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Transcript of Genetic Validation in Alcoholism Ru-Band Lu, MD Professor Department of Psychiatry National Cheng...
Genetic Validation in Alcoholism
Ru-Band Lu, MD
Professor
Department of PsychiatryNational Cheng Kung University, Taiwan
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)
The Importance of Subtypes Alcoholism
Heterogenesis of mental illnesses
Understanding different
pathogenesis
Different treatments and prognosis
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
Limitations
Lack of cutting point
Different risk factors in different
cultures
Inconvenience for clinical use
Lack of genetic validation
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
Clinical Subtyping of Alcoholism
(Huang et al., 2004)
Pure Alcoholism
Anxiety-Depression
Alcoholism
Antisocial Alcoholism
Mixed Alcoholism
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
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
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)
A: Alcoholics; C: Controls; P: Percentage; F: Allele Frequency
Author (A : C)Alcoholism, N (%) TaqI-A Non-alcoholism (n,%)
A1A1 A1A2 A2A2 A1 (P) A1 (F) A1A1 A1A2 A2A2 A1 (P) A1 (F)
Association
Blum et al. 1990 (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) 63.6 34.1 0 (0) 4 (16.7) 20
(83.3) 16.7 8.3
1 (2.0) 28 (53.8)
23 (44.2) 55.8 28.8 0 (0) 4 (13.3) 26
(86.7) 13.3 6.7
6 (6.5) 44 (47.8)
42 (45.7) 54.3 30.4 3 (3.5) 13 (15.3) 69
(81.2) 18.8 11.2
6 (28.6) 7 (33.3) 8 (38.1) 61.9 45.2 10 (10.8) 49 (52.7) 34
(36.5) 63.5 37.1
34 (16) 111 (53) 64 (31) 69 43 21 (14) 64 (42) 67 (44) 56 35
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) 37.5 21.3 8 (6.3) 30 (23.6) 89
(70.1) 29.9 18.1
3 (3.1) 31 (32) 63 (64.9) 35.1 19.8 4 (3.5) 35 (31.0) 74 (65.5) 34.5 19.0
13 (5.3) 75 (30.9) 155 (63.8) 36.2 20.8 3 (3.1) 32 (32.7) 63
(64.3) 35.8 19.4
96 (35) 130 (47) 50 (18) 82 58.3 63 (39.1) 70 (43.5) 28
(17.4) 82.6 60.3
2 (10) 10 (50) 8 (40) 60 35 3 (13) 14 (58) 7 (29 ) 71 42
28 (21.9) 26 (52) 33 (25.8) 73.9 48 11
(12.9) 44 (51.8) 30 (35.5) 64.7 38.8
DRD2 Gene and Alcoholism
(Huang et al.,2004)
Genes and Clinical Subtypes of Alcoholism
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)
DRD2 TaqI A and TaqI B Haplotypes Chinese Han Alcohol Dependence in ANX/DEP, and Controls
GroupHaplotype Number
(2n)
Haplotype frequency(%)p-valuea
Linkage disequilibrium
p-valueb
A1/B1 A1/B2 A2/B1 A2/B2 D D′
Controls 304 0.338 0.014 0.033 0.615 0.044c 0.2211 1.000 <0.001
Pure ALCd 142 0.387 0.000 0.014 0.599 0.366e 0.2318 0.999 <0.001
ANX/DEP ALCd 226 0.473 0.000 0.031 0.496 0.005f 0.2401 1.000 <0.001
