Because of higher levels of acetaldehyde, individuals with ALDH2 deficiency are at higher risk for numerous diseases, including liver cirrhosis, esophageal and gastric cancer, osteoporosis, and Alzheimer disease.
The observed ALDH2-alcohol drinking interaction and the direct effect of ALDH2 Lys alleles may suggest the involvement of acetaldehyde in the development of gastric cancer.
Genetic variants of rs2274223 in PLCE1 at 10q23.33 (per G allele: odds ratio (OR) = 1.26, 95% confidence interval (CI): 1.16-1.38, P = 6.51 × 10<sup>-8</sup>), rs10052657 in PDE4D at 5q11.2 (per C allele: OR = 1.12, 95% CI: 1.01-1.25, P = 3.28 × 10<sup>-2</sup>) and rs671 in ALDH2 at 12q24.12 (per A-allele: OR = 0.83, 95% CI: 0.75-0.91, P = 1.14 × 10<sup>-4</sup>) were significantly associated with GC risk.
The effect of alcohol consumption on the risk of gastric cancer (GC) has not yet been fully elucidated, and an aldehyde dehydrogenase 2 (ALDH2) polymorphism, rs671, is a genetic variant that influences alcohol consumption in East Asians.
In the codominant model, the AA genotype of ALDH2Glu487Lys significantly elevated the risk of gastric cancer in comparison with the GG genotype of ALDH2Glu487Lys.
Genetic polymorphisms of ADH1B, ADH1C and ALDH2, alcohol consumption, and the risk of gastric cancer: the Japan Public Health Center-based prospective study.
The results of our meta-analysis suggested that ALDH2 genetic polymorphisms might be strongly correlated with an increased risk of gastric cancer (allele model: OR = 1.21, 95%CI: 1.11 ∼ 1.32, P<0.001; dominant model: OR = 1.23, 95%CI: 1.09 ∼ 1.39, P = 0.001; respectively), especially for rs671 polymorphism.
In conclusion, ALDH2 and alcohol drinking showed interaction for risk factors of stomach cancer, indicating that acetaldehyde plays a role in stomach carcinogenesis.
Large meta-analyses confirmed the association between IL8, IL10, TNF-b, TP53 and PSCA, while genetic variation at different genes such as XPG, PLCE1, HFE, ERCC5, EZH2, DOC2, CYP19A1, ALDH2, and CDH1 have been reported to be associated with GC risk.
Individuals carrying variant alleles at both ADH1 (rs1230025) and ALDH2 (rs16941667) were twice as likely to develop GC (OR(A+T) = 2.0; 95% CI = 1.25-3.20) as those not carrying variant alleles.
Among heavy drinkers (n = 115), ALDH2 *1/*2 heterozygotes had a 4-fold increased risk for gastric cancer compared with *1/*1 homozygotes (OR 4.26, 95% CI 1.10-16.47); however, no risk increase was seen among never/rare drinkers.
When stratified by ALDH2 Ex1+82A>G polymorphism, alcohol-related increases in stomach cancer risk were restricted to individuals with the AG/GG genotypes, with a more than 2-fold risk among daily drinkers (OR=2.63, 95% CI=1.00-6.88) and 3-fold risk (OR=3.66, 95% CI=1.19-11.24) among those with 40 or more drink-years.
Polymorphisms of the CYP1A1, CYP2E1, GSTM1, GSTT1, and ALDH2 genes could modify the effects of some environmental factors on the risk of gastric cancer.
Furthermore, in the presence of ALDH2*1/2*2, the risks for multiple intra-esophageal cancers (OR = 3.43) and for esophageal cancer with oropharyngolaryngeal and/or stomach cancer (OR = 3.95) were higher than the risks for solitary intra-esophageal cancer and for esophageal cancer alone, but these tendencies were not observed for ADH2*1/2*1 genotype.
After adjustment for age, daily alcohol consumption and amount of cigarette smoking, significantly increased risks (odds ratios) in the presence of the ALDH2 *2 allele were found for oropharyngolaryngeal (11.14), esophageal (12.50), stomach (3.49), colon (3.35), lung (8.20) and esophageal cancer concomitant with oropharyngolaryngeal and/or stomach cancer (54.20) but not for liver or other cancers.