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

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Presentation on theme: "Copyright Alcohol Medical Scholars Program1 LEVEL OF RESPONSE TO ALCOHOL AS A GENETIC MARKER FOR ALCOHOLISM By Marc A. Schuckit, M.D."— Presentation transcript:

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

2 Copyright Alcohol Medical Scholars Program2 DATA SUPPORTING GENETIC INFLUENCES 4x Risk in 1 o Relatives MZ / DZ Concordance = 2 / 1 Adopted Away Children 4x Risk Animal Breeding / QTL Work

3 Copyright Alcohol Medical Scholars Program3 VARIANCE OF RISK (Heterogeneous and Polygenic)

4 Copyright Alcohol Medical Scholars Program4 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

5 Copyright Alcohol Medical Scholars Program5 LEVEL OF RESPONSE (LR) TO ALCOHOL Observe Less Response When Test with Alcohol Self Report of More Drinks for an Effect

6 Blood Ethanol (mg/dl) 150120906030 120 100 80 60 40 240210180 20 BA Post ETOH (min) 1.1 ml/kg 0.75 ml/kg Blood Ethanol Over Time Family History Positive (FHP) Family History Negative (FHN)

7 cortisol (  g/dl) 1.25 150120906030 1.15 1.10 1.05 1.00 0.95 1.20 240210180 0.90 BA Post ETOH (min) FHN FHP 1.1 ml/kg ETOH

8 Copyright Alcohol Medical Scholars Program8 LR IS RELIABLE n Correlation Across Doses =.7 n LR Predicts Outcome n Correlation with 15 year Follow-Up =.4 to.6

9 Copyright Alcohol Medical Scholars Program9 LR IS GENETICALLY INFLUENCED Animals Humans ä Twins Heritability =.4 to.5 ä Correlation Parents to Children =.2 to.3

10 Copyright Alcohol Medical Scholars Program10 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 ** p<.01

11 Copyright Alcohol Medical Scholars Program11 CORRELATIONS FOR ALCOHOL CHALLENGES FOR ALL SUBJECTS Sib PairsUnrelated N 59 Pairs 180 Subjective Feelings.30 -.01 Body Sway.35 -.01

12 POPULATION FOR FOLLOW-UP Number of Subjects453 Number Traced453 Number Interviewed450 99.3%

13 0.3 0.2 0.1 0.0 -0.1 -0.2 -0.3 -0.4 -0.5 BASELINE PEAK D1 D2 Reaction To Alcohol No Alcoholism Alcoholism Z-SCORE

14 Copyright Alcohol Medical Scholars Program14 CORRELATIONS LR to : P3 Amp=.10 Harm Avoidance=.07 Novelty Seeking=.12 Reward Dependence=.08

15 Copyright Alcohol Medical Scholars Program15 ALCOHOL AND PLACEBO CHALLENGE STUDIES n Costly n Time Consuming n Unsafe for Some Individuals ä Alcoholics ä ALDH2*2 Homozygotes The “Gold Standard”

16 SRE TIME FRAME: DRINKS 1st 5 Recent Heaviest NEEDED TO: Times 3 Mos Feel Effect Feel Dizzy or Slur Speech Stumble Fall Asleep

17 Copyright Alcohol Medical Scholars Program17 COGA SRE Retest Correlation =.82 Internal Consistent SHAS Correlation = -.36

18 Copyright Alcohol Medical Scholars Program18 GENOTYPES, LR, & ALCOHOL DEPENDENCE 5HTTGABA A  6 BOTH LL+ SS+ LL SL SS Pro/Ser Pro/Pro Pro/Ser Pro/Pro LR %ALC -.89 -.30 00 57 21 12 -1.01 -.27 71 23 -1.29 +.03 100 00

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21 Copyright Alcohol Medical Scholars Program21 POPULATIONS n UCSD n SDSU n Offspring of FHP/FHN Prospective Study n COGA

22 Copyright Alcohol Medical Scholars Program22 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

23 Copyright Alcohol Medical Scholars Program23 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

24 V ALC = V GEN + V ENV + V GEN x ENV

25 LRALC -.22

26 LR ALC FH -.14.21

27 Copyright Alcohol Medical Scholars Program27 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) 9/97

28 LR ALC FH BU

29 AEQ LR ALC FH BU.17.16

30 AEQ LR ALC FH BU Cope Soc S Drink Env -.15.15.33.-14.12.17.15.12.16.12.21 -.16 -.14

31 Copyright Alcohol Medical Scholars Program31 20 YEAR SAMPLE n 440 Subjects n 365 Spouses n 555 Children (x age = 12)

32 Copyright Alcohol Medical Scholars Program32 ESTABLISH FOR CHILDREN l Age Onset Drinking l Early Alcohol Problems l Drug Use and Problems l Psychiatric Disorders l LR l 6 Domains

33 Copyright Alcohol Medical Scholars Program33 IMPLICATIONS FOR PREVENTION Enhance Education of Vulnerabilities Find Environmental / Psychosocial Protective Factors Specific to Risk

34 Copyright Alcohol Medical Scholars Program34 IMPLICATIONS FOR TREATMENT Develop Rx for Specific Risk Factors Evaluate Rx Separately in Subgroups


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