Copyright Alcohol Medical Scholars Program 1

LEVEL OF RESPONSE TO ALCOHOL AS A GENETIC

MARKER FOR ALCOHOLISM

By Marc A. Schuckit, M.D.

Copyright Alcohol Medical Scholars Program 2

DATA SUPPORTING GENETIC INFLUENCES

4x Risk in 1o Relatives

MZ / DZ Concordance = 2 / 1

Adopted Away Children 4x Risk

Animal Breeding / QTL Work

Copyright Alcohol Medical Scholars Program 3

VARIANCE OF RISK

Environment40%

Genetics60%

(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

Copyright Alcohol Medical Scholars Program 5

LEVEL OF RESPONSE (LR) TO ALCOHOL

Observe Less Response When Test with Alcohol

Self Report of More Drinks for an Effect

6Copyright Alcohol Medical Scholars Program

Blo

od

Eth

ano

l (m

g/d

l)

150120906030

120

100

80

60

40

24021018020

BA

Post ETOH (min)

1.1 ml/kg

0.75 ml/kg

Blood Ethanol Over Time

Family History Positive (FHP)

Family History Negative (FHN)

7Copyright Alcohol Medical Scholars Program

cort

iso

l (

g/d

l)

1.25

150120906030

1.15

1.10

1.05

1.00

0.95

1.20

2402101800.90

BA

Post ETOH (min)

FHN

FHP

1.1 ml/kg ETOH

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LR IS RELIABLECorrelation Across Doses = .7

LR Predicts Outcome

Correlation with 15 year

Follow-Up =.4 to .6

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LR IS GENETICALLY INFLUENCED

Animals

HumansTwins Heritability = .4 to .5Correlation Parents to Children

= .2 to .3

10Copyright Alcohol Medical Scholars Program

CORRELATION OF SRE AMONG RELATIVES IN COGA FAMILIES AND AMONG UNRELATED

INDIVIDUALS SRE Score / First 5

First Degree RelativesMother/Daughter (n=561) .18 *Sisters (n=518) .21 *

Total Female/Female (n=1079) .20 * Father/Son (n=449) .22 *Brothers (n=467) .12 **Total Male/Male (n=916) .16 *

Second Degree RelativesFemale/Female (n=99) .16Male/Male (n=55) .09

Unrelated SubjectsFemale/Female (n=410) .02Male/Male (n=369) .03

* p < .001

** p<.01

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CORRELATIONS FOR ALCOHOL CHALLENGES FOR ALL SUBJECTS

Sib Pairs Unrelated

N 59 Pairs 180

Subjective Feelings .30 -.01

Body Sway .35 -.01

12Copyright Alcohol Medical Scholars Program

POPULATION FOR FOLLOW-UP

Number of Subjects 453

Number Traced 453

Number Interviewed 450

99.3%

13Copyright Alcohol Medical Scholars Program

0.3

0.2

0.1

0.0

-0.1

-0.2

-0.3

-0.4

-0.5BASELINE PEAK D1 D2

Reaction To Alcohol

No Alcoholism

Alcoholism

Z-S

CO

RE

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CORRELATIONS

LR to :P3 Amp = .10

Harm Avoidance = .07

Novelty Seeking = .12

Reward Dependence = .08

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ALCOHOL AND PLACEBO CHALLENGE STUDIES

Costly Time Consuming Unsafe for Some Individuals

AlcoholicsALDH2*2 Homozygotes

The “Gold Standard”

16Copyright Alcohol Medical Scholars Program

SRESRE TIME FRAME:

DRINKS 1st 5 Recent

HeaviestNEEDED TO: Times 3 Mos

Feel Effect

Feel Dizzy orSlur Speech

Stumble

Fall Asleep

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COGA SRE

Retest Correlation = .82

Internal Consistent

SHAS Correlation = -.36

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GENOTYPES, LR, & ALCOHOL DEPENDENCE

5HTT GABAA6 BOTH LL+ SS+

LL SL SS Pro/Ser Pro/Pro Pro/Ser Pro/ProLR

%ALC

-.89 -.30 00

57 21 12

-1.01 -.27

71 23

-1.29 +.03

100 00

19Copyright Alcohol Medical Scholars Program

20Copyright Alcohol Medical Scholars Program

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POPULATIONS UCSDSDSUOffspring of FHP/FHN

Prospective StudyCOGA

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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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TESTINGSubjects

Acute Challenge 0.75 to 0.90 ml / kg ETOHMeasure Reaction Over 3 Hours

Subjective FeelingsObserver RatingsBody SwayEtc.

Bloods

ParentsBloods & SRE

VALC=

VGEN + VENV + VGEN x ENV

25Copyright Alcohol Medical Scholars Program

LR ALC-.22

26Copyright Alcohol Medical Scholars Program

LR

ALC

FH

-.14

.21

Copyright Alcohol Medical Scholars Program 27

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

28Copyright Alcohol Medical Scholars Program

LR

ALC

FH

BU

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AEQ

LR

ALC

FH

BU

.17

.16

30Copyright Alcohol Medical Scholars Program

AEQ

LR

ALC

FH

BU

Cope

Soc S

Drink Env

-.15

.15.33

.-14

.12

.17.15

.12

.16

.12

.21

-.16

-.14

Copyright Alcohol Medical Scholars Program 31

20 YEAR SAMPLE

440 Subjects

365 Spouses

555 Children (x age = 12)

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ESTABLISH FOR CHILDREN

Age Onset DrinkingEarly Alcohol ProblemsDrug Use and ProblemsPsychiatric DisordersLR6 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