We know some of them already, such as the GABRA2, the
ADH4, and the CHRM2 that I mentioned.
Among these, variations in and near ADH4 are among the most widely replicated associations with alcohol dependence, in several populations.
Identification of a FOXA-dependent enhancer of human alcohol dehydrogenase 4 (ADH4).
A single SNP located 136 basepairs (bp) upstream of the translational start site of ADH4 results in a two-fold difference in gene expression in vitro (Edenberg et al.
A study of 110 SNPs across all seven ADH genes demonstrated that variations in ADH4 most strongly affected risk for alcoholism in European-American families (Edenberg et al.
For example, ADH4 variants strongly affect alcoholism risk in populations of European descent (Edenberg et al.
In addition, gastric ADH4 (Class IV ADH) activity was 177 percent higher in pregnant female rats compared with nonpregnant cohorts (Badger et al.
Metabolic deficiencies in alcohol dehydrogenase Adh1, Adh3, and Adh4 null mutant mice: Overlapping roles of Adh1 and Adh4 in ethanol clearance and metabolism of retinol to retinoic acid.
Table 1 Human Alcohol Dehydrogenase (ADH) Isozymes Gene Nomenclature [K.sub.m] [V.sub.max] Class New Former Protein mM [min.sup.-1] I ADH1A ADH1 [alpha] 4.0 30 ADH1B*1 ADH2*1 [[beta].sub.1] 0.05 4 ADH1B*2 ADH2*2 [[beta].sub.2] 0.9 350 ADH1B*3 ADH2*3 [[beta].sub.3] 40.0 300 ADH1C*1 ADH3*1 [[gamma].sub.1] 1.0 90 ADH1C*2 ADH3*2 [[gamma].sub.2] 0.6 40 II
ADH4 ADH4 [pi] 30.0 20 III ADH5 ADH5 [chi] >1,000 100 IV ADH7 ADH7 [sigma]([mu]) 30.0 1,800 V ADH6 ADH6 ?
Table 1 Kinetic Constants for Ethanol Oxidation by Human Alcohol Dehydrogenases1 Km Gene (Enzyme) (mM) [K.sub.M] [V.sub.max] % liver (mM) ([min.sup.-1]) contribution (2) at 22 mM ethanol (3) ADH1A ([alpha][alpha]) 4 20 8.1 ADH1B*1 0.05 4 21.8 (ADH1B-Arg48Arg370; [beta]1[beta]1) ADH1B*2 0.9 350 -2 (ADH1B-His48Arg370; [beta]2[beta]2) ADH1B*3 40 300 -2 (ADH1B-Arg48Cys370; [beta]3[beta]3) ADH1C*1 (ADH1C-Arg272, 1 90 41.5 Ile350; [gamma]1[gamma]1) ADH1C*2 (ADH1C-Gln272, 0.6 40 -2 Val350; [gamma]2[gamma]2)
ADH4 ([pi][pi]) 30 20 28.6 ADH5 ([chi][chi]) >1,000 100 <1 ADH7 ([sigma][sigma]) 30 1800 <1 (1) Data from Hurley, Edenberg and Li, 2002.
Giri and colleagues (1989) found ADH3 expressed in rat brain, and Martinez and colleagues (2001) found mRNA for ADH1 and
ADH4 in rat brain cells.