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Level of Response to alcohol as a genetic marker for

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					 LEVEL OF RESPONSE TO
 ALCOHOL AS A GENETIC
MARKER FOR ALCOHOLISM
   By Marc A. Schuckit, M.D.




     Copyright Alcohol Medical Scholars Program   1
   DATA SUPPORTING
  GENETIC INFLUENCES
                  o
4x Risk in 1 Relatives
MZ / DZ Concordance = 2 / 1
Adopted Away Children 4x Risk
Animal Breeding / QTL Work



       Copyright Alcohol Medical Scholars Program   2
    VARIANCE OF RISK




(Heterogeneous and Polygenic)



                  Copyright Alcohol Medical Scholars Program   3
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   4
LEVEL OF RESPONSE (LR)
     TO ALCOHOL
Observe Less Response When
 Test with Alcohol

Self Report of More Drinks for
 an Effect


        Copyright Alcohol Medical Scholars Program   5
                                        Blood Ethanol Over Time

                        120
Blood Ethanol (mg/dl)




                        100                                                 1.1 ml/kg


                        80


                        60                                                 0.75 ml/kg



                        40                Family History Positive (FHP)
                                          Family History Negative (FHN)
                        20
                              BA   30    60     90     120    150    180   210   240
                                              Post ETOH (min)
                                         1.1 ml/kg ETOH
                   1.25

                   1.20
cortisol (mg/dl)




                   1.15
                                                FHN
                   1.10


                   1.05

                   1.00                         FHP

                   0.95

                   0.90
                          BA   30   60     90    120   150   180   210   240
                                          Post ETOH (min)
       LR IS RELIABLE
n Correlation         Across Doses = .7
n LR   Predicts Outcome
n Correlation         with 15 year
 Follow-Up =.4 to .6

          Copyright Alcohol Medical Scholars Program   8
  LR IS GENETICALLY
     INFLUENCED

l Animals

l Humans
 ä Twins   Heritability = .4 to .5
 ä Correlation Parents to Children
   = .2 to .3

      Copyright Alcohol Medical Scholars Program   9
CORRELATION OF SRE AMONG RELATIVES IN
 COGA FAMILIES AND AMONG UNRELATED
             INDIVIDUALS
                                                      SRE Score / First 5
First Degree Relatives
Mother/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 Relatives
Female/Female (n=99)                                            .16
Male/Male (n=55)                                                .09

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

* p < .001
                   Copyright Alcohol Medical Scholars Program               10
** p<.01
    CORRELATIONS FOR ALCOHOL
   CHALLENGES FOR ALL SUBJECTS

                          Sib Pairs                      Unrelated
    N                     59 Pairs                         180
Subjective
    Feelings                  .30                          -.01

Body Sway                     .35                          -.01


            Copyright Alcohol Medical Scholars Program               11
  POPULATION FOR FOLLOW-UP

Number of Subjects      453
Number Traced           453
Number Interviewed      450




                     99.3%
                  Reaction To Alcohol
          0.3                           No Alcoholism
          0.2                           Alcoholism

          0.1
          0.0
Z-SCORE




          -0.1
          -0.2
          -0.3
          -0.4
          -0.5
                 BASELINE   PEAK   D1       D2
 CORRELATIONS
LR to :
 P3 Amp           =                                .10
 Harm Avoidance   =                                .07
 Novelty Seeking  =                                .12
 Reward Dependence=                                .08

      Copyright Alcohol Medical Scholars Program         14
    ALCOHOL AND PLACEBO
     CHALLENGE STUDIES
        The “Gold Standard”

n Costly
n Time Consuming
n Unsafe for Some Individuals
    ä Alcoholics
    ä ALDH2*2 Homozygotes
          Copyright Alcohol Medical Scholars Program   15
                  SRE
                    TIME FRAME:
DRINKS          1st 5   Recent    Heaviest
NEEDED TO:      Times   3 Mos
Feel Effect
Feel Dizzy or
Slur Speech
Stumble

Fall Asleep
    COGA SRE
Retest Correlation = .82

  Internal Consistent

SHAS Correlation = -.36
    Copyright Alcohol Medical Scholars Program   17
         GENOTYPES, LR, &
       ALCOHOL DEPENDENCE
         5HTT                     GABAAa6       BOTH
                                               LL+    SS+
       LL    SL    SS       Pro/Ser Pro/Pro Pro/Ser Pro/Pro


LR     -.89 -.30   00          -1.01          -.27         -1.29   +.03


%ALC    57   21    12            71            23           100      00




                   Copyright Alcohol Medical Scholars Program             18
  POPULATIONS
n UCSD
n SDSU
n Offspringof FHP/FHN
  Prospective Study
n COGA

      Copyright Alcohol Medical Scholars Program   21
            CRITERIA
n   18 - 25 Years Old
n   Non-Asian
n   Drinker
n   Not Alcohol Dependent
n   Not ASPD, Bipolar, or Schizophrenic
n   Has Alcoholic Parent
n   Available Sib

           Copyright Alcohol Medical Scholars Program   22
                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


             Copyright Alcohol Medical Scholars Program   23
        VALC=
VGEN + VENV + VGEN x
ENV
     -.22
LR          ALC
  LR

-.14         ALC

  FH   .21
             DOMAINS
  n    Behavioral Undercontrol (BU)
  n    Coping Style (WOC + DTC)
  n    Stress (LES + Work Stress)
  n    Social Support (SSQ N, S + SPS)
  n    Expectancies (AEQ)
  n    Drinking Environment
          (IPA + Spouse)
              Copyright Alcohol Medical Scholars Program   27
9/97
 LR




      BU
           ALC



FH
LR


           AEQ   .16


     .17

     BU                ALC



FH
       LR
                                               -.16
       .12   AEQ
                                     .16
                           .12
                   -.14
.-14         .17
                            Cope         .12
                     .15

                                                Drink
                                                              ALC
        BU                  .33                  Env    .15
             Soc S                -.15

                                               .21

  FH
  20 YEAR SAMPLE

n 440   Subjects

n 365   Spouses

n 555   Children (x age = 12)

         Copyright Alcohol Medical Scholars Program   31
ESTABLISH FOR CHILDREN

l   Age Onset Drinking
l   Early Alcohol Problems
l   Drug Use and Problems
l   Psychiatric Disorders
l   LR
l   6 Domains

          Copyright Alcohol Medical Scholars Program   32
   IMPLICATIONS FOR
      PREVENTION

Enhance Education of
 Vulnerabilities
Find Environmental /
 Psychosocial Protective
 Factors Specific to Risk
      Copyright Alcohol Medical Scholars Program   33
   IMPLICATIONS FOR
      TREATMENT

Develop Rx for
 Specific Risk Factors
Evaluate Rx Separately
 in Subgroups

     Copyright Alcohol Medical Scholars Program   34

				
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