Download - Copyright Alcohol Medical Scholars Program1 LEVEL OF RESPONSE TO ALCOHOL AS A GENETIC MARKER FOR ALCOHOLISM By Marc A. Schuckit, M.D.

Copyright Alcohol Medical Scholars Program 1

LEVEL OF RESPONSE TO ALCOHOL AS A GENETIC

MARKER FOR ALCOHOLISM

By Marc A. Schuckit, M.D.


DATA SUPPORTING GENETIC INFLUENCES

4x Risk in 1o Relatives

MZ / DZ Concordance = 2 / 1

Adopted Away Children 4x Risk

Animal Breeding / QTL Work


VARIANCE OF RISK

Environment40%

Genetics60%

(Heterogeneous and Polygenic)


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


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)


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


LR IS RELIABLECorrelation Across Doses = .7

LR Predicts Outcome

Correlation with 15 year

Follow-Up =.4 to .6


LR IS GENETICALLY INFLUENCED

Animals

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

= .2 to .3


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


CORRELATIONS FOR ALCOHOL CHALLENGES FOR ALL SUBJECTS

Sib Pairs Unrelated

N 59 Pairs 180

Subjective Feelings .30 -.01

Body Sway .35 -.01


POPULATION FOR FOLLOW-UP

Number of Subjects 453

Number Traced 453

Number Interviewed 450

99.3%


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


CORRELATIONS

LR to :P3 Amp = .10

Harm Avoidance = .07

Novelty Seeking = .12

Reward Dependence = .08


ALCOHOL AND PLACEBO CHALLENGE STUDIES

Costly Time Consuming Unsafe for Some Individuals

AlcoholicsALDH2*2 Homozygotes

The “Gold Standard”


SRESRE TIME FRAME:

DRINKS 1st 5 Recent

HeaviestNEEDED TO: Times 3 Mos

Feel Effect

Feel Dizzy orSlur Speech

Stumble

Fall Asleep


COGA SRE

Retest Correlation = .82

Internal Consistent

SHAS Correlation = -.36


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




POPULATIONS UCSDSDSUOffspring of FHP/FHN

Prospective StudyCOGA


CRITERIA 18 - 25 Years Old Non-Asian Drinker Not Alcohol Dependent Not ASPD, Bipolar, or Schizophrenic Has Alcoholic Parent Available Sib


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


LR ALC-.22


LR

ALC

FH

-.14

.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


LR

ALC

FH

BU


AEQ

LR

ALC

FH

BU

.17

.16


AEQ

LR

ALC

FH

BU

Cope

Soc S

Drink Env

-.15

.15.33

.-14

.12

.17.15

.12

.16

.12

.21

-.16

-.14


20 YEAR SAMPLE

440 Subjects

365 Spouses

555 Children (x age = 12)


ESTABLISH FOR CHILDREN

Age Onset DrinkingEarly Alcohol ProblemsDrug Use and ProblemsPsychiatric DisordersLR6 Domains


IMPLICATIONS FOR PREVENTION

Enhance Education of Vulnerabilities

Find Environmental / Psychosocial Protective Factors Specific to Risk


IMPLICATIONS FOR TREATMENT

Develop Rx for Specific Risk Factors

Evaluate Rx Separately in Subgroups