Variation in Alcohol Pharmacokinetics as a Risk Factor for Alcohol Dependence

Authors

  • J. B. Whitfield,

    Corresponding author
    1. Department of Clinical Biochemistry, Royal Prince Alfred Hospital, Sydney, Australia, and the University of Sydney (JBW); Queensland Institute of Medical Research, Brisbane, Australia, and Joint Genetics Program, the University of Queensland (GZ, DLD, AJB, NGM); and Missouri Alcoholism Research Center, Department of Psychiatry (PAFM, ACH), Washington University, St Louis, Missouri.
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  • G. Zhu,

    1. Department of Clinical Biochemistry, Royal Prince Alfred Hospital, Sydney, Australia, and the University of Sydney (JBW); Queensland Institute of Medical Research, Brisbane, Australia, and Joint Genetics Program, the University of Queensland (GZ, DLD, AJB, NGM); and Missouri Alcoholism Research Center, Department of Psychiatry (PAFM, ACH), Washington University, St Louis, Missouri.
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  • D. L. Duffy,

    1. Department of Clinical Biochemistry, Royal Prince Alfred Hospital, Sydney, Australia, and the University of Sydney (JBW); Queensland Institute of Medical Research, Brisbane, Australia, and Joint Genetics Program, the University of Queensland (GZ, DLD, AJB, NGM); and Missouri Alcoholism Research Center, Department of Psychiatry (PAFM, ACH), Washington University, St Louis, Missouri.
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  • A. J. Birley,

    1. Department of Clinical Biochemistry, Royal Prince Alfred Hospital, Sydney, Australia, and the University of Sydney (JBW); Queensland Institute of Medical Research, Brisbane, Australia, and Joint Genetics Program, the University of Queensland (GZ, DLD, AJB, NGM); and Missouri Alcoholism Research Center, Department of Psychiatry (PAFM, ACH), Washington University, St Louis, Missouri.
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  • P. A. F. Madden,

    1. Department of Clinical Biochemistry, Royal Prince Alfred Hospital, Sydney, Australia, and the University of Sydney (JBW); Queensland Institute of Medical Research, Brisbane, Australia, and Joint Genetics Program, the University of Queensland (GZ, DLD, AJB, NGM); and Missouri Alcoholism Research Center, Department of Psychiatry (PAFM, ACH), Washington University, St Louis, Missouri.
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  • A. C. Heath,

    1. Department of Clinical Biochemistry, Royal Prince Alfred Hospital, Sydney, Australia, and the University of Sydney (JBW); Queensland Institute of Medical Research, Brisbane, Australia, and Joint Genetics Program, the University of Queensland (GZ, DLD, AJB, NGM); and Missouri Alcoholism Research Center, Department of Psychiatry (PAFM, ACH), Washington University, St Louis, Missouri.
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  • N. G. Martin

    1. Department of Clinical Biochemistry, Royal Prince Alfred Hospital, Sydney, Australia, and the University of Sydney (JBW); Queensland Institute of Medical Research, Brisbane, Australia, and Joint Genetics Program, the University of Queensland (GZ, DLD, AJB, NGM); and Missouri Alcoholism Research Center, Department of Psychiatry (PAFM, ACH), Washington University, St Louis, Missouri.
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  • Supported in part by Grants AA07535, AA07728, AA10249, and AA11998 from the NIAAA, by a grant from the US Alcohol Beverage Medical Research Foundation, and by Grants 941177, 951023, and 990798 from the Australian National Health and Medical Research Council. The Alcohol Challenge Twin Study was supported by the Australian Associated Brewers.

John B. Whitfield, PhD, Biochemistry Department, Royal Prince Alfred Hospital, Camperdown NSW 2050, Australia; Fax: 61-2-9515-7931; E-mail: johnwhit@bioc.rpa.cs.nsw.gov.au

Abstract

Background: The significant association between alcohol dehydrogenase (ADH)-2 genotype and alcohol-dependence risk, demonstrated in both Asian and non-Asian populations, suggests a link between the metabolism of alcohol (ethanol) and individual differences in susceptibility to dependence.

Methods: We tested this hypothesis by following up on subjects who took part in the Alcohol Challenge Twin Study conducted in 1979–1981 and comparing the blood and breath alcohol results in that study between subjects who subsequently did or did not meet diagnostic criteria for lifetime alcohol dependence in 1992–1993.

Results: Subjects who met DSM-III-R criteria for lifetime alcohol dependence at follow-up had higher blood and breath alcohol values after alcohol challenge than never-dependent subjects. Multivariate analysis showed independent effects of susceptibility to alcohol dependence and smoking status on blood alcohol concentrations, whereas habitual alcohol intake at the time of the initial study had marginally significant effects. The risk of alcohol dependence was 2-fold higher in men and 3-fold higher in women with blood or breath alcohol concentrations in the highest quartile than in the lowest quartile.

Conclusions: In view of this association and the known genetic influences on both alcohol pharmacokinetics and alcohol dependence, it is probable that part of the heritability of dependence is mediated by genes (other than the known ADH2 and ADH3 polymorphisms) affecting alcohol metabolism.

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