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A study of the association of (Val66Met) polymorphism in the Brain-derived Neurotrophic Factor gene with alcohol dependence and extreme violence in Chinese males

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A study of the association of (Val66Met) polymorphism in the Brain-derived Neurotrophic Factor gene with alcohol dependence and extreme violence in Chinese males
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  Neuroscience Letters 381 (2005) 340–343 A study of the association of (Val66Met) polymorphism in the  Brain-derived Neurotrophic Factor   gene with alcohol dependenceand extreme violence in Chinese males Shih-Jen Tsai a , b , ∗ , Ding-Lieh Liao c , Younger W.-Y. Yu d , Tai-Jui Chen e , Hung-Chi Wu f  ,Chun-Hui Lin f  , Chih-Ya Cheng g , Chen-Jee Hong a , b a  Department of Psychiatry, Veterans General Hospital-Taipei, No. 201 Shih-Pai Road, Sec. 2, 11217 Taipei, Taiwan b  Division of Psychiatry, School of Medicine, National Yang-Ming University, Taipei, Taiwan c  Department of General Psychiatry, Pali Psychiatric Hospital, Central Taiwan Office, Department of Health, Taipei, Taiwan d Yu’s Psychiatric Clinic, Kaohsiung, Taiwan e  Department of Psychiatry, E-DA Hospital and I-Shou University, Kaohsiung, Taiwan f  Kai-Suan Psychiatric Hospital, Kaohsiung, Taiwan g Ching Kuo Institute of Management and Health, Keelung, Taiwan Received 18 November 2004; received in revised form 16 February 2005; accepted 17 February 2005 Abstract From studies of genetic-knockout animals, brain-derived neurotrophic factor (BDNF), a member of the neurotrophin growth-factor family,has been implicated in both alcohol preference and aggressive behaviour. To test whether a  BDNF   genetic variant may be associated withalcohol-dependentandviolentbehaviours,westudiedVal66Metpolymorphismofthe  BDNF  -genein110casesofalcohol-dependence,in134extremelyviolentconvicts,andin149individualswithoutpsychosisormooddisorders.Wealsoexaminedtheassociationofthispolymorphismwith antisocial personality disorder comorbidity in the extremely violent convicts. The results showed that the genotype and allele frequenciesfor Val66Met polymorphism at the  BDNF- gene site did not differ among the three groups. Furthermore, it was not demonstrated that thispolymorphism is associated with antisocial personality disorder comorbidity in the extremely violent convicts. Based on these findings, itseems reasonable to suggest that this  BDNF  -gene Val66Met polymorphism is unlikely to play a major role in the genetic susceptibility to thetraits of alcohol-dependence or violence proneness.© 2005 Elsevier Ireland Ltd. All rights reserved. Keywords:  Brain-derived neurotrophic factor; Male; Alcohol dependence; Violence; Polymorphism Brain-derived neurotrophic factor (BDNF) belongs to a fam-ily of proteins related to the nerve growth-factor family andis widely expressed in the adult mammalian brain where itis responsible for the proliferation, survival, and differentia-tion of neurons [1]. In addition, BDNF modulates synapticplasticity and molecular mediators of synaptic plasticity inmultiple neurotransmitter systems, and also modulates someintracellular signal-transduction pathways [15]. ∗ Corresponding author. Tel.: +886 2 28757027x267;fax: +886 2 28725643.  E-mail address:  sjtsai@vghtpe.gov.tw (S.-J. Tsai). Recent evidence indicates that BDNF may also be in-volved in the mechanisms underlying alcohol dependence.Data derived from a study in mice has demonstrated that,compared with wild-type mice, heterozygous  BDNF   (+/  − )mutant mice increased ethanol intake in a two-bottle choiceprocedure [5]. Furthermore, BDNF-treated animals havebeen found to have alterations in the mesolimbic DA sys-tem [6], a system important in ethanol reinforcement [16]. In another animal study, a relationship between alcohol con-sumption and BDNF was suggested by the observation thatchronic exposure to ethanol increased BDNF concentrationsin the parietal cortex and the basal forebrain and decreasedBDNF concentration in the hippocampus [12]. In humans, 0304-3940/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved.doi:10.1016/j.neulet.2005.02.043  S.