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Genetic Validation in Alcoholism Ru-Band Lu, MD Professor Department of Psychiatry National Cheng Kung University, Taiwan.

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Presentation on theme: "Genetic Validation in Alcoholism Ru-Band Lu, MD Professor Department of Psychiatry National Cheng Kung University, Taiwan."— Presentation transcript:

1 Genetic Validation in Alcoholism Ru-Band Lu, MD Professor Department of Psychiatry National Cheng Kung University, Taiwan

2 Genetic Component and Alcoholism  Family studies (Merigangas 1990)  Twin studies (Pickens et al. 1991)  Adoption studies (Cadoret et al. 1985)  Genetic component in alcoholism –More than 50 % (Reich et al. 1999)

3 The Importance of Subtypes Alcoholism  Heterogenesis of mental illnesses  Understanding different pathogenesis  Different treatments and prognosis

4 Alcoholism Subtypes  Jellineck (1960) : 2 subtypes  Morey and Skinner (1986) : 3 subtypes  Lesch (1988) : 4 subtypes  Zucker (1987) : 4 subtypes  Cloninger (1987) : 2 subtypes  Babor (1992) : 2 subtypes

5 Limitations  Lack of cutting point  Different risk factors in different cultures  Inconvenience for clinical use  Lack of genetic validation

6 Clinical Subtyping of Alcoholism (Huang et al., 2004)  Alcoholic patient often meeting most of the diagnostic criteria (DSM-IV-TR, 2000)  More homogeneous mental illness from the diagnostic criteria perspective.  Higher frequent comorbidity with other mental illnesses

7 Clinical Subtyping of Alcoholism (Huang et al., 2004)  Pure Alcoholism  Anxiety-Depression Alcoholism  Antisocial Alcoholism  Mixed Alcoholism

8 Clinical Subtypes of Alcoholism  Pure Alcoholism (Pure ALC) – late onset – without comorbidity with mental illnesses – less alcohol related problems  Anxiety- Depression Alcoholism (ANX/DEP ALC) – early adult onset – comorbid anxiety or depression – heavy alcohol consumption

9 Clinical Subtypes of Alcoholism  Antisocial Alcoholism (Antisocial ALC) – adolescent onset (very early onset) – comorbid antisocial personality disorder – more alcohol related problems  social consequence  Mixed Alcoholism (Mixed ALC) – comorbid major mental illnesses – comorbid multiple substance disorder – Alcoholism with bipolar disorders among Han Chinese

10 DRD2 Gene and Alcoholism (Blum et al. 1990)  An important candidate gene of alcoholism  Controversial results or borderline significance (Reich et al., 1999)  No association with non-subtyped alcoholism among Han Chinese population in Taiwan (Lee et al., 1999)

11 A: Alcoholics; C: Controls; P: Percentage; F: Allele Frequency Author (A : C) Alcoholism, N (%) TaqI-ANon-alcoholism (n,%) A1A1A1A2A2A2A1 (P) A1 (F)A1A1A1A2A2A2A1 (P)A1 (F) Association Blum et al (22:24) Neiswanger et al.1995(52:30) Noble et al.2000 (92:85) Kono et al. 1997,(21: 93) Ishiguro et al.1998(209:152) 1 (4.5)13 (59.1)8 (36.4) (0)4 (16.7)20 (83.3) (2.0)28 (53.8)23 (44.2) (0)4 (13.3)26 (86.7) (6.5)44 (47.8)42 (45.7) (3.5)13 (15.3)69 (81.2) (28.6)7 (33.3)8 (38.1) (10.8)49 (52.7)34 (36.5) (16)111 (53)64 (31) (14)64 (42)67 (44)5635 No Association Bolos et al. 1990(40:127) Heinz et al.1996 (97:113) Anghelescu et.2001(243:98) Goldman et al.1998 (276:161) Lu et al. 1996, (20:25) Lee et al. 1999, (128:85) 2 (5.0)13 (32.5)25 (62.5) (6.3)30 (23.6)89 (70.1) (3.1)31 (32)63 (64.9) (3.5)35 (31.0)74 (65.5) (5.3)75 (30.9)155 (63.8) (3.1)32 (32.7)63 (64.3) (35)130 (47)50 (18) (39.1)70 (43.5)28 (17.4) (10)10 (50)8 (40) (13)3 (13)14 (58)7 (29 ) (21.9)26 (52)33 (25.8) (12.9)44 (51.8)30 (35.5) DRD2 Gene and Alcoholism (Huang et al.,2004)

