addiction. This cyclic representation reveals that elimination of homeostatic accommodation of smoking is a critical success factor to the process of becoming a nonsmoker, while the act of stopping smoking is necessary yet insufficient to the success of that process. Homeostatic accommodation is described as having two components: metabolic and neuronal. A hypothesis for temporal displacement of metabolic and neuronal accommodation is presented to explain the behavior of "chippers" (occasional smokers) and adolescent smokers. Recommendations are made for research on the rates of development and dissipation of metabolic and neuronal accommodation of smoking, and for the development of a bimodal therapy that addresses both metabolic and neuronal accommodation and reduces relapse for quitting smokers.
Cessation of cigarette smoking is the single most important therapeutic intervention that is effective in reducing the symptoms of COPD and in preventing its onset. Smoking cessation is, therefore, a major goal in efforts to mitigate the burden of this disease. This review will consider the pharmacologic and behavioral therapies that have been used to assist smokers in overcoming their addiction. These strategies assist a significant minority of smokers to stop smoking and, thus, they can have an important positive impact on COPD as well as on other health outcomes.
Public health genetics is an exciting interdisciplinary area that brings all the public health sciences to bear on the emerging challenge of interpreting the medical and public health significance of genetic variation within populations. Sequencing of the human genome will generate an avalanche of genetic information to be linked with information about microbial, chemical, and physical exposures; nutrition, metabolism, lifestyle behaviors, and medications. The public health genetics mini-symposium in this volume includes articles dealing with educational innovations, host-pathogen interactions in infectious diseases, nutrition/genetic interactions in cancers, and population screening for hemochromatosis. Additional topics addressed here are ecogenetics and risk assessment, the genetics of unhealthful behaviors, and ethical and policy issues. Finally, a set of principles for community-based health research in populations is presented as a public health-oriented counterpart to the principle of autonomy and the practice of informed consent that have become key elements of ethics in medical care and medical research with individuals.
Several types of evidence, including experiments with mice that lack the nicotinic acetylcholine receptor beta2-subunit gene (CHRNB2), have suggested that a beta2-containing nicotinic receptor is necessary for at least some of the reinforcing properties of nicotine. However, sequence variations in CHRNB2 have not been reported, and its role in influencing human smoking behavior and nicotine dependence is not known. We screened most of the introns and exons and found five novel single nucleotide polymorphisms (SNPs). We tested four of these SNPs in three large, carefully selected samples: nonsmokers (n = 317) and regular smokers low levels of nicotine dependence (ND, n = 238), or smokers with high-ND (n = 317). None of the four polymorphisms we tested, nor their estimated haplotypes, were associated with smoking initiation or progression to nicotine dependence.
Genetic factors are believed to play a predominant role in the individual differences observed in behavioral and pharmacological responses to drugs of abuse. An increasing literature indicates, however, that epigenetic factors can be involved as well. In this report we examined whether developmental changes induced by prenatal stress could alter the way animals respond to the psychostimulant effect of nicotine when adults. The results show that nicotine induces a dose-dependent increase of locomotor activity in both groups, and that prenatally-stressed animals exhibit a higher behavioral response at all doses. This study emphasizes the importance of early environment in the later development of drug-related behavior.
Recent studies suggest that smoking habit may relate to genetic traits. This study examines the association with a polymorphism (C-31T) of interleukin 1B (IL-1B), which encodes IL-1beta, a multifunctional pro-inflammatory cytokine. Since the T allele makes a TATA box, the allele is thought to be responsible for a higher potency of IL-1B expression, indicating that individuals harboring the T allele are prone to inflammation. The study subjects were two different populations; 241 non-cancer outpatients (118 males and 123 females) at a cancer hospital and 462 examinees (127 males and 335 females) of a health checkup program provided by a local government. Current smokers were 36.4% for the male outpatients, 9.8% for the female outpatients, 38.6% for the male examinees, and 5.6% for the female examinees. The sex-age-adjusted odds ratios of current smokers were calculated for the genotypes with the T allele relative to the CC genotype by an unconditional logistic model. The estimate was 0.45 (95% confidence interval, 0.21-0.97) for the outpatients, and 0.83 (0.42-1.61) for the examinees. Although not significant for the examinees, the observed associations suggest that this polymorphism may influence smoking behavior through an inflammatory response of the respiratory tract to cigarette smoke.
This paper reviews the Theory of Self-Efficacy, Transtheoretical Model of Readiness for Change, and Theory of Addictions to provide a basis for smoking cessation, and explores how these theories have been used to guide clinical research and clinical interventions. Selected randomized controlled trials of the past ten years are reviewed for demonstrated efficacy, integration of theory into the design of the interventions, and how theories guide analysis. Results show that surprisingly little effort has been put forth to examine and develop these theories within the context of clinical interventions, despite the claims of importance. For example, the relationship between stages of readiness of change and smoking cessation outcome has not been examined. Despite the complexity of smoking behaviors (quitting, relapsing, maintaining, occasional smoking and so on), the concept of self-efficacy was mostly measured on single occasions over the course of most studies reviewed; multiple measurements of concepts were not utilized in the randomized controlled trials. Taking into account the gaps between theory and application, theory driven nursing strategies are offered.
In the UK, approximately one-third of the population currently smoke. It is estimated that up to 70% of these smokers want to stop smoking but smoking cessation rates currently only stand at 20-30%. In order to reduce the health burden associated with smoking in the short-term we need to increase cessation rates. This will stem from deeper understanding of the processes involved in nicotine addiction, targeted therapy and the development of new pharmacological cessation agents. This article is not intended to be an exhaustive examination of nicotine addiction but rather an overview of some of the genetic aspects and how we can go on to use this knowledge in order to develop a genetic test to aid smoking cessation.
The mapping of the human genetic code will enable us to identify potential gene products involved in human addictions and diseases that have hereditary components. Thus, large-scale, parallel gene-expression studies, made possible by advances in microarray technologies, have shown insights into the connection between specific genes, or sets of genes, and human diseases. The compulsive use of addictive substances despite adverse consequences continues to affect society, and the science underlying these addictions in general is intensively studied. Pharmacological treatment of drug and alcohol addiction has largely been disappointing, and new therapeutic targets and hypotheses are needed. As the usefulness of the pharmacotherapy of addiction has been limited, an emerging potential, yet controversial, therapeutic agent is the natural alkaloid ibogaine. We have continued to investigate programs of gene expression and the putative signaling molecules used by psychostimulants such as amphetamine in in vivo and in vitro models. Our work and that of others reveal that complex but defined signal transduction pathways are associated with psychostimulant administration and that there is broad-spectrum regulation of these signals by ibogaine. We report that the actions of methamphetamine were similar to those of cocaine, including the propensity to alter long-term potentiation (LTP) in the hippocampus of the rat brain. This action suggests that there may be a "threshold" beyond which the excessive brain stimulation that probably occurs with compulsive psychostimulant use results in the occlusion of LTP. The influence of ibogaine on immediate early genes (IEGs) and other candidate genes possibly regulated by psychostimulants and other abused substances requires further evaluation in compulsive use, reward, relapse, tolerance, craving and withdrawal reactions. It is therefore tempting to suggest that ibogaine signals addiction gene products.