-J. Tsai et al. / Neuroscience Letters 381 (2005) 340–343  341 Uhl et al. [19] used 1494 single-nucleotide polymorphismsto scan for genes conferring vulnerability to polysubstanceabuse and found that positive markers flank the  BDNF   gene.They further demonstrated that a dinucleotide-repeat poly-morphism located close to the 5  end of the  BDNF   gene alsodisplayed an association with drug-abuse vulnerability.The h  BDNF   gene has been mapped to chromosome 11[10]. Recently, a common single-nucleotide polymorphism( G196A ) in the  BDNF   gene, resulting in a valine (Val) to me-thionine(Met)substitutionintheprodomain,hasbeenshownto impact intracellular trafficking and activity-dependent se-cretion of BDNF [3,4]. Since genetic factors play an im- portant role in alcohol dependence [1] and  BDNF   might berelated to alcohol use,  BDNF   may represent an appropriatecandidate gene conferring risk for alcohol dependence. Re-cently, Matsushita et al. [11] demonstrated a significant as-sociation between the  BDNF   Val66Met polymorphism andJapanesemalealcoholicsubjectswithviolenttendenciesandahistoryofdeliriumtremens.Thisistheonlypublishedpaperso far on this topic. In the current investigation the relation-ship between the  BDNF  -gene Val66Met polymorphism andalcohol dependence was investigated in a male sample popu-lation.Inaddition,theexistenceof   BDNF  -deficientmicethatexhibit enhanced inter-male aggressiveness may suggest thatBDNF is related to violent behaviours [9]. In this study, we alsoinvestigatedthepossibleinvolvementofthis  BDNF  poly-morphisminahomogenousChinesemalesamplepopulationconsisting of extremely violent convicts. The population wasfurther analysed for antisocial personality disorder (ASPD)comorbidity. Since  BDNF  -deficient mice may have higheralcohol preference [5] and aggressiveness [9], and since one study demonstrated that depolarization-dependent secretionof BDNF in neuronal cells is impaired when Val66 in thepro-  BDNF   sequence is replaced with a Met [4], we hypoth- esized that the lower activity Met allele is a risk factor foralcohol-dependence and extreme violence.In this study, 110 patients exhibiting alcohol dependencewererecruitedfromatreatmentward.Allpatientswereolderthan 18 years, were evaluated by a senior psychiatrist, andmet the Diagnostic and Statistical Manual of Mental Disor-ders (DSM-IV) criteria of alcohol dependence. Patients withpsychotic disorders and other substance abuses were not in-cluded.TheviolentcriminalcaseswererecruitedfromjailsinNorthernTaiwan,asreportedinourpreviousstudy[8].Thesesubjectshadhistoriesofextremelyviolentcriminalbehaviourwithphysicalactionthatharmedorkilledanotherindividual,and were serving a minimum sentence of 2.5 years. The vio-lentcriminalswhoagreedtoparticipateinthestudyacceptedan in-depth interview by a senior psychiatrist (DLL). Ma- jor psychiatric diseases (psychosis or mood disorders) werescreened out using the Mini-International NeuropsychiatricInterview, a short, structured diagnostic interview [17]. A di- agnosis of ASPD was made according to criteria set downin the DSM-IV. Of the violent criminals, five individualswere diagnosed with psychotic or mood disorders, and 29who were not able to provide reliable information during in-terview were excluded from this study, with the remaining134 cases assigned to the violent criminal group. Among the134 violent-criminal cases, 95 cases (70.9%) met criteria forDSM-IV alcohol abuse/dependence. A total of 149 males re-cruited from the general community were interviewed by apsychiatristtoruleoutpsychoticormooddisordersservedascontrolgroup.Thecontrolswerenotscreenedforalcoholism.The entire sample comprised male Han Chinese. This studywas approved by the Institution Review Board of Taipei Vet-eran General Hospital and the Ministry of Justice, Republicof China. After a complete description of the study to thesubjects, written informed consent for all parts of the studywas obtained.DNA used in  BDNF Val66Met   genetic polymor-phism genotyping was extracted from peripheral lym-phocytes. The DNA fragments of interest were am-plified by the polymerase