12 Genes and Clinical Subtypes of Alcoholism

13 DRD2 Gene and Subtypes of Alcoholism  Association – Anxiety-Depression Alcoholism (Huang et al., 2004)  No Association – Pure Alcoholism (Huang et al., 2004) – Antisocial Alcoholism and Non-Alcoholism (Lu et al., 2002) – Mixed Alcoholism (data not shown)

14 DRD2 TaqI A and TaqI B Haplotypes Chinese Han Alcohol Dependence in ANX/DEP, and Controls Group Haplotype Number (2n) Haplotype frequency(%) p-value a Linkage disequilibrium p-value b A1/B1A1/B2A2/B1A2/B2DD′ Controls c <0.001 Pure ALC d e <0.001 ANX/DEP ALC d f <0.001 ANX/DEP d g <0.001 a p value of Fisher’s Exact test b p value of linkage disequilibrium in each of the four study groups c Controls vs. Pure ALC vs. ANX/DEP ALC χ 2 value=15.788,df=9 d ANX/DEP ALC, anxiety-depressive alcohol dependence ; Pure ALC, pure alcohol dependence; ANX/DEP, anxiety-depressive disorders; p value of the haplotype difference between ANX/DEP (p=0.023, χ 2 =8.324,df=3); ANX/DEP ALC vs. pure ALC (p=0.122, χ 2 =4.057,df=2) e Controls vs. Pure ALC ; χ 2 value=3.155,df=3 f Controls vs. ANX/DEP ALC ; χ 2 value=11.834, df=3 g Controls vs. ANX/DEP ; χ 2 value=1.444, df=3 (Huang et al., 2004)

15 Haplotype Frequency of the DRD2 TaqI A and TaqI B polymorphisms Group Haplotype Number (2n) Haplotype frequency (%) P Value † Linkage disequilibrium P Value ‡ A1/B1A1/B2A2/B1A2/B2DD’ Normal Controls a < Antisocial ALC § b < Antisocial Non-ALC § c < † p value of Fisher’s Exact test ‡ p value of linkage disequilibrium in each of two groups a Antisocial ALC vs. Antisocial Non-ALC vs. Normal Controls, χ 2 value= 10.65, df = 6 b Antisocial ALC vs. Normal Controls, χ 2 value = 5.74 df = 3 c Antisocial Non-ALC vs. Normal Controls, χ 2 value = 5.54 df = 3 § Antisocial ALC, subjects with antisocial personality disorder and alcohol dependence; Antisocial Non-ALC, subjects with antisocial personality disorder but without alcohol dependence (Lu et al., 2002)

16 MAOA Gene and Subtype Alcoholism  Association – Pure Alcoholism (Huang et al., 2007) – Mixed Alcoholism (Hu et al., 2013)  No Association – Anxiety-Depression Alcoholism (Huang et al., 2007) – Antisocial ALC or Non-Alcoholism (Lu et al., 2003; Wang et al., 2007)

17 Frequencies of MAOA polymorphisms in Han Chinese men with alcoholism and control subjects Groups/genotypes Sample size Promoter-uNTR; no (%) χ2χ2 P value Sample size EcoRV; no.(%) χ2χ2 P value 3-repeat4-repeat+- Control subjects (62.4)74 (37.6) (62.2)76 (37.8) Pure ALC (49.5)54 (50.5) (50.0)54 (50.8) ANX/DEP ALC (61.0)46 (39.0) (38.1) MAO A= monoamine oxidase-A; VNTR= variable number of tandem repeats; EcoRV=restriction enzyme rs ; pure ALC= pure alcohol dependence; ANX/DEP ALC= alcohol dependence and anxiety or depression or both. *Control subjects v.s. pure ALC v.s. ANX/DEP ALC; df=3 +Control subjects v.s. pure ALC Control subjects v.s. ANX/DEP ALC (Huang et al., 2007)

