N-acetyltransferase-2, glutathione S-transferase M1, alcohol dehydrogenase, and cytochrome P450IIE1 genotypes in alcoholic liver cirrhosis: a case-control study.
BACKGROUND
Only a small percentage of long-term alcoholics develop liver cirrhosis. Genetic and non-genetic factors have been implicated in the risk of developing this disease. Among the genetic factors, case-control studies suggest an association with some polymorphisms at the alcohol dehydrogenase and cytochrome P450IIE1 genes. N-Acetyltransferase-2 metabolizes multiple compounds, transforming some of them to organ-toxic compounds and others into non-toxic molecules. Slow- and rapid-acetylator individuals exist in most human populations, and the mutations responsible for the slow-acetylator genotype have been determined. Slow acetylators, who should be at higher risk of developing breast cancer, and fast acetylators, who have an increased risk of developing colon cancer, can be characterized by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) genotyping. GSTM1 is another detoxifying enzyme for which functional interindividual differences, on the basis of gene polymorphisms, have been described.


METHODS
We conducted a case-control study in which 120 alcoholic cirrhotics, 30 long-term non-cirrhotic alcoholics, and 200 healthy controls were genotyped for polymorphisms (RFLPs) at the ADH2, P450IIE1, and NAT2 genes. PCR, followed by restriction enzyme digestion, was performed. The homozygous deletion of the GSTM1 gene was also PCR-analyzed. Genotype frequencies were statistically compared.


RESULTS
Frequencies for the ADH2, P450IIE1, and GSTM1 polymorphisms did not differ between patients and controls. Individuals homozygous for the NAT2*5 allele, which is the most frequent slow-acetylator (SA) allele and shows the lowest acetylator activity, were at a significantly decreased frequency among the cirrhotic patients compared with controls (9% versus 16%; P = 0.042). The frequency of this SA genotype was significantly increased (40%) in long-term alcoholics who did not develop cirrhosis (P = 0.0041 compared with controls; P= 0.000017 compared with cirrhotics).


CONCLUSIONS
According to our results, NAT2 activity may be a factor that determines the risk of developing alcoholic liver cirrhosis, and slow acetylators would be protected.
Rodrigo
L
L
Digestive Unit, Hospital Central de Asturias, Oviedo, Spain.
Alvarez
V
V
Rodriguez
M
M
Pérez
R
R
Alvarez
R
R
Coto
E
E
D000107:Acetylation; D000426:Alcohol Dehydrogenase / Q000235:genetics*; D000437:Alcoholism / Q000201:enzymology / Q000235:genetics; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D016022:Case-Control Studies; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics*; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D008104:Liver Cirrhosis, Alcoholic / Q000201:enzymology* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D012307:Risk Factors
D000426:Alcohol Dehydrogenase; D001191:Arylamine N-Acetyltransferase; D019392:Cytochrome P-450 CYP2E1; D005982:Glutathione Transferase; D007527:Isoenzymes; C089384:N-acetyltransferase 1