chain reaction (PCR) withprimers 5  -ACTCTGGAGAGCGTGAAT-3  and 5  -ATACTGTCACACACGCTC-3  . The thermocyclingprogram for PCR was 34 cycles of 95 ◦ C for 30s;  ≥ 60 ◦ Cfor 30s;  ≥ 72 ◦ C for 30s. The 308-bp PCR product wasdigested with  Nla III at 37 ◦ C for at least 4h and thenelectrophoresed on a 2% agarose gel at 100V for 30min.The presence of 168 and 75-bp bands indicates the existenceof A (Met) allele, the presence of 243bp band indicatesthe existence of G (Val) allele, while the presence of 75bp,168bp and 243bp indicates AG (Met/Val) heterozygote.Partial digestion was ruled out by complete digestion of anAA (Met/Met) homozygous control sample in each batchof the experiment. Contaminated amplification was alwaysmonitored by a blank reaction in each batch of the laboratorywork.Between-group comparisons for genotype or allele fre-quency differences were performed using the chi-square testand the Fisher exact test where necessary. Between-groupdifferencesforcontinuousvariableswereevaluatedusingtheStudent’s t  -test.Dataarepresentedasmeansandstandardde-viation (S.D.). For all of the tests conducted, the criterion forsignificance was set at  P <0.05.Themeanagesofthealcohol-dependentgroup(36.1 ± 8.9years)andtheviolent-criminalgroup(34.5 ± 8.8years)weresimilartothatofcontrolgroup(35.7 ± 15.3years)( P =0.795and0.438,respectively).Thegenotypeandallelefrequenciesfor the  BDNF   Val66Met genetic polymorphism for the threegroupsarepresentedinTable1.Thedistributionforthegeno-types of the  BDNF   Val66Met polymorphism for each of thethree groups was in Hardy–Weinberg equilibrium.Comparing the alcohol-dependent group and control pop-ulations, neither the genotypic ( P =0.714) nor allelic fre-quencies ( P =0.477) were statistically different comparingthe two groups (Table 1). Furthermore, no statistical asso- ciation was demonstrated comparing genotype ( P =0.937)and allele ( P =0.800) frequencies between violent criminalcases and healthy controls. In the violent-criminal cases,66 (49.3%) were diagnosed ASPD. No statistical associa-tion was demonstrated comparing  BDNF   genotype between  342  S.-J. Tsai et al. / Neuroscience Letters 381 (2005) 340–343 Table 1Genotype and allele frequency for  BDNF   Val66Met genetic polymorphism in violent criminal subjects ( n =134), alcohol-dependent subjects ( n =110) andcontrols ( n =149)Patient Group Genotype,  n  (%)  P a Allele frequency (%)  P a Val/Val Val/Met Met/Met Val MetAlcohol dependence 25 (22 . 7) 63 (57 . 3) 22 (20 . 0) 0 . 714 51 . 4 48 . 6 0 . 477Violent criminals 24 (17 . 9) 77 (57 . 5) 33 (24 . 6) 0 . 937 46 . 6 53 . 4 0 . 800ASPD 9 (13 . 6) 44 (66 . 7) 13 (19 . 7) 0 . 391 47 . 0 53 . 0 0 . 917Non-ASPD 15 (22 . 1) 33 (48 . 5) 20 (29 . 4) 0 . 491 46 . 3 53 . 7 0 . 757Controls 29 (19 . 5) 85 (57 . 0) 35 (23 . 5) 48 . 0 52 . 0ASPD: antisocial personality disorder. a Compared with the control group. violent-criminal cases with or without ASPD and healthycontrols (Table 1). Among the 134 violent-criminal cases, 95cases met criteria for DSM-IV alcohol abuse or dependence.Nostatisticalassociationwasdemonstratedcomparinggeno-type frequencies between these patients (violent-criminalcaseswithalcoholabuseordependence)andhealthycontrols( P =0.787).BDNF has been implicated in alcohol preference andaggressive behaviours in studies of genetic knockout ani-mals [5,9]. In this study, we tested the association between  BDNF   genetic variants, alcohol-dependence, and violence.We found no association between the alcohol-dependenceandviolentcriminalsandthestudied  BDNF  geneticpolymor-phism, suggesting that the  BDNF  -gene Val66Met polymor-phism does not play a major role in alcohol-dependence andsusceptibility to violence. Recently, there is one genetic as-sociation study of the  BDNF  -gene Val66Met polymorphismand alcoholism in Japanese population [11]. In that study, thestudycasesincluded377malealcoholicsubjectsand336non-alcoholic male subjects, and the genotype and allele dis-tributions of the  BDNF  -gene Val66Met polymorphism didnot differ significantly between alcoholic and non-alcoholicsubjects.With the finding that, compared with wild-type mice, het-erozygous  