18 MAOA-uVNTR and DRD2 gene interaction for the risk of BP with ALC Model ALC+BP BOR95% CIp-Value MAOA-uVNTR 3-repeat− – * DRD2 TaqI A1/A1− – DRD2 TaqI A1/A2− – MAOA-uVNTR 3-repeat ∗ DRD2 TaqI A1/A – MAOA-uVNTR 3-repeat ∗ DRD2 TaqI A1/A – ** ALC+BP: alcoholism with bipolar disorder. B, coefficients; CI, confidence interval; OR, odds ratio. Reference groups are: MAOA-uVNTR 4-repeat, DRD2 TaqI A2/A2 genotypes, and controls;covarying for age. ** pb0.05. (Hu et al., 2013)

19 MAOA Haplotypes for the uVNTR and EcoRV RFLP Polymorphisms in Different Groups Sample (N) Haplotype Number (Frequency x100%) χ2χ2 p-value (2R +)(3R -)(3R +)(4R -)(4R +) Community control 771 (1.3)2 (2.6)40 (51.9)34 (44.2)0 (0.0) Jail control (ASB) 381 (2.6) 20 (52.6)14 (36.8)2 (5.3) Antisocial Non- ALC 501 (2.0) 27 (54.0)19 (38.0)2 (4.0) Antisocial ALC410 (0.0)1 (2.4)26 (63.4)11 (26.8)3 (7.3) ASPD: Antisocial Personality Disorder without meeting the diagnosis of Alcohol Dependence Antisocial ALC: Antisocial Personality Disorder with meeting the diagnosis of Alcohol Dependence ASB: Antisocial Behavior without meeting the diagnosis of ASPD-S-ALC or ASPD-C-ALC MAO A-uVNTR : Variable number of tandem repeat locating at upstream of the MAO A gene 2R, 3R and 4R= 2 repeats, 3 repeats and 4 repeats (+) and (-) = Presence and absence of restriction sites for EcoRV (Wang et al., 2007)

20 ADH1B, ALDH2 Gene and Subtypes of Alcoholism ADH1B*2 and/or ALDH2*2 Allele  Protection  Pure, Anxiety-Depression, Mixed (data not shown) and Antisocial NON-Alcoholism (Lu et al., 2005; 2012)  No protection  Antisocial Alcoholism (Lu et al., 2005; 2012)

21 ADH1B for the Risk of Antisocial Alcoholics Community controls vs. antisocial alcoholics Variable Regression coefficient Standard error Odds ratio 95% confidence interval P-value ADH1B a ADH1B * 2/ * Age <0.001 a Coding of ADH1B genotypes are * 1/ * 1 and * 1/ * 2=0, * 2/ * 2=1;reference group is ADH1B * 1/ * 1 and * 1/ * 2. (Lu et al., 2005;2012)

22 Dependent variable in regression model Total ASPD (N= 297) a (Antisocial ALC and Antisocial Non-ALC) Antisocial ALC (N=133) b Antisocial Non-ALC (N=164) c BSig. Odds ratio 95%CIBSig. Odds ratio 95%CIBSig. Odds ratio 95%CI Lower Bound Upper Bound Lower Bound Upper Bound Lower Bound Upper Bound DRD2 A DRD2 A ALDH2 *1* DRD2*A1 + X ALDH2*1* DRD2*A2 X ALDH2*1* Logistic regression of ALDH2 and DRD2 genes for ASPD, antisocial ALC and non ALC a Antisocial Participants (Antisocial ALC and Antisocial Non-ALC) vs. Healthy Controls. b Antisocial ALC vs. Healthy Controls. c Antisocial Non-ALC vs. Healthy Controls; A1 + (*A1/*A1 or*A1/*A2) Reference category: normal control, DRD2 A2A2 genotype, ALDH2*1*2+*2*2 genotype. (Lu et al., 2005;2012)

