Certain ADH1B alleles have large effects on alcohol metabolism, and this relationship particularly encourages further investigations in relation to alcoholism and alcohol-associated cancer to understand better the mechanisms by which alcohol metabolism contributes to alcohol abuse and carcinogenesis.
Alcohol drinking, ADH1B and ADH1C genotypes and the risk of postmenopausal breast cancer by hormone receptor status: the Netherlands Cohort Study on diet and cancer.
The enhanced AER in ADH1B*2 carriers and the increased sAcH levels in ALDH2*1/*2 carriers among intoxicated alcoholics provide possible mechanisms explaining how each genetic polymorphism affects the risk of alcoholism and upper aerodigestive tract cancer.
ADH1Brs1229984 polymorphism HRs for HNC and oesophageal cancer death and for alcohol related cancer death were 0.67 (95% CI: 0.42-1.08), and 0.64 (95% CI: 0.40-1.03), respectively.
Stratified analyses were carried out to determine the gene-environment interaction between ADH1BHis47Arg and alcohol drinking and gene-gene interaction between ADH1BHis47Arg and aldehyde dehydrogenase-2 (ALDH2) Glu/Lys related to UADT cancer risk.
The key findings of the earlier studies were that variations (i.e., polymorphisms) in the DNA sequences of the genes encoding alcohol dehydrogenase 1B (i.e., the ADH1B gene), aldehyde dehydrogenase 2 (i.e., the ALDH2 gene), and other alcohol-metabolizing enzymes mediate the risk for alcoholism; moreover, these polymorphisms also have an impact on the risk of alcohol-related cancers, such as esophageal cancer.
Among conventional markers of alcohol abuse, the mean corpuscular volume (MCV) of erythrocytes is prognostic of alcohol-related cancer and its predictivity increases when combined with functional polymorphisms of alcohol dehydrogenase (ADH1B [rs1229984] and ADH1C [rs698]) and the mitochondrial aldehyde dehydrogenase (ALDH2 [rs671]).
The effects of genetic polymorphism of aldehyde dehydrogenase-2 (ALDH2) on alcohol metabolism are striking in nonalcoholics, and the effects of genetic polymorphism of alcohol dehydrogenase-1B (ADH1B) are modest at most, whereas genetic polymorphisms of both strongly affect the susceptibility to alcoholism and upper aerodigestive tract (UADT) cancer of drinkers.
In Caucasians, significant associations between polymorphisms in ADH1B (rs1229984) and ADH1C (rs698 and rs1693482), and UAT cancer have been observed, despite strong linkage disequilibrium among them.
Gene variants rs1229984 (ADH1B) and rs1573496 (ADH7) were significantly protective against aerodigestive cancer in each individual study and overall (P = 10(-10) and 10(-9), respectively).
The risk for cancer multiplicity was associated with inactive heterozygous ALDH2 alone (OR=4.22) among the risk factors investigated, which also included smoking, less-active alcohol dehydrogenase-1B, and macrocytosis, enhancing the validity of the link between acetaldehyde exposure and cancer multiplicity.
The ADH1B histidine allele at codon 48 was associated with a decreased risk of upper aerodigestive tract cancer; odds ratios (OR) were 0.36 [95% confidence interval (95% CI), 0.17-0.77] for medium/heavy drinkers and 0.57 (95% CI, 0.36-0.91) for never/light drinkers.
The results revealed that (1) the less active allele of the ADH2 gene (ADH2*1) is associated with an increased risk for alcohol dependence, alcohol-induced persistent amnestic disorder, alcohol withdrawal syndrome, and cancer of the upper GI tract; (2) the inactive allele of the ALDH2 gene (ALDH2*2) is associated with a decreased risk for alcohol dependence, and an increased risk for alcoholic polyneuropathy and cancer in the same region; and (3) these genetic variations modify clinical features of alcohol dependence.
After adjustment for age, drinking and smoking habits, and ADH2/ALDH2 genotypes, the presence of either ADH2*1/2*1 or ALDH2*1/2*2 significantly increased the risk for oropharyngolaryngeal cancer [odds ratios (ORs), 6.68 with ADH2*1/2*1 and 18.52 with ALDH2*1/2*2] and esophageal cancer (ORs, 2.64 and 13.50, respectively).
After adjustment for drinking and smoking, the analysis showed significantly increased cancer risk for alcoholics with either ADH2*1/2*I (OR = 2.03) or ALDH2*1/2*2 (OR = 12.76).