ANX/DEPd 258 0.353 0.004 0.027 0.616 0.711g 0.2211 1.000 <0.001a p value of Fisher’s Exact testb p value of linkage disequilibrium in each of the four study groupsc Controls vs. Pure ALC vs. ANX/DEP ALC χ2 value=15.788,df=9d 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, χ2 =8.324,df=3); ANX/DEP ALC vs. pure ALC (p=0.122, χ2 =4.057,df=2)e Controls vs. Pure ALC ; χ2 value=3.155,df=3f Controls vs. ANX/DEP ALC ; χ2 value=11.834 , df=3g Controls vs. ANX/DEP ; χ2 value=1.444 , df=3
(Huang et al., 2004)
Haplotype Frequency of the DRD2 TaqI A and TaqI B polymorphisms
Group
Haplotype
Number (2n)
Haplotype frequency (%)
P Value†
Linkage disequilibrium
P Value‡
A1/B1 A1/B2 A2/B1 A2/B2 D D’
Normal Controls 230 0.32 0.01 0.05 0.62 0.10a 0.20 0.94 <0.0001
Antisocial ALC§ 144 0.45 0.01 0.04 0.50 0.12b 0.23 0.97 <0.0001
Antisocial Non-ALC§ 316 0.42 0.01 0.05 0.53 0.14c 0.21 0.95 <0.0001† p value of Fisher’s Exact test‡ p value of linkage disequilibrium in each of two groupsa Antisocial ALC vs. Antisocial Non-ALC vs. Normal Controls, χ2 value= 10.65, df = 6b Antisocial ALC vs. Normal Controls, χ2 value = 5.74 df = 3c Antisocial Non-ALC vs. Normal Controls, χ2 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)
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)
Frequencies of MAOA polymorphisms in Han Chinese men with alcoholism
and control subjects
Groups/genotypes Sample
size
Promoter-uNTR;no (%)
χ2 P valueSample
size
EcoRV; no.(%)
χ2 P value
3-repeat 4-repeat + -
Control subjects 197 123 (62.4) 74 (37.6) 5.160 0.160 201 165 (62.2) 76 (37.8) 5.174 0.159
Pure ALC 107 53 (49.5) 54 (50.5) 4.736 0.030 108 54 (50.0) 54 (50.8) 4.283 0.039
ANX/DEP ALC 118 72 (61.0) 46 (39.0) 0.063 0.802 118 45 (38.1) 45 (38.1) 0.003 0.954
MAO A= monoamine oxidase-A; VNTR= variable number of tandem repeats; EcoRV=restriction enzyme rs 1137070; 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)
MAOA-uVNTR and DRD2 gene interaction for the risk of BP with ALC
Model ALC+BP
B OR 95% CI p-Value
MAOA-uVNTR 3-repeat −0.839 0.432 0.198–0.942 0.035*
DRD2 TaqI A1/A1 −0.123 0.884 0.323–2.419 0.810
DRD2 TaqI A1/A2 −1.182 0.833 0.392–1.770 0.635
MAOA-uVNTR 3-repeat∗DRD2 TaqI A1/A1 1.186 3.273 0.810–13.224 0.096
MAOA-uVNTR 3-repeat∗DRD2 TaqI A1/A2
1.239 3.451 1.240–9.608 0.018**
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)
MAOA Haplotypes for the uVNTR and EcoRV RFLP Polymorphisms in Different Groups
Sample(N)
Haplotype Number (Frequency x100%)
χ2 p-value(2R +) (3R -) (3R +) (4R -) (4R +)
Community control
77 1 (1.3) 2 (2.6) 40 (51.9) 34 (44.2) 0 (0.0) 11.58 0.480
Jail control (ASB)
38 1 (2.6) 1 (2.6) 20 (52.6) 14 (36.8) 2 (5.3)
Antisocial Non- ALC
50 1 (2.0) 1 (2.0) 27 (54.0) 19 (38.0) 2 (4.0)
Antisocial ALC 41 0 (0.0) 1 (2.4) 26 (63.4) 11 (26.8) 3 (7.3)
ASPD: Antisocial Personality Disorder without meeting the diagnosis of Alcohol DependenceAntisocial 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 gene2R, 3R and 4R= 2 repeats, 3 repeats and 4 repeats (+) and (-) = Presence and absence of restriction sites for EcoRV (Wang et al., 2007)