Our previous study showed that A2 allele of dopamine D2 (DRD2) TaqI A polymorphism related to smoking habits, which was opposed to the results of studies for Caucasians. In order to confirm our finding, a similar study was conducted for the first-visit outpatients of Aichi Cancer Center Hospital, who participated in HERPACC-II (Hospital-based Epidemiologic Research Program at Aichi Cancer Center-II). Among consecutive 1,577 first-visit patients between November 2000 and February 2001, 800 patients provided a 7 ml of peripheral blood. Smoking habit data were available for 798 participants. Excluding five participants aged < 20 years or > 80 years, the remaining 793 participants (346 males and 447 females) were analyzed. The DRD2 genotype was determined by a new method, polymerase chain reaction with confronting two-pair primers (PCR-CTPP). In males, current smokers were 35.3% of individuals with A1A1 genotype, 43.1% of individuals with A1A2 genotype, and 57.0% of individuals with A2A2 genotype, while in females, they were 19.6%, 14.6%, and 10.9%, respectively. Age-adjusted odds ratio (OR) of current smoking relative to A1A1 was 1.61 (95% confidence interval, 0.71-3.46) for A1A2 and 2.32 (1.02-5.29) for A2A2 in males, and 0.72 (0.32-1.61) and 0.51 (0.22-1.18) in females, respectively. The present study indicated that Japanese males with A2A2 genotype have a higher risk of being current smokers. No association for Japanese females suggested that female smoking behavior is differently affected in biological and/or psychological manner.
Although nicotine dependence is one of the primary reasons why smokers cannot quit smoking, nicotine cannot explain all of the psychopharmacological effects of tobacco smoke. Accumulating evidence points to potent inhibition of monoamine oxidase (MAO) which metabolizes neurotransmitters relating to additive behaviour. We have therefore investigated the association between smoking behaviour and MAO ( variable number of tandem repeat in the promoter region and A644G) polymorphisms. The genotypes were examined in 504 Japanese outpatients (217 men and 287 women) who visited Aichi Cancer Centre Hospital. The age-adjusted odds ratios (aORs) were estimated by a logistic model. Among males, we did not find a significant association of the smoking habit with either of the polymorphisms. The median Fargastrom test for nicotine dependence (FTND) score among male current smokers was significantly higher with than without the 4-repeat allele (5.8 and 4.7, respectively). The aOR of FTND 6 versus FTND 6 was 2.72 (95% confidence interval 1.13-6.50) for males with the 4-repeat allele. Among females, the aOR of being current smokers compared to never smokers was 0.49 (0.26-0.93) for individuals with the 4-repeat allele. Our results indicate that the polymorphisms of influence the smoking habit for female, as well as the nicotine dependence and smoking initiation for male smokers. These findings among male smokers support the view that MAO affects a smokers' requirement for nicotine and may explain why some people are predisposed to tobacco addiction and why some individuals find it difficult to stop smoking.
Human personality traits which can be reliably measured by any of a number of rating scales, show a considerable heritable component. The tridimensional personality questionnaire (TPQ) is one such instrument and was designed by Cloninger to measure four distinct domains of temperament - Novelty Seeking, Harm Avoidance, Reward Dependence and Persistence-that are hypothesized to be based on distinct neurochemical and genetic substrates. Cloninger proposed that individual variations in the Novelty Seeking trait are mediated by genetic variability in dopamine transmission. Individuals who score higher than average on the TPQ Novelty Seeking scale are characterized as impulsive, exploratory, fickle, excitable, quick-tempered and extravagant, whereas those who score lower than average tend to be reflective, rigid, loyal, stoic, slow-tempered and frugal. We now show that higher than average Novelty Seeking test scores in a group of 124 unrelated Israeli subjects are significantly associated with a particular exonic polymorphism, the 7 repeat allele in the locus for the D4 dopamine receptor gene (D4DR). The association of high Novelty Seeking and the 7-repeat allele was independent of ethnicity, sex or age of the subjects. This work, together with the accompanying confirmations in this issue, provides the first replicated association between a specific genetic locus involved in neurotransmission and a normal personality trait.
Activation of the mesolimbic dopamine system is known to trigger relapse in animal models of cocaine-seeking behavior. We found that this "priming" effect was selectively induced by D2-like, and not by D1-like, dopamine receptor agonists in rats. Moreover, D1-like receptor agonists prevented cocaine-seeking behavior induced by cocaine itself, whereas D2-like receptor agonists enhanced this behavior. These results demonstrate an important dissociation between D1- and D2-like receptor processes in cocaine-seeking behavior and support further evaluation of D1-like receptor agonists as a possible pharmacotherapy for cocaine addiction.
Monoamine neurotransmitter systems are widely thought to be involved in the pathophysiology of affective disorders and schizophrenia and the mechanism of action of antidepressant and antipsychotic drugs. Previous clinical studies have focused on individual monoamine function in isolation, even though a large number of preclinical studies have demonstrated that monoamine neurotransmitter systems interact with one another. In the present paper, preclinical data on monoamine neurotransmitter interactions are reviewed, and two methods for examining monoamine neurotransmitter system interactions in clinical data are presented. One of the best replicated findings in biological psychiatry is that monoamine metabolites in CSF correlate with one another. The degree of correlation may be in part a measure of the degree of interaction between the parent monoamine neurotransmitter systems. Another approach to studying interactions is the use of HVA/5HIAA and HVA/MHPG ratios as an index of interactions between 5HT-DA and NE-DA. When these methods are applied in schizophrenia, patients are found to have decreased monoamine metabolite correlations compared to normal controls. Metabolite correlations increase significantly after antipsychotic treatment, and the HVA/5HIAA and HVA/MHPG ratios also increase, suggesting that neuroleptics may act in part by strengthening interactions between monoamines. BPRS ratings are negatively correlated with HVA/5HIAA and HVA/MHPG so that patients with higher ratios have fewer symptoms, particularly after treatment. These results provide direct experimental support for hypotheses suggesting that interactions between monoamine neurotransmitters are important in schizophrenia. Some of the effects of the atypical neuroleptic, clozapine, on metabolite correlations and ratios are also discussed.
