Functional role of the polymorphic 647 T/C variant of ENT1 (SLC29A1) and its association with alcohol withdrawal seizures.

Adenosine is involved in several neurological and behavioral
disorders including alcoholism. In cultured cell and animal
studies, type 1 equilibrative nucleoside transporter (ENT1,
slc29a1), which regulates adenosine levels, is known to regulate
ethanol sensitivity and preference. Interestingly, in humans, the
ENT1 (SLC29A1) gene contains a non-synonymous single nucleotide
polymorphism (647 T/C; rs45573936) that might be involved in the
functional change of ENT1. Our functional analysis showed that
prolonged ethanol exposure increased adenosine uptake activity of
mutant cells (ENT1-216Thr) compared to wild-type (ENT1-216Ile)
transfected cells, which might result in reduced extracellular
adenosine levels. We found that mice lacking ENT1 displayed
increased propensity to ethanol withdrawal seizures compared to
wild-type littermates. We further investigated a possible
association of the 647C variant with alcoholism and the history of
alcohol withdrawal seizures in subjects of European ancestry
recruited from two independent sites. Analyses of the combined data
set showed an association of the 647C variant and alcohol
dependence with withdrawal seizures at the nominally significant
level. Together with the functional data, our findings suggest a
potential contribution of a genetic variant of ENT1 to the
development of alcoholism with increased risk of alcohol
withdrawal-induced seizures in humans.