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)
ADH1B for the Risk of Antisocial Alcoholics
Community controls vs. antisocial alcoholics
Variable Regression coefficient
Standard error Odds ratio 95%
confidence interval P-value
ADH1Ba
ADH1B*2/*2 -0.379 0.315 0.684 0.369-1.269 0.229
Age 0.082 0.021 1.086 1.043-1.131 <0.001
aCoding 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)
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
B Sig. Odds
ratio
95%CI B Sig. Odds
ratio
95%CI B Sig. Odds
ratio
95%CI
Lowe
r
Boun
d
Upper
Bound
Lower
Bound
Uppe
r
Boun
d
Lower
Bound
Upper
Bound
DRD2 A1 -.10
.78 .91 .45 1.81 .36 .45 1.43 .57 3.62
-.35 .38 .70 .32 1.55
DRD2 A2 .24 .38 1.27 .75 2.13 .43 .26 1.53 .73 3.22
.15 .60 1.16 .66 2.05
ALDH2 *1*1
-.24
.40 .79 .45 1.38 .64 .09 1.89 .90 3.96
-1.0
1
.01 .36 .18 .74
DRD2*A1+
X ALDH2*1*1
1.10
.04 3.01 1.05
8.62 .42 .52 1.53 .42 5.52
1.69
.01 5.39 1.53 18.98
DRD2*A2 X ALDH2*1*1
.10 .81 1.10 .51 2.36 -.37 .46 .69 .26 1.85
.57 .24 1.76 .69 4.50
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)
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
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 0.1 - 0.3% in Han Chinese (Hwu et al. 1988), but
3.3% among Caucasian Americans (Goodwin &
Hamilton 2003)
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?
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)
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)
The Roles of MAO, ADH and ALDH in Dopamine
Catabolism
Dopamine Metabolism
ARs
ADH
DOPET
DOPET: 3,4-dihydroxyphenylethanolARs : aldose (aldehyde) reductaseDOPAL:3,4-dihydroxyphenylacetaldehydeCOMT:catechol-O-methyltransferase
DOPAL
(Feldman et al., 1997)
Gene to Gene and Clinical Subtypes of
Alcoholism
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)
Antisocial ALC and Non-ALC after Stratification for
MAOA-uVNTR polymorphisms
Gene and Group Sample Size (n)
Genotype number (Frequency, %)
χ2 p-value Odds ratio
95% Confiden
ce IntervalALDH2*1/
*1ALDH2*1/*2+*2/*2
MAOA 3-repeat
Antisocial ALC 81 49(60.5) 32(39.5) 18.787
1.46E-05
3.913 2.085-7.344
Antisocial Non-ALC
96 27(28.1) 69(71.9)
MAOA 4-repeat
Antisocial ALC 51 26(51) 25(49) 1.178 0.278 1.502 0.719-3.137
Antisocial Non-ALC
66 27(40.9) 39(59.1)
Breslow-Day Homogeneity test of odds ratio: χ2=3.772, df=1, p=0.052 (Lee et al., 2009)
Logistic regression of interaction for MAOA and ALDH2 gene and the
risk of ANX/DEP ALC
B SE p-value Odds Ratio
95% Confidence Interval for Odds ratio
Lower Bound
Upper Bound
MAOAa -.519 .426
. .233 .595 .258 1.372
ALDH2b -2.142 .412
2.0E-7 .117 .052 .263
ALDH2 *MAOA
1.017 .512
.036 2.918 1.070 7.962
B, coefficients; SE, standard errors; p<0.05 is considered significantReference group: normal control, MAOA-uVNTR 3 allele, ALDH2 *1*1 genotypeaMAOA-uVNTR 4-repeat to 3-repeat allelebALDH2 *1*2+*2*2 to *1*1 genotype