23 Specific Meanings  A candidate gene reported for many times, still controversial; this gene still the pathogenesis of the subtype mental illness  The commonly reason (Parsian et al., 1991)  phenotypic heterogeneity  different definitions of control groups  different racially or ethnically mixed study populations  DRD2 gene a pathogenesis of ANX/DEP alcoholism

24 Specific Meanings  The ALDH2*1 risk drinking and un-subtype alcoholism (Chen et al. 1999)  50% of Han Chinese belonging ALDH2*1/*1 but nearly 100% in Western populations (Agarwal and Goedde, 1992)  ASPD only % in Han Chinese (Hwu et al. 1988), but 3.3% among Caucasian Americans (Goodwin & Hamilton 2003)

25 Specific Meanings  70% ASPD with alcoholism higher than 15-20% alcoholism from community in Western population (Goodwin & Hamilton 2003)  6% ASPD with alcoholism (from jail) higher than1.5-3% alcoholism from community in Han Chinese (Hwu et al. 1988; Lu et al., 2013)  ASPD demonstration higher prevalence rate of alcoholism than general population in Han Chinese and Western populations  Alcoholism one of the symptoms of ASPD?

26 Specific Meanings  A Dutch family with a MAOA deficiency in exon 8, male demonstration severe aggressive behavior and borderline mental retardation (Brunner et al., 1993)  Difference genotype frequencies in exons 8 and 14 of MAOA genes Higher ASPD with alcoholism than controls (Parsian., 1999)  MAOA 3-repeat & early childhood maltreatment development higher antisocial behavior in adult male (Capri., 2002)

27 Specific Meanings  Aggressive and/or antisocial behavior, the major symptoms of ASPD, but not the diagnosis of ASPD  Probable reasons for the positive or negative finding of ASPD lack of antisocial non-alcoholism as a controls (Lu et al., 2005; 2012)

28 The Roles of MAO, ADH and ALDH in Dopamine Catabolism

29 Dopamine Metabolism AR s ADH DOPET DOPET: 3,4-dihydroxyphenylethanol ARs : aldose (aldehyde) reductase DOPAL:3,4-dihydroxyphenylacetaldehyde COMT:catechol-O-methyltransferase DOPAL (Feldman et al., 1997)

30 Gene to Gene and Clinical Subtypes of Alcoholism

31 ALDH2 and MAOA Gene  Association – MAOA-uVNTR 3-repeat and ALDH2 gene  Antisocial Alcoholism  Antisocial Non-Alcoholism – ALDH2 x MAOA in ANX/DEP, Antisocial & Mixed alcoholism (Lee et al., 2009; 2010; Hu et al., 2013)

32 Antisocial ALC and Non-ALC after Stratification for MAOA-uVNTR polymorphisms Gene and GroupSample Size (n) Genotype number (Frequency, %) χ2p-valueOdds ratio 95% Confidence Interval ALDH2*1/* 1 ALDH2*1/*2 +*2/*2 MAOA 3-repeat Antisocial ALC 8149(60.5)32(39.5) E Antisocial Non-ALC9627(28.1)69(71.9) MAOA 4-repeat Antisocial ALC5126(51)25(49) Antisocial Non-ALC6627(40.9)39(59.1) Breslow-Day Homogeneity test of odds ratio: χ2=3.772, df=1, p=0.052 (Lee et al., 2009)

33 Logistic regression of interaction for MAOA and ALDH2 gene and the risk of ANX/DEP ALC BSEp-valueOdds Ratio 95% Confidence Interval for Odds ratio Lower Bound Upper Bound MAOA a ALDH2 b E ALDH2 *MAOA B, coefficients; SE, standard errors; p<0.05 is considered significant Reference group: normal control, MAOA-uVNTR 3 allele, ALDH2 *1*1 genotype a MAOA-uVNTR 4-repeat to 3-repeat allele b ALDH2 *1*2+*2*2 to *1*1 genotype DRD2 x MAOA x ALDH2 gene in ANX/DEP Alcoholism (Lee et al., 2010)