To determine whether mutations in the D5 dopamine receptor gene (DRD5) are associated with schizophrenia, the gene was examined in 78 unrelated schizophrenic individuals (156 DRD5 alleles). After amplification by the polymerase chain reaction, products were examined by dideoxy fingerprinting (ddF), a screening method related to single strand conformational polymorphism analysis that detects essentially 100% of mutations. All samples with abnormal ddF patterns were sequenced. Nine different sequence changes were identified. Five of these were sequence changes that would result in protein alterations; of these, one was a nonsense change (C335X), one was a missense change in an amino acid conserved in all dopamine receptors (N351D), two were missense changes in amino acids that are identical in only some dopamine receptors and in only some species (A269V; S453C), and one was a missense change in a non-conserved amino acid (P330Q). To investigate whether the nonsense change (C335X), predicted to prematurel
Several studies have documented a strong association between smoking and depression. Because cigarette smoke has been reported to inhibit monoamine oxidase (MAO) A in vitro and in animals and because MAO A inhibitors are effective antidepressants, we tested the hypothesis that MAO A would be reduced in the brain of cigarette smokers. We compared brain MAO A in 15 nonsmokers and 16 current smokers with [11C]clorgyline and positron emission tomography (PET). Four of the nonsmokers were also treated with the antidepressant MAO inhibitor drug, tranylcypromine (10 mg/day for 3 days) after the baseline PET scan and then rescanned to assess the sensitivity of [11C]clorgyline binding to MAO inhibition. MAO A levels were quantified by using the model term λk3which is a function of brain MAO A concentration. Smokers had significantly lower brain MAO A than nonsmokers in all brain regions examined (average reduction, 28%). The mean λk3 values for the whole brain were 0.18 ± 0.04 and 0.13 ± 0.03 ccbrain (mlplasma)−1 min−1 for nonsmokers and smokers, respectively; P < 0.0003). Tranylcypromine treatment reduced λk3 by an average of 58% for the different brain regions. Our results show that tobacco smoke exposure is associated with a marked reduction in brain MAO A, and this reduction is about half of that produced by a brief treatment with tranylcypromine. This suggests that MAO A inhibition needs to be considered as a potential contributing variable in the high rate of smoking in depression and in the development of more effective strategies for smoking cessation.
The effect of various drugs on the extracellular concentration of dopamine in two terminal dopaminergic areas, the nucleus accumbens septi (a limbic area) and the dorsal caudate nucleus (a subcortical motor area), was studied in freely moving rats by using brain dialysis. Drugs abused by humans (e.g., opiates, ethanol, nicotine, amphetamine, and cocaine) increased extracellular dopamine concentrations in both areas, but especially in the accumbens, and elicited hypermotility at low doses. On the other hand, drugs with aversive properties (e.g., agonists of kappa opioid receptors, U-50,488, tifluadom, and bremazocine) reduced dopamine release in the accumbens and in the caudate and elicited hypomotility. Haloperidol, a neuroleptic drug, increased extracellular dopamine concentrations, but this effect was not preferential for the accumbens and was associated with hypomotility and sedation. Drugs not abused by humans [e.g., imipramine (an antidepressant), atropine (an antimuscarinic drug), and diphenhydramine (an antihistamine)] failed to modify synaptic dopamine concentrations. These results provide biochemical evidence for the hypothesis that stimulation of dopamine transmission in the limbic system might be a fundamental property of drugs that are abused.
Nicotine maintains tobacco addiction and has therapeutic utility to aid smoking cessation and possibly to treat other medical diseases. Nicotine acts on nicotinic cholinergic receptors, which demonstrate diversity in subunit structure, function, and distribution within the nervous system, presumably mediating the complex actions of nicotine described in tobacco users. The effects of nicotine in people are influenced by the rate and route of dosing and by the development of tolerance. The metabolism of nicotine is now well characterized in humans. A few individuals with deficient C-oxidation of nicotine, unusually slow metabolism of nicotine, and little generation of cotinine have been described. Nicotine affects most organ systems in the body, although its contribution to smoking-related disease is still unclear. Nicotine as a medication is currently available as a gum, a transdermal delivery device, and a nasal spray, all of which are used for smoking cessation. Nicotine is also being investigated for therapy of ulcerative colitis, Alzheimer's disease, Parkinson's disease, Tourette's syndrome, sleep apnea, and attention deficit disorder.
Positron emission tomography (PET) studies have shown decreased glucose metabolism in brain regions of detoxified alcoholics and cocaine abusers. However, it is not clear whether this decrease is due to chronic drug abuse or a pre-existing condition. Molecular genetic studies have found an association of the D2 dopamine receptor (DRD2) A1 allele with alcoholism and drug abuse. Moreover, reduced central dopaminergic function has been suggested in subjects who carry the A1 allele (A1+) compared with those who do not (A1-). In the present study, using 18F-deoxyglucose, regional glucose metabolism was determined in healthy nonalcohol/nondrug-abusing subjects with the A1+ or A1- allele. The mean relative glucose metabolic rate (GMR) was significantly lower in the A1+ than the A1- group in many brain regions, including the putamen, nucleus accumbens, frontal and temporal gyri and medial prefrontal, occipito-temporal and orbital cortices. Decreased relative GMR in the A1+ group was also found in Broca's area, anterior insula, hippocampus, and substantia nigra. A few brain areas, however, showed increased relative GMR in the A1+ group. Since polymorphism of the DRD2 gene is commonly observed in humans, the importance of differentiating A1+ and A1- alleles subjects in PET studies is suggested.
Background:
There is compelling evidence for the existence of susceptibility genes for bipolar disorder. Association studies using functional DNA variations are an important approach for identifying these genes. The enzyme catechol-O-methyltransferase (COMT) plays a key role in the degradation of catecholamine neurotransmitters and is a candidate for involvement in bipolar disorder. Recently a common functional genetic polymorphism that underlies population variation in COMT activity has been elucidated and a simple assay developed.
Method:
In a collaboration involving seven European centres, we have undertaken an association study of this functional polymorphism in 412 unrelated West European caucasian DSM-III-R bipolar patients and 368 ethnically matched controls.
Results:
We found no evidence of allelic or genotypic association.
Conclusions:
We can conclude that variation at this functional polymorphism does not make an important contribution to bipolar disorder in the Western European population. Future studies using this powerful experimental approach can be expected to contribute to identification of bipolar susceptibility genes.
• Among 1566 personally evaluated female twins from a population-based register, average lifetime daily cigarette consumption was strongly related to lifetime prevalence and to prospectively assessed 1-year prevalence of major depression (MD). Using the cotwin control method, we evaluated whether the association between smoking and lifetime MD was causal or noncausal. While the relative risk (95% confidence interval) for ever smoking given a lifetime history of MD was 1.48 (1.30 to 1.65) in the entire sample, it was 1.18 (0.88 to 1.47) and 0.98 (0.71 to 1.26), respectively, in dizygotic and monozygotic twin pairs discordant for a history of MD. The relative risk for a history of MD given ever smoking was 1.60 (1.39 to 1.83) in the entire sample, while in dizygotic and monozygotic twins discordant for smoking, it was 1.29 (0.87 to 1.74) and 0.96 (0.59 to 1.42), respectively. Controlling for personal smoking history, family history of smoking predicted risk for MD; controlling for the personal history of MD, family history of MD predicted smoking. The best-fitting bivariate twin model suggested that the relationship between lifetime smoking and lifetime MD resulted solely from genes that predispose to both conditions. These results suggest that the association between smoking and MD in women is not a causal one but arises largely from familial factors, which are probably genetic, that predispose to both smoking and MD.
