Transcript Level of Response to alcohol as a genetic marker for

LEVEL OF RESPONSE TO
ALCOHOL AS A GENETIC
MARKER FOR ALCOHOLISM
By Marc A. Schuckit, M.D.
Copyright Alcohol Medical Scholars Program
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DATA SUPPORTING
GENETIC INFLUENCES
o
4x Risk in 1 Relatives
MZ / DZ Concordance = 2 / 1
Adopted Away Children 4x Risk
Animal Breeding / QTL Work
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VARIANCE OF RISK
Environment
40%
Genetics
60%
(Heterogeneous and Polygenic)
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GENETIC FACTORS IN :
I. Alcohol Metabolism
II. Disinhibition / Impulsivity
III. Level of Response to Alcohol
IV. Independent Psychiatric Disorders
V. Others
Opioids
CRF and the HPA
Neuropeptide Y
Etc.
Second Messenger Systems
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LEVEL OF RESPONSE (LR)
TO ALCOHOL
Observe Less Response When
Test with Alcohol
Self Report of More Drinks for
an Effect
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Blood Ethanol Over Time
Blood Ethanol (mg/dl)
120
1.1 ml/kg
100
80
0.75 ml/kg
60
Family History Positive (FHP)
40
Family History Negative (FHN)
20
BA
30
60
90
120
150
Post ETOH (min)
180
210
240
1.1 ml/kg ETOH
1.25
cortisol (g/dl)
1.20
1.15
FHN
1.10
1.05
FHP
1.00
0.95
0.90
BA
30
60
90
120
150
Post ETOH (min)
180
210
240
LR IS RELIABLE
 Correlation
 LR
Across Doses = .7
Predicts Outcome
 Correlation
with 15 year
Follow-Up =.4 to .6
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LR IS GENETICALLY
INFLUENCED
 Animals
 Humans
 Twins
Heritability = .4 to .5
 Correlation Parents to Children
= .2 to .3
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CORRELATION OF SRE AMONG RELATIVES IN
COGA FAMILIES AND AMONG UNRELATED
INDIVIDUALS
SRE Score / First 5
First Degree Relatives
Mother/Daughter (n=561)
Sisters (n=518)
Total Female/Female (n=1079)
Father/Son (n=449)
Brothers (n=467)
Total Male/Male (n=916)
.18 *
.21 *
.20 *
.22 *
.12 **
.16 *
Second Degree Relatives
Female/Female (n=99)
Male/Male (n=55)
.16
.09
Unrelated Subjects
Female/Female (n=410)
Male/Male (n=369)
.02
.03
* p < .001
** p<.01
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CORRELATIONS FOR ALCOHOL
CHALLENGES FOR ALL SUBJECTS
N
Subjective
Feelings
Body Sway
Sib Pairs
59 Pairs
Unrelated
180
.30
-.01
.35
-.01
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11
POPULATION FOR FOLLOW-UP
Number of Subjects
453
Number Traced
453
Number Interviewed
450
99.3%
Reaction To Alcohol
0.3
No Alcoholism
Alcoholism
0.2
Z-SCORE
0.1
0.0
-0.1
-0.2
-0.3
-0.4
-0.5
BASELINE
PEAK
D1
D2
CORRELATIONS
LR to :
P3 Amp
=
Harm Avoidance
=
Novelty Seeking
=
Reward Dependence=
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.10
.07
.12
.08
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ALCOHOL AND PLACEBO
CHALLENGE STUDIES
The “Gold Standard”
 Costly
 Time
Consuming
 Unsafe for Some Individuals
 Alcoholics
 ALDH2*2
Homozygotes
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SRE
TIME FRAME:
DRINKS
NEEDED TO:
Feel Effect
Feel Dizzy or
Slur Speech
Stumble
Fall Asleep
1st 5
Times
Recent
3 Mos
Heaviest
COGA SRE
Retest Correlation = .82
Internal Consistent
SHAS Correlation = -.36
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GENOTYPES, LR, &
ALCOHOL DEPENDENCE
5HTT
LL
LR
%ALC
SL
-.89 -.30
57
21
GABAA6
SS
BOTH
LL+
SS+
Pro/Ser Pro/Pro Pro/Ser Pro/Pro
00
-1.01
-.27
-1.29
+.03
12
71
23
100
00
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POPULATIONS
UCSD
SDSU
Offspring
of FHP/FHN
Prospective Study
COGA
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CRITERIA
18 - 25 Years Old
 Non-Asian
 Drinker
 Not Alcohol Dependent
 Not ASPD, Bipolar, or Schizophrenic
 Has Alcoholic Parent
 Available Sib

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TESTING
Subjects
Acute Challenge 0.75 to 0.90 ml / kg ETOH
Measure Reaction Over 3 Hours
Subjective Feelings
Observer Ratings
Body Sway
Etc.
Bloods
Parents
Bloods & SRE
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VALC=
VGEN + VENV + VGEN x ENV
LR
-.22
ALC
LR
ALC
-.14
FH
.21
DOMAINS
 Behavioral
Undercontrol (BU)
 Coping Style (WOC + DTC)
 Stress (LES + Work Stress)
 Social Support (SSQ N, S + SPS)
 Expectancies (AEQ)
 Drinking Environment
(IPA + Spouse)
9/97
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LR
BU
FH
ALC
LR
AEQ
.16
.17
BU
FH
ALC
LR
.12
-.16
AEQ
.16
.12
.-14
.17
-.14
.15 Cope
BU
Drink
Env
.33
Soc S
.12
-.15
.21
FH
ALC
.15
20 YEAR SAMPLE
 440
Subjects
 365
Spouses
 555
Children (x age = 12)
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ESTABLISH FOR CHILDREN
 Age
Onset Drinking
 Early Alcohol Problems
 Drug Use and Problems
 Psychiatric Disorders
 LR
 6 Domains
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IMPLICATIONS FOR
PREVENTION
Enhance Education of
Vulnerabilities
Find Environmental /
Psychosocial Protective
Factors Specific to Risk
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IMPLICATIONS FOR
TREATMENT
Develop Rx for
Specific Risk Factors
Evaluate Rx Separately
in Subgroups
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