Genetic determinants of alcohol addiction and metabolism: a survey in Italy.
BACKGROUND
Although multiple genes are involved in alcoholism and can contribute differently to the risk of dependence and liver damage, no studies have investigated susceptibility to addiction in combination with susceptibility to liver damage due to differences in ethanol metabolism.


METHODS
We evaluated the role of three polymorphic genes related to alcohol metabolism (CYP2E1) and, possibly, dependence (DRD2 and SLC6A4 promoter) in a series of 60 alcoholics admitted to a specialized referral center in Florence, Italy. Eighteen had a diagnosis of liver cirrhosis. A control series of 64 blood donors were identified at the same hospital. Genotyping was done by polymerase chain reaction-restriction fragment length polymorphism methods.


RESULTS
No difference was found in the frequency of the CYP2E1 Rsal c2 allele (2.5% among alcoholics and 4.7% among controls) and the DraI C allele (6.7% and 10.1%). Similarly, no difference was found in the frequency of the DRD2 A1 allele (15.8% and 13.3%) and the B1 allele (10.8% and 8.6%). The proportion of controls with a combined B1 genotype (B1/B1 or B1/B2) was significantly associated with smoking (p = 0.03). The distribution of the S and L allele of the SLC6A4 gene was similar in the two groups, with 15% and 14%, respectively, homozygous S/S carriers. A significant association, however, emerged in the group of alcoholics, with a five times higher risk for S/S carriers of developing cirrhosis (p < 0.05). This association with liver persisted even after exclusion of the subgrouped of 10 hepatitis C virus positive alcoholics.


CONCLUSIONS
Overall, our results provided no evidence of an increased susceptibility to develop alcoholism that was associated with the three genotypes investigated, either alone or in combination. An increased risk of developing liver cirrhosis for S/S homozygous carriers among alcohol-dependent patients was observed for the first time.
Pastorelli
R
R
Molecular Toxicology Laboratory, Istituto di Richerche Farmacologiche Mario Negri, Milan, Italy. rpastorelli@marionegri.it
Bardazzi
G
G
Saieva
C
C
Cerri
A
A
Gestri
D
D
Allamani
A
A
Airoldi
L
L
Palli
D
D
D000328:Adult; D000437:Alcoholism / Q000235:genetics* / Q000821:virology; D002352:Carrier Proteins / Q000235:genetics; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics; D000431:Ethanol / Q000378:metabolism*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006526:Hepatitis C / Q000150:complications; D006801:Humans; D007558:Italy; D008104:Liver Cirrhosis, Alcoholic / Q000235:genetics / Q000821:virology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D026901:Membrane Transport Proteins; D008875:Middle Aged; D009419:Nerve Tissue Proteins; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D011401:Promoter Regions, Genetic; D017448:Receptors, Dopamine D2 / Q000235:genetics; D050486:Serotonin Plasma Membrane Transport Proteins; D012907:Smoking / Q000235:genetics
D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D017448:Receptors, Dopamine D2; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D000431:Ethanol; D019392:Cytochrome P-450 CYP2E1