• The allelic association of the human D2 dopamine receptor gene with the binding characteristics of the D2 dopamine receptor was determined in 66 brains of alcoholic and nonalcoholic subjects. In a blinded experiment, DNA from the cerebral cortex was treated with the restriction endonuclease Taql and probed with a 1.5-kilobase (kb) digest of a clone (XhD2G1) of the human D2 dopamine receptor gene. The binding characteristics (Kd [binding affinity] and Bmax [number of binding sites]) of the D2 dopamine receptor were determined in the caudate nuclei of these brains using tritiated spiperone as the ligand. The adjusted Kd was significantly lower in alcoholic than in nonalcoholic subjects. In subjects with the A1 allele, in whom a high association with alcoholism was found, the Bmax was significantly reduced compared with the Bmax of subjects with the A2 allele. Moreover, a progressively reduced Bmax was found in subjects with A2/A2, A1/A2, and A1/A1 alleles, with subjects with A2/A2 having the highest mean values, and subjects with A1/A1, the lowest. The polymorphic pattern of the D2 dopamine receptor gene and its differential expression of receptors suggests the involvement of the dopaminergic system in conferring susceptibility to at least one subtype of severe alcoholism.
Objective.
—To examine the dopamine D2 receptor (DRD2) gene coding sequences for abnormalities associated with schizophrenia or alcoholism and thereby help to resolve the controversy surrounding the reported association of alcoholism with a restriction fragment length polymorphism located close to the DRD2 gene.Design.
—Mutational analysis of complete DRD2 gene coding sequences by denaturing gradient gel electrophoresis followed by direct nucleotide sequencing of detected variants.Setting.
—Patients and controls from clinical and epidemiologic collections in the United States and Europe.Patients.
—A total of 253 unrelated individuals, including 106 patients with schizophrenia, 113 with alcoholism, and 34 controls. For alcoholism we included patients from previously published series in which an association of illness with allele A1 was reported (Taq site 3' to the DRD2gene) and from other published series in which nonconfirmations of this association were reported. Nearly all persons examined were white.Main Outcome Measures.
—Frequency of nonsilent variations in DRD2 gene DNA sequences in the different diagnostic groups.Results.
—We found three infrequent DNA variants that predict altered amino acid sequence of the receptor. None of these is associated with either alcoholism or schizophrenia.Conclusion.
—No structural coding abnormalities in the DRD2gene are present in alcoholism or schizophrenia.(JAMA. 1994;271:204-208)
The carrier molecule that transports dopamine (DA) across the synaptic membrane is known as the dopamine transporter (DAT). Depending on the ionic conditions, DAT may function as a mediator of both the inward directed DA transport known as the "reuptake" and the outward directed DA transport known as the "release." The functional significance of DAT is in the regulation of DA neurotransmission by terminating the action of DA in the synapse via reuptake. With use of DAT binding as a presynaptic marker to measure altered DA innervation, abnormalities of the DAT binding have been demonstrated in idiopathic Parkinson's disease, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity, and progressive supranuclear palsy. Moreover, the identification of DAT as the neuronal element that mediates the addictive properties of cocaine highlights its significance in cocaine addiction. Cocaine binding in the brain is heterogeneous, and there is an uneven distribution of the high- and low-affinity binding sites across the anatomical regions. Regional differences in ligand binding are observed by using both [3H]cocaine and the diphenyl-substituted piperazine derivatives known as the "GBR series" of ligands. The identification of compounds that inhibit the binding of cocaine without affecting DA uptake could potentially lead to development of medications for cocaine abuse. Furthermore, clarification of the various binding domains that may be relevant to transporter function in human neuropsychiatric disorders may lead to the development of new medications for schizophrenia, Tourette's disease, and drug addiction.
The hydroxylation of S-mephenytoin is catalysed by the polymorphic CYP2C19 isozyme. About 3% of Caucasians, but as many as 12 to 20% of Oriental persons, are PM of S-mephenytoin and of omeprazole, another CYP2C19 substrate. Among psychotropic drugs, tertiary amine antidepressants (amitrip-tyline, citalopram, clomipramine and imipramine) are N-demethylated by CYP2C19. Both diazepam and its demethyl metabolite are partly metabolised by this polymorphic enzyme. The high incidence of PM (and of heterozygous extensive metabolisers) of S-mephenytoin in Asia might be the reason for the reported higher sensitivity of Orientals to diazepam compared with Caucasians. Various probe drugs may be used for phenotyping of CYP2D6 (debrisoquine, dextromethorphan and sparteine) and CYP2C19 (mephenytoin and omeprazole). Allele-specific polymerase chain reaction (PCR)-based methods are now available for genotyping using leucocyte DNA. A major advantage of genotyping over phenotyping is that the former may be performed using blood samples from patients irrespective of treatment with psychotropic drugs.
Results from adoption, association, family, trait-marker, and twin studies indicate that both the acquisition and maintenance of smoking are influenced by heredity. The magnitude of the effect of heredity on smoking is small but similar to that for alcohol use. Results from personality and animal breeding studies suggest genotype may influence smoking via inborn differences in personality or in the sensitivity to the reinforcing, the punishing, or the dependence-producing properties of nicotine or tobacco. This article hypothesizes that with further refinements in the measurement of smoking behavior and dependence, studies will report larger genetic effects. If so, then genetic analysis might help tailor prevention and treatment programs for smoking.
Nature Medicine is the premier journal for biomedical research. Respected internationally for the quality of its papers on areas ranging from infectious disease to cancer and neurodegeneration, Nature Medicine aims to bridge the gap between basic research and medical advances and is consistently ranked the number one journal by the Institute of Scientific Investigation in the Medicine, Research and Experimental category.
The dopamine D4 receptor (DRD4) is a candidate gene for schizophrenia because the dopaminergic system has been implicated in this neuropsychiatric disorder. Several research groups have reported an association between allelic variants at DRD4 and schizophrenia, while others have been unable to replicate that finding. Knowledge of the appropriate gene frequencies in the underlying populations may resolve these inconsistencies. We have determined the frequencies of 8 different alleles of the 48 bp imperfect tandem repeat of exon 3 at the DRD4 locus in samples from 33 populations around the world. The frequencies vary considerably in the different populations with the most common allele ranging from 16% to 95%. Frequencies and Fst values will be presented for the 3 most common alleles (4-, 7-, and 2- repeat) by continental groupings, but the individual populations vary significantly around the averages. The populations averaged 4.3 alleles (range 2 to 7).
