"We were interested in examining the role of the functional Thr105Ile variant of HNMT because this is the enzyme which accounts for the degradation of histamine in mammalian brain," said Gabor Oroszi, a researcher at the National Institute on Alcohol Abuse and Alcoholism and first author of the study. "Since clinical experience with antihistamine drugs has indicated that blockade of histamine 1 receptors results in sedation, anxiolysis and sleepiness - which are very strong in many patients - we hypothesized that altered function of the sole histamine metabolizing enzyme in the brain might alter anxiety, a state frequently encountered by alcoholics."
Oroszi and his colleagues examined two distinct populations of alcoholics - 218 Finnish Caucasians (206 males, 12 females) and 186 Plains American Indians (98 males, 88 females) - for an association among the Thr105lle polymorphism, alcoholism, and "harm avoidance," a dimensional measure of anxious personality. Researchers also examined two groups of nonalcoholic "controls," 313 Finns (220 males, 93 females) and 140 Plains Indians (36 males, 104 females) for comparison's sake.
"We chose these two populations because they were well characterized in terms of both alcohol abuse and dependence, as well as harm avoidance," said Oroszi. "There was a sufficient number of alcoholics and nonalcoholic controls to allow us to compare the distribution of genotypes and alleles between the alcoholic and nonalcoholic groups. Finally, since the populations are independent, meaning genetically distinct, we assumed that if any association with alcoholism and harm avoidance were to be found in the same direction in both populations, it would support a true role of the variant, thereby strengthening the power of the finding."
Harm avoidance, Oroszi added, is a dimensional measure of anxious personality or anxiety proneness. "Harm avoidance measures the range of 'normal' anxiety present in the general populations; it is not a measure of pathological anxiety, although individuals with clinical anxiety disorders tend to have high harm avoidance."
Results showed that Thr105 allele frequencies were significantly higher in the alcoholics, compared to the nonalcoholics, in both populations.
"Our findings can be interpreted in two ways," said Oroszi. "First, the Thr105 allele is more frequent among alcoholics as compared with nonalcoholics, suggesting that the presence of the Thr105 allele might increase vulnerability to the development of alcoholism. Second, the [frequency of the rarer] Ile105 allele is more abundant among nonalcoholics, suggesting that carriers of the Ile105 allele might be protected against the development of alcoholism. Since harm avoidance was also lower among nonalcoholics, it would appear that the protective effect of the Ile105 allele against alcoholism is mediated by lower harm avoidance."
Oroszi said that his study's most important message is that a common functional variant of a histamine-metabolizing enzyme in the human brain may be able to influence behavior and individual vulnerability to various psychiatric diseases such as alcoholism. "What we also need to emphasize is the fact that there is a potent amine in the brain, histamine, whose contribution to anxiety and alcoholism has not been exhaustively investigated." Additionally, he said, the polymorphism may not only be able to influence vulnerability to psychiatric diseases, it might also be able to influence a patient's response to drug treatment or the severity of side effects.
Oroszi cautioned that, although the findings were consistent in two different populations, it is nonetheless a genetic association study. "Our explanation of how the altered histamine levels lead to differences in alcoholism vulnerability and alter harm avoidance is hypothetical, based on previous studies addressing the activity of the enzyme," he said. "In addition, whereas we focused on a common functional variant in the gene of a histamine-metabolizing enzyme, there might be additional, as-yet-unknown variants in this gene which might also contribute to differences in susceptibility to alcoholism, anxiety and other psychiatric diseases."
He plans to further examine and corroborate the role of the polymorphism in alcoholism in other populations and ethnic groups, such as African-Americans. "In addition, we plan to address the role of the polymorphism in flushing response, allergic diseases and other pathological states in which histamine has a putative or well-established role," said Oroszi.
Alcoholism: Clinical & Experimental Research (ACER) is the official journal of the Research Society on Alcoholism and the International Society for Biomedical Research on Alcoholism. Co-authors of the ACER paper, "Thr105lle, a functional polymorphism of histamine N-methyltransferase (HNMT), is associated with alcoholism in two independent populations," were: Mary-Anne Enoch, Jeffrey Chun, and David Goldman of the Laboratory of Neurogenetics at the National Institute on Alcoholism and Alcohol Abuse; and Matti Virkkunen of the Department of Psychiatry at the University of Helsinki in Finland. The study was funded in part by the Office of Research on Minority Health.