BDNF   (+/  − ) mutant mice increased ethanol in-take [5], and BDNF-treated animals have been shown tohave alterations in the mesolimbic reward system [6], it ispossible that additional variants of the gene not detectedby analysis of the Val66Met polymorphism may influencethedevelopmentofalcohol-dependentdisorders.Beforedef-initely excluding a role for the  BDNF   gene in the aetiologyof alcohol-dependent disorders, further studies are neededexamining other  BDNF   variants and larger sample popula-tions. An alternative interpretation of our negative resultsis that while the  BDNF  -gene Val66Met polymorphism maynot be involved in the primary etiological mechanism of alcohol-dependent disorder, it may be related to alcoholismsubtypes or alcohol-related comorbidity. In an animal study,chronic ethanol administration increased BDNF concentra-tion in the parietal cortex and the basal forebrain and de-creased BDNF concentration in the hippocampus [12]. Since BDNFplaysanimportantroleinneuronalsurvivalandmem-ory formation [13], and chronic alcohol consumption ofteninduces neurotoxicity and neurocognitive impairments [2],it will be of interest to test if the  BDNF   polymorphism hasany effect on alcohol comorbidity. In our study, no statis-tical association was demonstrated comparing  BDNF   geno-typefrequenciesbetweenviolent-criminalcaseswithalcoholabuse/dependence and healthy controls. In the study by Mat-sushita et al. [11], they found that alcoholic subjects withviolent tendencies and a history of delirium tremens had ahigher frequency of   BDNF   Met/Met genotypes and Met al-lele frequencies than those without them. However, the re-sultswereonlybarelysignificant,suggestingthatthisvariantmay exert only a small effect on violent behaviour in alco-holics.Furthermore, a recent study found that partial deletionof the cAMP response element-binding protein (CREB)promotes alcohol drinking in animals [14]. Phosphorylated CREB regulates the expression of several downstream c-AMP-inducible genes, including  BDNF   [18]. The mecha-nisms of alcohol-dependence may involve polygenic inter-action, and individual genes may have small effects. Furtherstudy of genetic variants in the CREB-BDNF pathway mayhelptorevealthemechanismunderlyingalcohol-dependenceand related disorders.One major limitation of this study is the relatively smallnumbers of subjects. In this study, the sample size was largeenough to detect a moderate allelic association; the size of effect that could be detected with 80% power at the 5% sig-nificancelevelisoddsratioof1.6forthealcohol-dependenceand 1.7 for the extreme violence. Given the assumption thatalcohol-dependence disorder and the violent behaviours areprobablymulti-determined,ifthe  BDNF  isanuncommondis-easelocusoroneofsmalleffect,ourpowertodetectthegenemust consequently be reduced and may result in false nega-tive finding, especially in the sub-group analysis. A secondlimitation in this study is that the control samples were notscreened for alcohol dependence, therefore, a false negativeresult due to inclusion of alcohol dependence in the controlgroup was likely. However, epidemiological study in Taiwanshowed a relatively low prevalence of alcohol dependence(1.5% in city and 1.8% in town) in community population[7]. Therefore, the chance inclusion of a few affected casesin the control group will have minimal effect on the result of genetic association.  S.-J. Tsai et al. / Neuroscience Letters 381 (2005) 340–343  343 Acknowledgments This work was supported by Grant DOH89-TD-1095,provided by the Department of Health, Taiwan, and GrantVGH89-398-15, provided by the Taipei Veterans GeneralHospital. The authors wish to thank Mr. Chiou-Ting Feng,Tsung-Ho Liu and the staff at the Taiwan Taipei DetentionCenter for their assistance with sample collection. The au-thors would like to thank Mr. Joshua Feng for the help inEnglish editing. References [1] D.P. Agarwal, Molecular genetic aspects of alcohol metabolism andalcoholism, Pharmacopsychiatry 30 (1997) 79–84.[2] M.E. Charness, Brain lesions in alcoholics, Alcohol Clin. Exp. Res.17 (1993) 2–11.[3] Z.Y. 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