Association between the genetic polymorphism of the catechol-O-methyltransferase (COMT) and type 1 alcoholism

Objective: Catechol-O-methyltransferase (COMT) is an enzyme which has a crucial role in the metabolism of dopamine and, therefore, it has been suggested that genetic polymorphism of COMT may contribute to the etiology of mental disorders such as schizophrenia, obsessive compulsive disorder (OCD), and alcoholism. Since ethanol-induced euphoria is associated with the rapid increase of the release of dopamine in the limbic areas, it is logical to assume that those subjects having low activity (L) COMT allele - resulting in a low dopamine inactivation rate - would be more vulnerable to the development of ethanol dependence than those having high activity (H) alleles. The aim of this study was to test the hypothesis that L allele frequency is higher among type 1 (late-onset alcholics when compared with healthy controls or general population. Methods: The polymorphic nucleotide (A or G) in the first position of codon 158 of the COMT gene was identified by a PCR-based restriction fragment length polymorphism analysis using the restriction enzyme Nla III. The polymorphism was studied between two independent male late onset (type 1) alcoholic populations in Turku (N = 67, and Kuopio (N = 57) by comparing the genotype and allele frequencies with previously published data from 3,140 blood donors (general population) and 47 age- and sex-matched healthy controls. Results: The L allele frequency was markedly higher among the patients both in Turku (X² = 5.21, P = 0.02, and in Kuopio (X² = 7.91, P = 0.005) when compared with the general population. When the pooled data from all patients were compared with the data from the general population (blood donors), the difference was even greater (X² = 12.6, P = 0.0004). The odds ratio (OR) for those subjects having the L allele (LL and LH genotypes) vs. those with the HH genotype was 2.37, 95%CI 1.36 - 4.19, P = 0.001 when all alcoholics (N = 124) were compared with the general population. When alcoholics were compared with matched healthy controls, the OR was even higher (OR 2.86, 95%CI 1.17 - 6.99, P = 0.0096). The population etiological (attributable) fraction for the L allele genotypes (LL and LH) in alcoholism was 49.4% (95%CI 21.6% - 68.2%). Conclusions: The results indicate that the COMT polymorphism has marked contribution (population etiological fraction at least 21%) to the development of late-onset alcoholism in Finland.