34 Logistic regression analysis of MAOA gene and ALDH2 gene and their interaction for the risk of Antisocial ALC a. The reference category is: Antisocial Non ALC, MAOA 4-repeat, ALDH2*1/*2+*2/*2 Antisocial ALC vs Antisocial non ALC a Bdf.Sig.Exp (B) 95% Confidence Interval for Exp (B) Lower BoundUpper Bound ALDH MAOA ALDH2 * MAOA (Lee et al., 2009)

35 MAOA-uVNTR and DRD2 gene interaction for the risk of (bipolar disorder) BP with ALC Model ALC+BP BOR95% CIp-Value MAOA-uVNTR 3-repeat− – DRD2 TaqI A1/A1− – DRD2 TaqI A1/A2− – MAOA 3-repeat ∗ DRD2 TaqI A1/A – MAOA 3-repeat ∗ DRD2 TaqI A1/A – ALC+BP: alcoholism with bipolar disorder. B, coefficients; CI, confidence interval; OR, odds ratio. Reference groups are: MAOA-uVNTR 4-repeat, DRD2 TaqI A2/A2 genotypes, and controls;covarying for age.. (Hu et al., 2013)

36 ALDH2 and DRD2 Gene Interaction  Association – ALDH2*1/*1, DRD2 A1/A1 genotypes and ANX/DEP Antisocial Non-Alcoholism and ASPD (Huang et al.,2004; Lu et el.,2012) – ALDH2 * DRD2 gene in ASPD and Antisocial Non-Alcoholism (Lu et el., 2012)  No Association – ALDH2 & DRD2 gene and Pure (Huang et el., 2004) – Mixed Alcoholism (data not shown)

37 Variable ANX/DEP ALCPure ALC Odds ratio 95% CIP-value Odds ratio 95% CIP-value ALDH2 * 1/ * 1 DRD2A1/A DRD2A1/A ALDH2 * 1/ * 2& * 2/ * 2 DRD2A1/A DRD2A1/A Multiple Logistic Regression Analysis of the DRD2 TaqI A for Risk of Alcohol Dependence with Stratification of ALDH2 genotypes The genotype of ALDH2 * 2/ * 2 was not found in the alcohol-dependence subjects. Reference group is DRD2 A2/A2. Model 1:Neither controlling for age, gender nor stratification of ADH1B and Model2:Stratification of ADH1B and controlling for gender and age. Model 3:Stratification of ALDH2 and controlling for gender and age. (Huang et al., 2004)

38 GenotypeSubgroup DRD2 genotype distribution (and %)Χ2Χ2 p value A1A1A1A2A2A2 Antisocial ALC vs. Controls ALDH2*1/*1Antisocial ALC 16(21.0)30(39.5) Normal control 12(10.6)46(40.7)55(48.7) ALDH2*1/*2+*2/*2Antisocial ALC 12(21.0)29(50.9)16(28.1) Normal control 24(18.3)58(44.3)49(37.4) Antisocial Non ALC vs. Controls ALDH2*1/*1Antisocial Non ALC 13(23.2)28(50.0)15(26.8) Normal control 12(10.6)46(40.7)55(48.7) ALDH2*1/*2+*2/*2Antisocial Non ALC 14(13.0)55(50.9)39(36.1) Normal control 24(18.3)58(44.3)49(37.4) Antisocial personality disorder vs. Controls ALDH2*1/*1Antisocial PD 29(22.0)58(43.9)45(34.1) Normal control 12(10.6)46(40.7)55(48.7) ALDH2*1/*2+*2/*2Antisocial PD 26(15.8)84(50.9)55(33.3) Normal control 24(18.3)58(44.3)49(37.4) DRD2TaqI A in Han Chinese Subjects after Stratification for ALDH2 polymorphisms (Lu et al., 2010; 2011)