DRD2 x MAOA x ALDH2 gene in ANX/DEP Alcoholism (Lee et al., 2010)
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 ALCa
B df. Sig. Exp (B)
95% Confidence Interval for Exp (B)
Lower Bound Upper Bound
ALDH2 .383 1 .313 1.466 .697 3.084
MAOA -.410 1 .227 .663 .341 1.291
ALDH2 * MAOA 1.074 1 .032 2.927 1.099 7.795
(Lee et al., 2009)
MAOA-uVNTR and DRD2 gene interaction for the risk of (bipolar disorder) BP with ALC
Model ALC+BP
B OR 95% CI p-Value
MAOA-uVNTR 3-repeat −0.839 0.432 0.198–0.942 0.035
DRD2 TaqI A1/A1 −0.123 0.884 0.323–2.419 0.810
DRD2 TaqI A1/A2 −1.182 0.833 0.392–1.770 0.635
MAOA 3-repeat∗DRD2 TaqI A1/A1 1.186 3.273 0.810–13.224 0.096
MAOA 3-repeat∗DRD2 TaqI A1/A2
1.239 3.451 1.240–9.608 0.018
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)
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)
VariableANX/DEP ALC Pure ALC
Odds ratio 95% CI P-value Odds
ratio 95% CI P-value
ALDH2* 1/* 1
DRD2A1/A1 3.58 1.36-9.48 0.010 1.565 0.47-5.22 0.466
DRD2A1/A2 2.10 1.02-4.32 0.043 2.278 0.99-5.23 0.052
ALDH2* 1/*2&*2/*2
DRD2A1/A1 1.60 0.43-6.04 0.485 0.857 0.15-5.01 0.864
DRD2A1/A2 2.45 0.85-7.060 0.096 1.572 0.46-5.39 0.472
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)
Genotype Subgroup DRD2 genotype distribution (and %) Χ2 p value
A1A1 A1A2 A2A2
Antisocial ALC vs. Controls
ALDH2*1/*1 Antisocial ALC 16(21.0) 30(39.5) 30(39.5) 4.211 0.122
Normal control 12(10.6) 46(40.7) 55(48.7)
ALDH2*1/*2+*2/*2 Antisocial ALC 12(21.0) 29(50.9) 16(28.1) 1.530 0.465
Normal control 24(18.3) 58(44.3) 49(37.4)
Antisocial Non ALC vs. Controls
ALDH2*1/*1 Antisocial Non ALC
13(23.2) 28(50.0) 15(26.8) 9.084 0.011
Normal control 12(10.6) 46(40.7) 55(48.7)
ALDH2*1/*2+*2/*2 Antisocial Non ALC
14(13.0) 55(50.9) 39(36.1) 1.649 0.483
Normal control 24(18.3) 58(44.3) 49(37.4)
Antisocial personality disorder vs. Controls
ALDH2*1/*1 Antisocial PD 29(22.0) 58(43.9) 45(34.1) 8.008 0.018
Normal control 12(10.6) 46(40.7) 55(48.7)
ALDH2*1/*2+*2/*2 Antisocial PD 26(15.8) 84(50.9) 55(33.3) 1.298 0.522
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)
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
B Sig. Odds
ratio
95%CI B Sig. Odds
ratio
95%CI B Sig. Odds
ratio
95%CI
Lowe
r
Boun
d
Upper
Bound
Lower
Bound
Uppe
r
Boun
d
Lower
Bound
Uppe
r
Boun
d
DRD2 A1 -.10 .78 .91 .45 1.81 .36 .45 1.43 .57 3.62 -.35 .38 .70 .32 1.55
DRD2 A2 .24 .38 1.27 .75 2.13 .43 .26 1.53 .73 3.22 .15 .60 1.16 .66 2.05
ALDH2 *1/*1 -.24 .40 .79 .45 1.38 .64 .09 1.89 .90 3.96 -1.01 .01 .36 .18 .74
DRD2*A1/+ A1 * ALDH2*1/*1
1.10
.04 3.01 1.05 8.62 .42 .52 1.53 .42 5.52 1.69 .01 5.39 1.53 18.98
DRD2*A2 /*A2 * ALDH2*1/*1
.10 .81 1.10 .51 2.36 -.37 .46 .69 .26 1.85 .57 .24 1.76 .69 4.50
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)
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)
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.