Objective
To assess the effectiveness of moclobemide on smoking cessation and abstinence in heavy, dependent smokers. There is a strong association between smoking and depression, especially in dependent smokers. It was hypothesized that smoking is a self-medication to treat depression. Cigarette smoke has monoamine oxidase (MAO)-inhibitory properties, and smokers have lower MAO activity than nonsmokers.Methods
We used a randomized, double-blind, placebo-controlled parallel-group study. Placebo or moclobemide, 400 mg/day for 2 months and 200 mg/day during the third month, was given. Main outcome measures were self-reported and biochemically verified (plasma cotinine levels, <20 ng/ml) abstinence rate. Secondary outcome measures were withdrawal symptoms, Montgomery-Asberg Depression Rating Scale, Hamilton anxiety rating scores, platelet MAO-B activity, and plasma dihydroxyphenylglycol as a measure of MAO-A activity.ResultsEighty-eight smokers were randomized to receive moclobemide (n = 44) or placebo (n = 44). The continuous self-reported abstinence rate was higher with moclobemide than with placebo (intention-to-treat analysis until the end point, 6 months: p < 0.05; until the end of follow-up, 1 year: p = 0.09). The abstinence rate according to plasma cotinine levels showed a trend to effectiveness of moclobemide (end point: p = 0.13; follow-up: p = 0.12). Platelet MAO-B activity increased after smoking cessation but without a significant difference. Plasma dihydroxyphenylglycol levels did not change in the placebo group but decreased dose dependently in the moclobemide group. No difference occurred for withdrawal symptoms, Montgomery-Asberg Depression Rating Scale, and Hamilton anxiety scores. Cessation of moclobemide had no adverse effect. More subjects reported insomnia with moclobemide (n = 16) than with placebo (n = 3).Conclusion
In this preliminary study, the reversible, selective MAO inhibitor moclobemide facilitated smoking cessation in highly dependent smokers. Further studies with substantially more smokers are needed to evaluate the role of MAO inhibitors in smoking cessation and abstinence in smokers with high nicotine dependence.Clinical Pharmacology & Therapeutics (1995) 58, 444-452; doi:
Association of the dopamine D3 receptor gene (DRD3) and schizophrenia was examined in unrelated Israeli and Italian schizophrenic patients and ethnically matched normal control subjects. In the combined sample, there was a siginificant excess of DRD3 allele 2 among the schizophrenic patients (χ2 = 4.70, d.f. 1, p = 0.03). Comparison of genotype frequencies revealed an excess of the 2-2 genotype in the combined schizophrenic sample (χ2 = 8.30, d.f. 1, p = 0.01) and in the non-Ashkenazi Israeli schizophrenics alone (χ2 = 5.70, d.f. 2, p = 0.05). DRD3 2-2 genotype conferred a significantly increased risk of schizophrenia (χ2 = 8.21, d.f. 1, p = 0.004; OR = 2.87, CI 95% = 1.36-5.76) in the combined sample and in the non-Ashkenazi Israeli schizophrenics (χ2 = 7.22, d.f. 1, p = 0.04; OR = 7.22, CI 95% = 1.04-24.83). In the combined and Italian samples, allele 2 was associated with early age of onset as was the 2-2 genotype in the combined sample and non-Ash-kenazi group. The 2-2 genotype was associated with poor response to neuroleptics, particularly in the non-Ashkenazi, Israeli schizophrenics. The possibility that DRD3 or a locus in linkage disequilibrium with it may play a role in the transmission of schizophrenia, is considered in relation to previous positive and negative reports.
Drug and alcohol seeking behaviour has become a great global problem affecting millions of inhabitants with a cost to society in the billions. Dopaminergic reward pathways have frequently been implicated in the etiology of addictive behaviour. While other neurotransmitters have also been implicated, to date the only molecular genetic defect which has been found to associate with alcoholism, drug dependency, obesity, smoking, pathological gambling, attention-deficit-hyperactivity disorder (ADHD), Tourette syndrome, as well as other related compulsive behaviours, are the variants of the dopamine D2 receptor gene (DRD2). In this review of the available data on the subject, we report a number of independent meta-analyses that confirm an association of DRD2 polymorphisms and impulsive-addictive-compulsive behaviour (IACB), which we have termed "Reward Deficiency Syndrome". While we agree that Meta-analyses of all exant studies support an association of variants of DRD2 and IACB, correct negative findings with alcoholism may be due to differences in assessing controls and inclusion/exclusion criteria for selection of diseased probands.
(C) Lippincott-Raven Publishers.
Dysfunctions in dopaminergic transmission in the brain may occur in several mental disorders. Among the five dopamine receptor genes cloned, the dopamine D3 receptor is expressed almost exclusively in limbic brain areas. The receptor is well recognized by most neuroleptics and is therefore a likely site for antipsychotic drug action and a candidate for being involved in mental disorders. We have detected a point mutation in the gene that creates a Ball restriction enzyme site and leads to a substitution of a Serine by a Glycine residue in the 5' part of the receptor gene. A method using the polymerase chain reaction was developed to analyze this polymorphism, which was codominantly inherited in 15 nuclear families. To assess allele frequencies in a healthy population, psychiatric interviews were made and 53 individuals without present or earlier psychiatric disturbances were included as controls. A high frequency of both alleles was detected in this population, with a PIC-value (Polymorphism Information Content) of 0.32, which implies a reasonable informativity of the polymorphism in linkage analysis. Use of the polymorphism, in linkage and association studies, should represent a rapid mean to assess the D3 receptor gene as a candidate gene in psychiatric disorders.
(C) Lippincott-Raven Publishers.
Despite strong evidence for genetic involvement in the etiology of affective disorders (from twin adoption and family studies), linkage and association methodologies are still exploring the nature of genetic factors in these diseases. Interesting testable hypotheses have been described, including candidate genes involved in catecholamine neurotransmission. We studied 69 bipolar patients and 69 matched controls (for age, sex, and geographical origin) for association and linkage disequilibrium with DNA markers at the following genes: the tyrosine hydroxylase gene, dopamine transporter gene, and dopamine D2 and D3 receptor genes. Association and linkage disequilibrium were excluded between bipolar affective disorder and these four candidate genes in our sample. © 1996 Wiley-Liss, Inc.
A possible dysregulation of dopaminergic neurotransmission has been implicated in a variety of neuropsychiatric diseases. In the present study we systematically searched for the presence of mutations in the 5′-flanking region of the dopamine D1 receptor (DRD1) gene. This region has previously been shown to contain a functional promoter [Minowa et al., 1992: Proc Natl Acad Sci 89:3045–3049; Minowa et al., 1993: J Biol Chem 268:23544–23551]. We investigated 119 unrelated individuals (including 36 schizophrenic patients, 38 bipolar affective patients, and 45 healthy controls) using single-strand conformation analysis (SSCA). Eleven overlapping PCR fragments covered 2,189 bp of DNA sequence. We identified six single base substitutions: −2218T/C, −2102C/A, −2030T/C, −1992G/A, −1251G/C, and −800T/C. None of the mutations was found to be located in regions which have important influence on the level of transcriptional activity. Allele frequencies were similar in patients and controls, indicating that genetic variation in the 5′-regulatory region of the DRD1 gene is unlikely to play a frequent, major role in the genetic predisposition to either schizophrenia or bipolar affective disorder. © 1996 Wiley-Liss, Inc.
