Gender Differences in the Effects of ADH1B and ALDH2 Polymorphisms on Alcoholism Mitsuru Kimura, Tomohiro Miyakawa, Sachio Matsushita, Mirai So, and Susumu Higuchi Background: Gender differences are known to exist in the prevalence, characteristics, and course of alcohol dependence. Elucidating gender differences in the characteristics of alcohol dependence is important in gender-based medicine and may improve treatment outcomes. Many studies have shown that genetic factors are associated with the risk of alcohol dependence in both genders. Polymorphisms of alcohol dehydrogenase-1B (ADH1B) and aldehyde dehydrogenase-2 (ALDH2) are strong genetic determinants of alcohol dependence. This study aimed to clarify gender differences in the effects of ADH1B and ALDH2 polymorphism on the development of alcohol dependence. Methods: Subjects were 200 female alcoholics and 415 male alcoholics hospitalized in Kurihama Alcoholism Center. Clinical information and background data were obtained by chart review. ALDH2 and ADH1B genotyping was performed by the polymerase chain reaction–restriction fragment length polymorphism method. Results: The onset age of female alcoholics with inactive ALDH2 genotype was significantly lower than those with active ALDH2 genotype, but the onset age did not differ between the inactive and active ALDH2 group in male alcoholics. The difference in onset age between the ADH1B genotype groups did not reach significant levels. The prevalence of comorbid psychiatric disorders, including major depression, eating disorder, panic disorder, and borderline personality disorder, was significantly higher in female alcoholics with inactive ALDH2 or superactive ADH1B than in those with active ALDH2 or normal ADH1B. Conclusions: ALDH2 polymorphism appears to have contrasting effects on the development of alcoholism in women and men. One possible reason for this gender difference may be the high prevalence of psychiatric comorbidities in female alcoholics with inactive ALDH2. Key Words: Gender Difference, Alcoholism, Alcohol Dehydrogenase, Aldehyde Dehydroge- nase, Comorbidity. G ENDER DIFFERENCES ARE known to exist in the prevalence of alcoholism. Studies have consistently shown that the prevalence of alcoholism is much lower in women than in men (Kessler et al., 1997), and that alcohol consumption is lower in healthy women than in healthy men. The reasons for these gender differences include biological, psychological, and social factors (Holmila and Raitasalo, 2005). Studies have suggested that women are likely to show higher blood alcohol concentrations after consuming the same amount of alcohol, because of smaller liver and muscle size, lower water content, higher lipid content (Ramchandani et al., 2001), and lower gastric ethanol elimination rates when compared with men (Baraona et al., 2001). Psychologically, women drink more commonly to express their feelings and address interpersonal problems, while men more commonly drink for pleasure or amusement (Makela and Mustonen, 2000). Cultural conceptions of gender also lead to differences in alcohol consumption (Room, 1996), and this is part of the reason why the gender differences in alcohol consumption vary among different cultures (Wilsnack et al., 2009). Gender differences in the characteristics and course of alco- holism have also been reported. Female alcoholics are more likely to have psychiatric comorbidities than male alcoholics (Kessler et al., 1997), particularly eating disorders (Higuchi et al., 1993) and major depression (Grant and Harford, 1995). Some studies have suggested that treatment outcomes are better in women than in men (Satre et al., 2007), but most studies have failed to show a gender difference in relapse into alcohol dependence (Walitzer and Dearing, 2006). The effi- cacy of naltrexone for alcohol dependence has been reported to be poorer in women than in men (Suh et al., 2008). Eluci- dating gender differences in characteristics of alcohol depen- dence can thus lead to better gender-based medicine that may improve treatment outcomes in both genders. Regardless of gender, genetic factors are significant deter- minants of alcoholism. The heritability of alcoholism is estimated to be 50 to 60% (Kendler et al., 1992). Twin studies in men have consistently reported significantly more From the National Hospital Organization, Kurihama Alcoholism Center (MK, TM, SM, SH), Yokosuka, Kanagawa, Japan; and Institute of Psychiatry, King’s College London (MS), London, UK. Received for publication October 15, 2010; accepted February 25, 2011. Reprint requests: Mitsuru Kimura, MD, PhD, National Hospital Organization, Kurihama Alcoholism Center, 5-3-1 Nobi, Yokosuka, Kanagawa 2390841, Japan; Tel.: +81 46848 1550; Fax: +81 46849 7743; E-mail: kimura.mitsuru@gmail.com Copyright Ó 2011 by the Research Society on Alcoholism. DOI: 10.1111/j.1530-0277.2011.01543.x Alcoholism: Clinical and Experimental Research Vol. 35, No. 11 November 2011 Alcohol Clin Exp Res, Vol 35, No 11, 2011: pp 1923–1927 1923