0145-600810012402-0135$03.00/0 zyxwvutsrqpon ALCOHOLISM: CLINICAL AND EXPERIMENTAL RESEARCH Vol. 24, NO. zy 2 February 2000 Association Between the Functional Polymorphism of Catechol-0-Methyltransferase Gene and Alcohol Consumption Among Social Drinkers zy Jussi Kauhanen, Tero Hallikainen, Tomi-Pekka Tuomainen, Markku Koulu, Matti K. Karvonen, Jukka T Salonen, and Jari Tiihonen Background A common functional genetic polymorphism in the catechol-0-methyltransferase (COMT) gene (Val158 Met) results in 3- to 4-fold differences in COMT enzyme activity and dopamine inactivation rate. Previous studies have shown that type I alcoholism is more common among subjects with low activity COMT genotype (LL), compared with high activity (HH) or heterozygotic (LH) genotypes. Methods: We studied alcohol consumption and the COMT genotype in middle-aged Finnish men (n = 896), who represented an unselected ethnically homogenous population sample and reported using alcohol during the past year. Average alcohol use in pure ethanol (grams per week) was compared between subjects with LL genotype and subjects with LH or HH genotypes. Results: Men with LL genotype (30% of all subjects) reported zyxwvut 27% higher weekly alcohol consumption compared with the two other genotype groups (p < 0.05). The difference remained statistically significant after a multivariate adjustment for sociodemographic factors and prior or existing diseases (p = 0.031). Conclusions: The results indicate that COMT polymorphism may contribute significantly to alcohol intake not only in alcoholics but also in a general male population. Key Words: Alcohol, Catechol-0-Methyltransferase, Polymorphism, Genetics, Epidemiology. ATECHOL-0-METHYLTUNSFEUSE (COMT) C is an enzyme that has a crucial role in dopamine metabolism. The variability of COMT enzyme activity in humans is substantially regulated by a common functional polymorphism. A low activity variant of the enzyme con- tains a methionine residue at amino acid 158 of membrane- bound COMT protein, whereas the high activity variant has a valine at this site (Syvanen et al., 1997). Homozygosity for the low activity allele (LL genotype) is found in approxi- mately 25% of Whites. The high activity homozygosity (HH genotype) results into 3- to 4-fold increased activity of dopamine metabolism and is also found in about 25% of Whites (Gutierrez et al., 1997; Syvanen et al., 1997). Het- erozygotes (LH genotype) have intermediate levels of COMT activity. Evidence shows that this functional polymorphism in the From the Department of Public Health and General Practice, University of Kuopio, Finland (J.K., J. T.S.); the Department of Forensic Psychiatry, Uni- versity of Kuopio (T.H., zyxwvutsrqp J. T.); the Department of Pharmacology, University of Turku, Finland (M. X, M. X K.); and the Research Institute of Public Health, University of Kuopio (T-P.T.). Received for publication September zyxwvutsrqp 8, 1999; accepted December 7, 1999. This research was supported in part by the Academy of Finland and the Ministry of Education in Finland and by the grant from the National Heart, Lung, and Blood Institute (HL44199). Reprint requests: Jussi Kauhanen, M.D., Ph.D., Department of Public Health and General Practice, University of Kuopio, P.O.B. 1627, 70211 Kuopio, Finland; Fax: 358-1 7-1 6-2937; E-mail: jussi. kauhanen@uku.j Copyright zyxwvutsrqp 0 2000 by the Research Society on Alcoholism. Alcohol Clin Exp Res, Vol24, No 2, 2000: pp 135-1 39 COMT gene is associated with certain mental disorders such as obsessive-compulsive disorder (Lachman et al., 1996), rapid cycling bipolar disorder (Kirov et al., 1998; Papolos et al., 1998), and schizophrenia with increased violent behavior (Lachman et al., 1998; Strouss et al., 1997). It is also possible that the allelic variants at the COMT locus are candidates in the etiology of substance abuse. Ethanol-induced euphoria is associated with rapid increase in the release of dopamine in the limbic areas (Yoshimoto et al., 1991). Therefore, individuals homozygous for low activity COMT alleles, which result in low dopamine inac- tivation rate, may be at an increased risk of developing alcohol abuse or dependence as compared to heterozygotes and high activity homozygotes. In a recent study, we observed a markedly higher LL genotype frequency in two samples of late-onset (type I) alcoholic patients (LL frequency 33-36%) compared with a general population sample of blood donors (LL frequency 24%) (Tiihonen et al., 1999). As we further compared the type I alcoholic patients with gender- and race-matched unrelated controls, we found the odds ratio for alcoholism in subjects who have the LL genotype versus those with the HH genotype to be 2.51 (95% CI 1.22-5.19) (Tiihonen et al., 1999). These findings indicate that dopaminergic path- ways and COMT enzymatic activity also may be involved in drinking behavior even when alcohol dependence or abuse is not present. However, this has not yet been examined among social drinkers in general population. zy 135