Several groups have reported an association between schizophrenia and the MscI polymorphism in the first exon of the dopamine D3 receptor gene (DRD3). We studied this polymorphism using a North American sample (117 patients plus 188 controls) and an Italian sample (97 patients plus 64 controls). In the first part of the study, we compared allele frequencies of schizophrenia patients and unmatched controls and observed a significant difference in the total sample (P = 0.01). The second part of the study involved a case control approach in which each schizophrenia patient was matched to a control of the same sex, and of similar age and ethnic background. The DRD3 allele frequencies of patients and controls revealed no significant difference between the two groups in the Italian (N = 53) or the North American (N = 54) matched populations; however, when these two matched samples were combined, a significant difference was observed (P = 0.026). Our results suggest that the MscI polymorphism may be associated with schizophrenia in the populations studied. © 1995 Wiley-Liss, Inc.
In recent years, a possible role of the dopamine D2 receptor (DRD2) locus in the etiology of alcoholism has been the focus of considerable attention. The literature now contains a mix of association studies with positive and negative conclusions. Various methodological flaws undermine the claims in many of the studies that conclude a positive association exists between alcoholism and the DRD2*A1 allele at the TaqI “A” site. Although the studies with negative findings have more often come from studies using better analytic methodology, satisfactory resolution of whether or not genetic variation at the DRD2 locus plays some role in the etiology of alcoholism is unlikely to come from additional studies of the kind conducted thus far; an approach enlightened by a more thorough understanding of the population genetics of DRD2 and the phylogenetic origins of the DRD2 alleles is one alternative. If genetic variation at the DRD2 locus affects susceptibility to alcoholism, then such variation has a mutational and evolutionary history that can be traced with the aid of the various genetic polymorphisms that have been identified at the DRD2 locus. In this study, a third TaqI restriction fragment-length polymorphism at DRD2, the TaqI “D” site, has been converted to polymerase chain reaction-based typing and its frequencies determined in 22 populations from around the world. Haplotypes defined by the polymorphisms at the TaqI “B” and “A” sites, and the short tandem repeat polymorphism in intron 2 have been constructed and the diversity of haplotypes containing the DRD2*A1 allele examined for all 22 populations. The ancestral origins of the three Taql polymorphisms have also been determined by sequencing the homologous regions in other higher primates. Because A1-containing haplotypes in populations of European, Middle Eastern, and African origin show considerable diversity within and among populations, properly designed association studies in populations descended from those areas of the world need to use haplotypes, not a single allelic system, and need to use appropriate methods to compensate for the near impossibility of genetically matching unrelated control samples.
We recently reported an association between the long repeat allele of the dopamine D4 exon III receptor polymorphism and a human personality dimension, novelty seeking, as measured by the tridimensional personality questionnaire (TPQ), a personality instrument designed by Cloninger to reflect heritable facets of human temperament. The D4 receptor polymorphism (D4DR) accounts for only a small percent of the variance for this trait, suggesting that additional genes influence both novelty seeking as well as the other temperaments that are inventoried by the Cloninger TPQ. In the current investigation, we examined, in the original cohort of 120 normal volunteers, two additional coding region polymorphisms, a glycine to serine substitution in the dopamine D3 receptor (D3DR) and a cysteine to serine substitution in the 5-HT2C serotonin receptor (HTR2C). Three-way analysis of variance (TPQ score grouped by D4DR, D3DR and 5-HT2C) demonstrated that reward dependence and persistence scores were significantly reduced by the presence of the less common 5-HT2Cser polymorphism. The effect of the serine substitution in this X-linked serotonin receptor polymorphism on reward dependence was also observed when male and female subject groups were separately analyzed. There was also a significant interaction between the two dopamine receptor polymorphisms and the serotonin polymorphism on reward dependence. In particular, the effect of the 5-HT2C polymorphism on reward dependence was markedly accentuated in individuals who had the long version of the D4DR exon III repeat polymorphism. When present in the same individual, the 5-HT2C and dopamine receptor polymorphisms account for 30% of the observed variance for persistence (RD2) and 13% of the variance for reward dependence scores (RD134). However, the number of subjects with both less common D4DR and 5-HT2C polymorphisms is small, underscoring the importance of verifying this interaction in a larger cohort.
The human dopamine D2 receptor gene (DRD2) has received considerable attention for the past several years as a potential candidate that may affect susceptibility to alcoholism. The association studies that compared the frequencies of alleles of DRD2 gene between alcoholics and control groups have produced equivocal results. Dopamine D3 and D4 receptor genes (DRD3 and DRD4) are in the same class as DRD2 but with different pharmacological properties. We have used relative risk and haplotype relative risk approaches to test associations between alleles of DRD3 and DRD4 genes and alcoholism. For relative risk studies 162 probands from multiple incidence alcoholic families have been compared to 89 psychiatrically normal controls. Haplotype relative risk approaches have used 29 alcoholic probands in which both parents were available for genotyping. The Bal I restriction enzyme site in DRD3 and tandem repeat (VNTR) in DRD4 genes polymorphisms were used to genotype the above samples. The results of relative risk approaches for both DRD3 and DRD4 genes were negative for comparisons of alcoholics and subtypes of alcoholics with normal controls. Haplotype relative risk approaches also were negative for both genes. These results suggest that any role played by these receptors may account for only part of the variation in susceptibility to alcoholism. Am. J. Med. Genet. 74:281–285, 1997. © 1997 Wiley-Liss, Inc.
Anxiety disorders have been reported to be associated with low-voltage EEG (LVEEG). Some cases with LVEEG (approximately 1/3) have been linked to chromosome 20q13.2-q13.3. In the same chromosomal region, the gene for the neuronal nicotinic acetylcholine receptor 4 subunit (CHRNA4) has been located. We therefore tested the hypothesis that polymorphisms in the CHRNA4 gene show an allelic association with panic disorder. We examined the allele frequencies of three different CHRNA4 polymorphisms in patients with panic disorder and in healthy controls. No significant differences in the allele frequencies of these three polymorphisms were noted. This study does not support an association between panic disorder and the CHRNA4 gene. Am. J. Med. Genet. 74:199–201, 1997. © 1997 Wiley-Liss, Inc.