39 Dependent variable in regression model Total ASPD (N= 297) a (Antisocial ALC and Antisocial Non- ALC) Antisocial ALC (N=133) b Antisocial Non-ALC (N=164) c BSig. Odds ratio 95%CIBSig. Odds ratio 95%CIBSig. Odds ratio 95%CI Lower Bound Upper Bound Lower Bound Upper Bound Lower Bound Upper Bound DRD2 A DRD2 A ALDH2 *1/* DRD2*A1/ + A1 * ALDH2*1/* DRD2*A2 /*A2 * ALDH2*1/* Logistic regression of ALDH2 and DRD2 genes for ASPD, antisocial ALC and non ALC a Antisocial Participants (Antisocial ALC and Antisocial Non-ALC) vs. Healthy Controls. b Antisocial ALC vs. Healthy Controls. c Antisocial Non-ALC vs. Healthy Controls; A1 + (*A1/*A1 or*A1/*A2) Reference category: normal control, DRD2 A2A2 genotype, ALDH2*1*2+*2*2 genotype. (Lu et al., 2010; 2011)

40 Specific Meanings  Stratification of ALDH2*1/*1, DRD2 gene ASPD and ANX/DEP ALC (Lu et al., 2012).  54.3% ASPD with anxiety disorder in western population  Positive correlation with ASPD and anxiety disorder. (Goodwin & Hamilton., 2003)  Anxiety disorders and ASPD associated with higher odds of alcohol use disorder (Goodwin and Hamilton, 2003)

41 Specific Meanings  ALDH2 * DRD2 gene and BP (Lee et al., 2010)  70-90% BP with anxiety disorder in Western, 20-40% in Han Chinese populations (Chang et al., 2012).  50% of Han Chinese belonging ALDH2*1/*1 but nearly 100% in Western populations (Agarwal and Goedde, 1992)  ALDH2 gene relation to alcoholism, ASPD, anxiety disorder & bipolar disorder.

42 In Summary  DRD2 Association ─ ANX/DEP Alcoholism  MAOA Association ─ Pure and Mixed Alcoholism  ALDH2 Association ─ Pure, ANX/DEP Alcoholism and Antisocial non-alcoholism  ADH1B and ALDH2 Association ─ Pure, ANX/DEP and Mixed Alcoholism

43 In Summary  ALDH2*1/*1, DRD2 A1 /A1 − Anxiety-Depression Alcoholism − ASPD and Antisocial Non-ALC  MAOA 3-repeat,ALDH2 Association – Antisocial Alcoholism  MAOA X ALDH2 Association – Anxiety-Depression Alcoholism – Antisocial Alcoholism – Mixed Alcoholism  ALDH2 X DRD2 Association – ASPD and Antisocial Non-ALC

44 Ongoing Studies  Preliminary studies of low dose (5mg) of memantine : (6 M )  Pure and anxiety-depression alcoholism 1/3 completing discontinue drinking; 1/3 markedly reduced drinking; 1/3 poor response  Antisocial and Mixed Alcoholism (bipolar alcoholism) Poorer response than pure and anxiety-depression alcoholism

45 Comments  Possible mechanism of mematine effect  Inhibition NADPH in microglial and stimulation neurotrophic factors (BDNF etc.) in astroglial cells  Plasma level of memantine (5mg/day): ng/ml (mean 16 ng/ml). No effect in NMDA receptor (required > 86.3 – ng/ml) (Parsons et al., 1999)

46 Conclusion  More studies about MAO, ADH1B, ALDH2 and dopamine/5-HT related genes in different ethnics of major mental illnesses  The lower prevalence of a disease, the higher statistic meaning for a fixed number of trait loci (Rice et al., 2001)  Han Chinese populations playing a specific contribution to the molecular genetic studies of alcoholism (Lu et al., 1999)  Inflammatory press & neurodegenoration involving alcoholism & substance use disorders.  Alcoholism: An important role in substance use disorder and addiction behavior

47 Acknowledgements  Professor Kenneth K. Kidd, Ph. D.  Professor Ting-Kai Li, Ph. D.  Research Scientist Judy R. Kidd, Ph.D  Professor Jean-Shih Chen, Ph. D  Research Scientist Andrew J. Pakstis, Ph. D.  Professor Shin-Jiun Yin, Ph. D.  Professor Huei-Chen Ko, Ph. D  Associate Professor San-Yuan Huang, M.D., Ph. D.  Associate Professor Yaun-Hwa Chou, M.D., Ph. D.  Assistant Professor Wei-Wen Lin, M.D., Ph. D.  Assistant Professor Jia-Fu Lee, M.D., Ph. D.

