We confirmed two ESCC susceptibility loci, rs671 in aldehyde dehydrogenase 2 family member gene (ALDH2) and rs1042026 in alcohol dehydrogenase 1B (class I), beta polypeptide gene (ADH1B), that significantly altered alcohol consumption behavior and subsequently modified the association between alcohol consumption and ESCC risk.
Previously, we identified that rs1229984 in ADH1B, rs671 in ALDH2, and smoking status were independently associated with the risk of developing metachronous squamous cell carcinoma (SCC) after endoscopic resection (ER) for esophageal SCC (ESCC).
We evaluated the risk for developing metachronous SCC following ER for ESCC based on the genetic polymorphisms for alcohol dehydrogenase-1B (ADH1B) and aldehyde dehydrogenase-2 (ALDH2) as well as the alcohol consumption and smoking habits.
The ADH1B, ADH1C and ALDH2 gene polymorphisms influence the risk of OSCC through modulation of acetaldehyde metabolism and propensity to alcohol intake.
We also analyzed the potential risk factors for metachronous SCC development using Cox's proportional hazards model. rs1229984 GG located on ADH1B and rs671 GA located on ALDH2 were significantly associated with ESCC progression (P = 7.93 × 10(-4) and P = 1.04 × 10(-5) ).
Our data demonstrated that these ADH1B-ADH1C-ADH7 cluster SNPs confer susceptibility to ESCC in these two case-control sets, which were consistent to results of the previous GWAS.
We found significant association with risk of ESCC for four SNPs, including rs1494961 in HEL308 at 4q21 [odds ratio (OR) = 1.15, 95 % confidence interval (CI) = 1.05-1.26], rs1229984 in ADH1B at 4q23 (OR = 1.24, 95 % CI = 1.13-1.36) and rs1789924 near ADH1C at 4q23 (OR = 1.20, 95 % CI = 1.03-1.39), and rs671 in ALDH2 at 12q24 (OR = 0.83, 95 % CI = 0.75-0.91).
We confirmed the known association of the ALDH2 locus on 12q24 to ESCC, and a joint analysis showed that drinkers with both of the ADH1B and ALDH2 risk alleles had a fourfold increased risk for ESCC compared to drinkers without these risk alleles.
We confirmed the known association of the ALDH2 locus on 12q24 to ESCC, and a joint analysis showed that drinkers with both of the ADH1B and ALDH2 risk alleles had a fourfold increased risk for ESCC compared to drinkers without these risk alleles.
The ADH1B*47Arg allele was found to be associated to increased risk of ESCC, with the odds ratios (OR) being 1.62 (95% CI: 1.49-1.76) and 3.86 (2.96-5.03) for the His/Arg and the Arg/Arg genotypes, respectively.
Risk alleles of rs1229984 (ADH1B) and rs671 (ALDH2) were highly associated with OSCC (odds ratio (OR)=4.08, p=4.4×10(-40) and OR=4.13, p=8.4×10(-76), respectively).
The genetic variations of ADH1BHis47Arg and ALDH2 Glu487Lys are susceptible loci for ESCC in Chinese Han population and interact substantially with alcohol consumption.
We identified the significant associations of ESCC with 4q21-23 and 12q24 regions, which include nonsynonymous single nucleotide polymorphisms (SNP) in ADH1B (rs1229984, P = 6.76 x 10(-35)) and ALDH2 (rs671, P = 3.68 x 10(-68)) that were previously shown to be associated with ESCC susceptibility.
Genetic modulation of ADH1B and ALDH2 polymorphisms with regard to alcohol and tobacco consumption for younger aged esophageal squamous cell carcinoma diagnosis.
The histidine allele at codon 48 of ADH1B gene was associated with a significantly decreased risk of ESCC in the joint data set (primary and validation set) under a recessive model (odds ratio, 0.41; 95% confidence interval, 0.29-0.76; P = 4 x 10(-4)).
The risk of the ESCC in moderate-to-heavy drinkers with ALDH2 (*1/*2) combined the ADH1B (*1/*1) genotype or ALDH2 (*1/*2) combined the CYP2E1 (*c1/*c1) genotype leads to synergistic interactions, higher than drinkers with ALDH2 (*1/*1)+ADH1B (*1/*2+*2/*2), ALDH2 (*1/*1)+CYP2E1 (*c1/*c2+*c2/*c2) respectively , ORs (95% CI) of 7.46 (3.28-18.32) and 6.82 (1.44-9.76) respectively.
Further, a supra-multiplicative combined risk of ESCC for alcohol and tobacco use was identified among carriers of the ADH1B*1/*1 genotype (p for interaction = 0.042).
The inactive ALDH2 encoded by ALDH2*1/*2 and the less-active ADH1B encoded by ADH1B*1/*1 increase the risk of esophageal squamous cell carcinoma in East Asian drinkers.
In our previous study, we found that polymorphisms of alcohol and aldehyde dehydrogenase (ADH1B and ALDH2) are important risks for esophageal squamous cell carcinoma in a Taiwanese population.
Japanese alcoholic men with (n = 65) and without (n = 206) esophageal squamous cell carcinomas, excluding those with liver cirrhosis, were assessed for MCV within 7 days of their last drink, alone or in combination with findings from either the alcohol flushing questionnaire or genotyping to identify inactive aldehyde dehydrogenase-2 (ALDH2*1/2*2) and the less-active form of alcohol dehydrogenase-2 (ADH2*1/2*1), which pose risks for esophageal squamous cell carcinoma.
Furthermore, persons with the combined genotypes ADH2(1)/ADH2(1) and ALDH2(1)/ALDH2(2) were at extraordinarily high risk for esophageal squamous cell carcinoma, with an odds ratio of 17.9 (p < 0.001).