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
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
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
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): 10-50
ng/ml (mean 16
ng/ml). No effect in NMDA receptor (required > 86.3
– 431.5 ng/ml) (Parsons et al., 1999)
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
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.
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.
THANK YOU FOR YOUR ATTENTION
Strategies for developing therapy for drug addiction
Pre-inflammatory Factors
(ROS, NO., TNFa, ILs, PGs)
Reactive Microgliosis
(Self-propelling)
Drugs or toxin (Extro-neurotoxin)
Act
iva
tion
Genetic factors
(Endo-neurotoxin)
Microglia
(Working Model)
Dopaminergic
Neuronal
Damage
NADPH oxidase (PHOX)
Activated
O2O2 • –
NADPH NADP+ + H +
Resting
gp91
p22rap1a
p40
p47rac2
p67
a MAC-1
LPS
out
in
PKC
P
P
Naloxone,Dextromethorphan Gly-Gly-Phe
O2
O2 • –
Dual Functions of Superoxide Radicals
gp91
Microglia
MAC1
TLR4
LBPCD14
PHOX
ROS
H2O2
O2 • –
TNF- IL-1
NO •
ONOO -
2) Gene Expression
1) Neurotoxicity
NF-kB,AP-1
PKCLPS
LPS
DA neurons
Transfection of gp91PHOX, a membrane subunit of PHOX, increases [3H]-naloxone binding
0
100
200
300
[3H]-(-)-Nal
Bin
din
g C
apac
ity
(% W
T)
WT
[3H]-(+)-Nal
*
Gp91-transfected
400COS-7 Cells (WT)
Ligand Binding Assay
StableTransfection
COS-7 gp91 (gp91)
gp91
*
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
ADH1B*2 allele: protective factor
ALDH 2 *2 allele: protective factor (Thomasson et al. 1991)
Ethanol Metabolic Genes and Alcoholism
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
(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 1.00.c Alcoholics are significantly different from nonalcoholics (P<.002). The AD H2 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 ALDHGenotype Frequencies and Allele
Frequencies
Genotype Frequencyb Allele Frequency
Group (Na) ADH1B*1/*1 ADH1B*1/*2 ADH1B*2/*2 ADH1B*1 ADH1B*2
Nonalcoholics (47)……. 0.06 0.40 0.53 0.27 0.73
Alcoholics (49)………… 0.37c 0.31c 0.33c 0.52d 0.48d
Genotype Frequencyb Allele Frequency
ALDH2*1/*1 ALDH2*1/*2 ALDH2*2/*2 ALDH2*1 ALDH2*2
Nonalcoholics (50)……. 0.52 0.36 0.12 0.70 0.30
Alcoholics (50)………… 0.88d 0.12d 0.00d 0.94d 0.06d
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
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:ap<0.001 vs. ADH2*1/*1, ALDH2*1/*1 bp<0.01 vs. ADH2*1/*2, ALDH2*1/*1cp<0.001 vs. ADH2*2/*2, ALDH2*1/*1 dp<0.05 vs. ADH2*2/*2, ALDH2*1/*2
(Peng et al. 1999)
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:ap<0.05 vs. ALDH2*1/*1 bp<0.01 vs. ALDH2*1/*1 cp<0.001 vs. ALDH2*1/*1
(Peng et al. 1999)
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:ap<0.05 vs. ADH2*1/*1, ALDH2*1/*1 bp<0.01 vs. ADH2*1/*2, ALDH2*1/*1cp<0.05 vs. ADH2*1/*2, ALDH2*1/*1 dp<0.01 vs. ADH2*1/*2, ALDH2*1/*1ep<0.05 vs. ADH2*2/*2, ALDH2*1/*1 fp<0.01 vs. ADH2*2/*2, ALDH2*1/*1
(Peng et al. 1999)
Process of DSM Diagnosis
DSM-III : reliability of mental illnesses
DSM-III-R → DSM-IV-TR
–developed the validity for diagnostic
criteria