48 Acknowledgements  Assistant Professor Yi-Chyan Chen, M.D., Ph. D.  Assistant Professor Michael V. Osier, Ph. D.  Assistant Professor Tso-Jen Wang, M.D., Ph. D.  Hsin-Yi, Lo M.D., Ph. D. student  Cheng-Yi Hahn, M.D., M.S., Ph. D. student  Sheng-Yu Lee, M.D., M.S.  Ms. Ju-Ping Weng, M.S.  Ms. Yi-Syuan Wu, M.S.  Ms. Pei-Ling Wu, M.S.  Mr. Tsun-En Lu, M.S.  Ms. Yu-Shan Wang.

49 THANK YOU FOR YOUR ATTENTION

50

51 Strategies for developing therapy for drug addiction Pre-inflammatory Factors (ROS, NO., TNF , ILs, PGs) Reactive Microgliosis (Self-propelling) Drugs or toxin (Extro-neurotoxin) Activation Genetic factors (Endo-neurotoxin) Microglia (Working Model) Dopaminergic Neuronal Damage

52 NADPH oxidase (PHOX) Activated O2O2 O2 –O2 – NADPH NADP + + H + Resting gp91 p22 rap1a p40 p47 rac2 p67  MAC-1 LPS out in PKC P P Naloxone, Dextromethorphan Gly-Gly-Phe

53 O2O2 O 2 – Dual Functions of Superoxide Radicals gp91 Microglia MAC1 TLR4 LBP CD14 PHOX ROS H2O2H2O2 O 2 – TNF-  IL-1 NO ONOO - 2) Gene Expression 1) Neurotoxicity NF-kB,AP-1 PKC LPS DA neurons

54 Transfection of gp91 PHOX, a membrane subunit of PHOX, increases [ 3 H]-naloxone binding [ 3 H]-(-)- Nal Binding Capacity (% WT) WT [ 3 H]-(+)-Nal * Gp91- transfected 400 COS-7 Cells (WT) Ligand Binding Assay Stable Transfection COS-7 gp91 ( gp91 ) gp91 *

55 Serotonin Metabolism (Svensson et al. 1999) The metabolism pattern of serotonin (5-HT). MAO = monoamine oxidase; ADH = alcohol dehydrogenase; ALR = aldehyde/aldose reductase; ALDH = aldehyde dehydrogenase; 5-HIAL = 5-hydroxyindole-3-acetaldehyde; 5-HTOL = 5-hydroxytryptophol; 5-HIAA = 5-hydroxyindole-3-acetic acid

56  ADH1B*2 allele: protective factor  ALDH 2 *2 allele: protective factor (Thomasson et al. 1991) Ethanol Metabolic Genes and Alcoholism

57  ALDH2 deficiency, which slows the elimination of acetaldehyde (Thomasson et al. 1991)  Higher acetaldehyde levels generated by the more active ADH isozymes should deter heavy drinking (Thomasson et al. 1991) Ethanol Metabolic Genes and Alcoholism

58 (Thomasson et al. 1991) a Number of individuals in group. Note that some exons did not amplify well or gave ambiguous results; thus some individuals were excluded. b Fraction of group with each genotype; because of rounding errors, some groups’ frequencies do not sum to c Alcoholics are significantly different from nonalcoholics (P<.002). The ADH2 genotype distribution among alcoholics did not fit the Hardy-Weinberg equilibrium; all other genotype distribution did. d Alcoholics are significantly different from nonalcoholics (P<.005). ADH and ALDH Genotype Frequencies and Allele Frequencies Genotype Frequency b Allele Frequency Group (N a )ADH1B*1/*1ADH1B*1/*2ADH1B*2/*2ADH1B*1ADH1B*2 Nonalcoholics (47)…… Alcoholics (49)…………0.37 c 0.31 c 0.33 c 0.52 d 0.48 d Genotype Frequency b Allele Frequency ALDH2*1/*1ALDH2*1/*2ALDH2*2/*2ALDH2*1ALDH2*2 Nonalcoholics (50)…… Alcoholics (50)…………0.88 d 0.12 d 0.00 d 0.94 d 0.06 d

