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Thr105Ile, a Functional Polymorphism of Histamine N‐Methyltransferase, Is Associated with Alcoholism in Two Independent Populations
Author(s) -
Oroszi Gabor,
Enoch MaryAnne,
Chun Jeffrey,
Virkkunen Matti,
Goldman David
Publication year - 2005
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1097/01.alc.0000156128.28257.2e
Subject(s) - histamine n methyltransferase , harm avoidance , histamine , genotype , allele , medicine , allele frequency , endocrinology , genetics , psychology , biology , gene , receptor , personality , temperament , social psychology , histamine h2 receptor , antagonist
Background: Histamine is expressed in cortical and limbic areas that are involved in emotion and cognition and modulates these behaviors. H 1 receptor antagonists are sedative. Histamine N‐methyltransferase (HNMT) catalyzes the Nτ methylation of histamine, the sole pathway for termination of the neurotransmitter action of histamine in mammalian brain. A common and functionally significant polymorphism, a C314T transition in exon 4 of the HNMT gene results in a Thr105Ile substitution of the protein encoded. The Thr105 allele is associated with ˜2‐fold higher enzyme activity, leading to the prediction that it might be associated with diminished histamine levels, resulting in differences in anxiety, cognition, and sedation that play important roles in alcoholism. In two ethnically distinct populations, we tested whether the Thr105Ile polymorphism was associated with alcoholism and with harm avoidance, a dimensional measure of anxious personality. Methods: A 5′ exonuclease assay (TaqMan) was used to genotype Thr105Ile in psychiatrically interviewed Finnish Caucasian ( n = 218) and Plains American Indian ( n = 186) alcoholics, along with ethnically matched, psychiatrically interviewed, controls (Finns: n = 313, Plains Indian: n = 140). Results: Ile105 allele frequencies were significantly lower in alcoholics compared with nonalcoholics in both populations (Finns: 0.12 vs. 0.17, χ 2 = 6, p = 0.015; Plains Indians: 0.03 vs. 0.08, χ 2 = 5, p = 0.023). Genotype distributions also differed significantly. In Finns, Ile105 showed borderline significance for an association with lower harm avoidance ( p = 0.070) after correcting for alcoholism diagnosis. Conclusions: Decreased levels of brain histamine consequent to the Thr105 allele may result in higher levels of anxiety and, as a consequence, vulnerability to alcoholism.