The monoamine oxidase B (MAO-B) gene was examined in 100 alleles derived from 80 Caucasian, 10 African-American, 5 Asian, and 5 Native American male patients with schizophrenia to identify sequence changes that might be associated with the disease. Approximately 235 kb of genomic sequence, primarily in coding regions, were screened by dideoxy fingerprinting, a modification of single-strand conformational polymorphism (SSCP) analysis that detects virtually 100% of sequence changes [Sarkar et al. (1992): Genomics 13:441–443; Liu and Sommer (1994): PCR Methods Appl 4:97–108]. No sequence changes of likely functional significance were identified, suggesting that mutations affecting the structure of the MAO-B protein are uncommon in the general population and are unlikely to contribute significantly to the genetic predisposition to schizophrenia. Eight polymorphisms were identified in African-Americans and Native Americans, but none were identified among Caucasians. Of the eight observed polymorphisms, a set of five transitions and one microdeletion was identified within approximately 17 kb of genomic sequence in the same 3 African-American individuals, while the remaining 7 African-Americans had a sequence identical to that in Caucasians. The presence of two such haplotypes, without intermediates, is compatible with the hypothesis that germline mutations can occur in clusters, as also suggested by other recent findings. Am. J. Med. Genet. 74:44–49, 1997. © 1997 Wiley-Liss, Inc.
Monoamine oxidases (MAO) A and B, which are encoded by two distinct genes located on the human X chromosome, are both involved in the oxidative metabolism of dopamine. Decreased levels of platelet MAO-B activity has been reported in patients with schizophrenia and genetic variation in MAO activity had been proposed as a significant factor in the etiology of this disease. We carried out an association study using two intragenic polymorphisms within the MAO-A and MAO-B genes in 110 schizophrenic patients and 87 control subjects. For each polymorphic marker, no significant difference in allelic frequencies was observed between patients and controls. Nevertheless, a trend toward an association between allele 1 of the MAO-B gene and paranoid schizophrenia was found. Our results do not support the hypothesis that inherited variants of MAO genes might play a major role in a genetic predisposition to schizophrenia. Since several previous reports found a low MAO-B platelet activity in patients with paranoid schizophrenia, the identification of polymorphisms related to enzyme activity would be useful.
The analysis of the behavioural and neural mechanisms of reinforcement and motivation has benefited from the recent application of learning theory and better anatomical knowledge of the connectivity of certain key neural structures, such as the nucleus accumbens. This progress has enabled the dissection of motivational processes into components that can begin to be related to the functioning of specific limbic cortical structures that project to different compartments of the ventral striatum.
We have recently characterized a functional polymorphism in the catechol-O-methyltransferase (COMT) gene that is responsible for substantial variability in COMT enzymatic activity found in humans. A common low-activity variant of the enzyme contains a methionine residue at amino acid 158 of membrane-bound COMT whereas the common high activity variant has a valine at this site. Considering the role of COMT in dopamine metabolism and the involvement of dopaminergic pathways in the pathogenesis of schizophrenia and violence, we screened 37 patients with schizophrenia to determine whether or not a behavioral association with the COMT polymorphism exists. Patients were assessed for dangerousness on the basis of a history of violent and threatening behavior, crime, cocaine and alcohol abuse, and other antisocial behaviors. We found that schizophrenic patients who were homozygous for the low activity allele were judged by their psychiatrists to be at higher risk for aggressive and dangerous behavior than those who were homozygous for the high activity allele (Kruskal-Wallis statistic = 10.43; P = 0.003).
A group of human cytochrome P450 genes encompassing the CYP2A, CYP2B, and CYP2F subfamilies were cloned and assembled into a 350-kb contig localized on the long arm of chromosome 19. Three complete CYP2A genes—CYP2A6, CYP2A7, and CYP2A13—plus two pseudogenes truncated after exon 5, were identified and sequenced. A variant CYP2A6 allele that differed from the corresponding CYP2A6 and CYP2A7 cDNAs previously sequenced was found and was designated CYP2A6ν2. Sequence differences in the CYP2A6ν2 gene are restricted to regions encompassing exons 3, 6, and 8, which bear sequence relatedness with the corresponding exons of the CYP2A7 gene, located downstream and centromeric of CYP2A6ν2, suggesting recent gene-conversion events. The sequencing of all the CYP2A genes allowed the design of a PCR diagnostic test for the normal CYP2A6 allele, the CYP2A6ν2 allele, and a variant—designated CYP2A6ν1—that encodes an enzyme with a single inactivating amino acid change. These variant alleles were found in individuals who were deficient in their ability to metabolize the CYP2A6 probe drug coumarin. The allelic frequencies of CYP2A6ν1 and CYP2A6ν2 differed significantly between Caucasian, Asian, and African-American populations. These studies establish the existence of a new cytochrome P450 genetic polymorphism.
The human dopamine transporter (DAT1) gene is localized to chromosome 5p15.3 by in situ hybridization and PCR amplification of rodent somatic cell hybrid DNA. Analysis of a 40-bp repeat in the 3' untranslated region of the message revealed variable numbers of the repeat ranging from 3 to 11 copies. These results will aid in the investigation of a role for this gene in genetic disorders of the dopaminergic system in humans.
The results of twin and family studies suggest that heredity has a small influence on smoking behavior.
We conducted a genetic analysis of several aspects of smoking behavior among subjects in the National Academy of Sciences-National Research Council Twin Registry. The registry includes male twins who were born in the United States between 1917 and 1927 and who were members of the armed services during World War II. Information on smoking history was available for 4775 pairs of twins, who were first surveyed in 1967 through 1969, when they were 40 to 50 years old, and then re-surveyed in 1983 through 1985, when they were 56 to 66. Eighty percent of the subjects in this cohort had smoked at some time in their lives, 60 percent were smokers in 1967 through 1969, and 39 percent were smoking in 1983 through 1985. Similarities between twins in smoking habits at base line and at the second follow-up 16 years later were examined. The comparison of concordance for smoking between monozygotic and dizygotic twins was used to assess the relative contribution of familial and genetic factors.
In 1967-1969 survey the ratio of observed to expected concordance for smoking was higher among the monozygotic twins than among the dizygotic twins for those who had never smoked (overall rate ratio, 1.38; 95 percent confidence interval, 1.25 to 1.54), for former smokers (overall rate ratio, 1.59; 95 percent confidence interval, 1.35 to 1.85), for current cigarette smokers (overall rate ratio, 1.18; 95 percent confidence interval, 1.11 to 1.26), and for current cigar or pipe smokers (overall rate ratio, 1.60; 95 percent confidence interval, 1.22 to 2.06). The data also suggest genetic influences on quitting smoking. Monozygotic twins were more likely than dizygotic twins to be concordant for quitting smoking (overall rate ratio, 1.24; 95 percent confidence interval, 1.06 to 1.45).
In this cohort of adult male twins, there were moderate genetic influences on lifetime smoking practices.