59 Contradictory Findings of ADH  ADH1B*1 among most of world population (~90%) (Bosron et al. 1993)  ADH1B*2 among Han Chinese (~70%) ( Osier et al. 2002)  ADH1B*2 among Taiwanese aborigines (70-86%) (Chen et al. 1996)  Alcohol prevalence (30-50%) among Taiwanese aborigines >15 times Han Chinese in Taiwan  No support the variance of ADH1B related to rice (Kidd et al., 2010)  Ethnic genetic heterogeneity of ADH1B*2

60 Figure 1. Blood ethanol concentrations after administration of a low-to-moderate dose of ethanol (0.3g/kg) to men with different ADH2 and ALDH2 allelotypes during 4-h period. All subjects were homozygous ADH3*1. The genotypic groups are denoted as ADH2*1/*1, ALDH2*1/*1 ( , n=12); ADH2*1/*2, ALDH2*1/*1 ( , n=10); ADH2*2/*2, ALDH2*1/*1 ( , n=11); ADH2*1/*1, ALDH2*1/*2 (, n=10); ADH2*1/*2, ALDH2*1/*2 (, n=12); ADH2*2/*2, ALDH2*1/*2 ( , n=11). Vertical bars (only the upper or lower portion shown) represent standard errors of the means. Statistically significant differences between the groups at corresponding times by ANOVA: a p<0.001 vs. ADH2*1/*1, ALDH2*1/*1 b p<0.01 vs. ADH2*1/*2, ALDH2*1/*1 c p<0.001 vs. ADH2*2/*2, ALDH2*1/*1 d p<0.05 vs. ADH2*2/*2, ALDH2*1/*2 (Peng et al. 1999)

61 Figure 2. Alterations of blood ethanol in men with homozygous ALDH2*1/*1 and heterozygous ALDH2*1/*2 genotypes, both included three different ADH2 allelotypes (see Fig. 1), following a low-to- moderate dose of ethanol (0.3g/kg) during 4-h period. All subjects were homozygous ADH3*1. The genotypic groups are denoted as ALDH2*1/*1 ( , n=33) and ALDH2*1/*2 (, n=33). Vertical bars (both the upper or lower portion shown) represent standard errors of the means. Statistically significant differences between the groups at corresponding times by Student’s t-test: a p<0.05 vs. ALDH2*1/*1 b p<0.01 vs. ALDH2*1/*1 c p<0.001 vs. ALDH2*1/*1Fig. 1 (Peng et al. 1999)

62 Figure 3. Blood acetaldehyde concentrations after administration of a low-to-moderate dose of ethanol (0.3g/kg) to men with different ADH2 and ALDH2 allelotypes during 4-h period. All subjects were homozygous ADH3*1. The genotypic groups are denoted as ADH2*1/*1, ALDH2*1/*1 ( , n=12); ADH2*1/*2, ALDH2*1/*1 ( , n=10); ADH2*2/*2, ALDH2*1/*1 ( , n=11); ADH2*1/*1, ALDH2*1/*2 (, n=10); ADH2*1/*2, ALDH2*1/*2 (, n=12); ADH2*2/*2, ALDH2*1/*2 ( , n=11). Vertical bars (only the upper or lower portion shown) represent standard errors of the means. Statistically significant differences between the groups at corresponding times by ANOVA: a p<0.05 vs. ADH2*1/*1, ALDH2*1/*1 b p<0.01 vs. ADH2*1/*2, ALDH2*1/*1 c p<0.05 vs. ADH2*1/*2, ALDH2*1/*1 d p<0.01 vs. ADH2*1/*2, ALDH2*1/*1 e p<0.05 vs. ADH2*2/*2, ALDH2*1/*1 f p<0.01 vs. ADH2*2/*2, ALDH2*1/*1 (Peng et al. 1999)

63 Process of DSM Diagnosis  DSM-III : reliability of mental illnesses  DSM-III-R → DSM-IV-TR – developed the validity for diagnostic criteria


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