The application of modern molecular biological methods has had an increasing and dramatic impact upon the discipline of molecular neuropharmacology. This is particularly true for the study of neurotransmitter receptors, where the use of recombinant DNA techniques has resulted in the cloning of multiple and sometimes unexpected receptor subtypes for a given neurotransmitter and, in some cases, the cloning of receptors for which no neurotransmitter is known. Within the past couple of years, it has become readily apparent that dopamine receptors will be no exception to this trend. Five different dopamine receptors have now been cloned and identified using molecular biological techniques, while only a few years ago only two receptor subtypes were thought to exist. David Sibley and Frederick Monsma review the molecular characteristics of the recently cloned dopamine receptors and discuss prospects for the cloning and identification of additional subtypes in this receptor family.
Monoamine oxidase (MAO) is a critical enzyme in the degradative deamination of biogenic amines throughout the body. Two biochemically distinct forms of the enzyme, A and B, are encoded in separate genes on the human X chromosome. In these studies we investigated the role of the structural gene for MAO-A in determining levels of activity in humans, as measured in cultured skin fibroblasts. The coding sequence of the mRNA for MAO-A was determined by first-strand cDNA synthesis, PCR amplification, and direct dideoxy sequencing. Two single-basepair substitutions were observed in cDNAs from cells with a 30-fold difference in activity levels. These two substitutions were in the third base of a triplet codon and hence did not affect the deduced amino acid sequence but did affect the presence or absence of restriction-enzyme sites for EcoRV and Fnu4HI, which could be elucidated on PCR fragments derived from genomic DNA or cDNAs. A third polymorphism for MspI in the noncoding region of the MAOA gene was also evaluated by Southern blot analysis using genomic DNA. Statistically significant associations were observed between the alleles for MAOA and levels of MAO activity in human male fibroblast lines. This association indicates that the MAOA gene itself is a major determinant of activity levels, apparently, in part, through noncoding, regulatory elements.
The allelic association of the human D2 dopamine receptor gene with the binding characteristics of the D2 dopamine receptor was determined in 66 brains of alcoholic and non-alcoholic subjects. In a blinded experiment, DNA from the cerebral cortex was treated with the restriction endonuclease Taql and probed with a 1.5-kilobase (kb) digest of a clone (lambda hD2G1) of the human D2 dopamine receptor gene. The binding characteristics (Kd [binding affinity] and Bmax [number of binding sites]) of the D2 dopamine receptor were determined in the caudate nuclei of these brains using tritiated spiperone as the ligand. The adjusted Kd was significantly lower in alcoholic than in nonalcoholic subjects. In subjects with the A1 allele, in whom a high association with alcoholism was found, the Bmax was significantly reduced compared with the Bmax of subjects with the A2 allele. Moreover, a progressively reduced Bmax was found in subjects with A2/A2, A1/A2, and A1/A1 alleles, with subjects with A2/A2 having the highest mean values, and subjects with A1/A1, the lowest. The polymorphic pattern of the D2 dopamine receptor gene and its differential expression of receptors suggests the involvement of the dopaminergic system in conferring susceptibility to at least one subtype of severe alcoholism.
The mesolimbic dopaminergic system appears to mediate the rewarding effects of certain stimulant drugs, such as (+)amphetamine. Autoradiographic mapping techniques have revealed that these neurons are potential targets for nicotine, since they possess nicotinic receptors located on their cell bodies and terminals in rat brain. Functional studies are consistent with this proposal: nicotine can increase the firing rate of these neurons, and nicotine-induced dopamine release has been demonstrated in vitro and in vivo. The locomotor stimulant effect resulting from the acute administration of nicotine is accompanied by, and appears to be dependent upon, activation of mesolimbic neurons. Likewise, destruction of this system appears to attenuate the acute rewarding effects of intravenous nicotine in rats. Thus, when administered intermittently, nicotine, like certain other stimulant drugs, may activate the mesolimbic dopamine system, and this action may contribute to the tobacco habit.
Three cDNAs, designated IIA3, IIA3v, and IIA4, coding for P450s in the CYP2A gene subfamily were isolated from a lambda gt11 library prepared from human hepatic mRNA. Only three nucleotide differences and a single amino acid difference, Leu160----His, were found between IIA3 and IIA3v, indicating that they are probably allelic variants. IIA4 displayed 94% amino acid similarity with IIA3 and IIA3v. The three cDNAs were inserted into vaccinia virus, and recombinant viruses were used to infect human hepatoma Hep G2 cells. Only IIA3 was able to produce an enzyme that had a reduced CO-bound spectrum with a lambda max at 450 nm. This expressed enzyme was able to carry out coumarin 7-hydroxylation (turnover number of 15 min-1) and ethoxycoumarin O-deethylation. cDNA-expressed IIA3v and IIA4 failed to incorporate heme and were enzymatically inactive. Analysis of IIA proteins in human liver microsomes, using antibody against rat IIA2, revealed two proteins of 49 and 50 kDa, the former of which appeared to correlate with human microsomal coumarin 7-hydroxylase activity. A more striking correlation was found between IIA mRNA and enzyme activity. The rat antibody was able to completely abolish coumarin 7-hydroxylase activity in 12 liver samples. In addition, kinetics of coumarin metabolism in two livers were monophasic over the substrate concentration tested. Km values obtained from human liver (2.3 microM) were similar to those obtained from lysates of hepatoma cells expressing IIA3 (3.6-7.1 microM).(ABSTRACT TRUNCATED AT 250 WORDS)
Advancement in the study of receptors for neurotransmitters facilitated the analysis of neural mechanisms underlying reinforcement. Two subtypes of dopamine receptors, D1 and D2, play distinct roles in producing reinforcing effects. Experiments using SCH 23390 suggest that the reinforcing effects of food, water, saccharin, heroin and brain stimulation all critically depend on the activation of D1 dopamine receptors, particularly those in the nucleus accumbens and the ventral tegmental area. Raclopride, a D2 dopamine antagonist, also reduced bar-pressing responses for food, heroin, and brain stimulation. Thus, both D1 and D2 receptors seem to be involved in the reinforcement mechanisms. There were some differences between D1 and D2 dopamine antagonists in the manner of reducing operant responding. It appears that D1 receptors are related to the efficacy of reinforcements while D2 receptors are related to the type of reinforcers.
To address the controversy surrounding DRD2 and alcoholism, we performed linkage and association studies utilizing alcoholic men from high-density families largely uncontaminated by other psychopathology and female alcoholics for whom secondary drug dependence (averaging 10 years later onset) was a prominent feature. The males and females were combined for a total of 52 alcoholics, and compared to 30 controls screened for the absence of alcoholism and other psychopathology, revealing a significant association between the frequency of the TaqI A1 allele and alcoholism. However, linkage and family-based association studies conducted on 20 families of male alcoholics found no evidence for association or linkage between Taq A and alcoholism. The results of our population-based association study, placed in the context of the literature, suggest that minimizing psychopathology in control groups is probably a more important explanation for divergent results than either sampling error or population stratification. When combined with the complete lack of within-family evidence, we concluded that the association, while not appearing to be artifactual, is not specific to the alcoholism phenotype, per se.