Gene-gene and gene-environment interactions between alcohol drinking habit and polymorphisms in alcohol-metabolizing enzyme genes and the risk of head and neck cancer in Japan

Cancer Sci. 2007 Jul;98(7):1087-91. doi: 10.1111/j.1349-7006.2007.00505.x. Epub 2007 May 8.


Alcohol consumption is a strong risk factor for squamous cell carcinoma of the head and neck (SCCHN). The genetic polymorphisms aldehyde dehydrogenase2 (ALDH2) Glu487Lys and alcohol dehydrogenase 2 (ADH2) His47Arg, which have a strong impact on alcohol metabolism, are common in the Japanese population. To clarify the significance of these polymorphisms in SCCHN carcinogenesis, we conducted a matched case-control study with 239 incident SCCHN subjects and 716 non-cancer controls. Both ADH2 Arg/Arg and ALDH2 Glu/Lys were found to be independently associated with increased risk, with odds ratios (OR) of 2.67 (95% confidence interval [CI] 1.51-4.57) and 1.66 (95% CI 1.20-2.31), respectively. Further, compared with subjects having both ADH2 His/His and ALDH2 Glu/Glu, the adjusted OR and its 95% CI for those with both ADH2 Arg/Arg and ALDH2 Glu/Lys was 5.00 (2.32-10.71) in all subjects. This combination effect was evident in heavy drinkers (OR 11.3, 95% CI 2.97-43.3) but not in moderate or non-drinkers. Statistically significant gene-environment interactions between the two polymorphisms and drinking level were seen (ADH2 P = 0.035, ALDH2, P = 0.013). Furthermore, we also found a statistically significant gene-gene interaction between the two polymorphisms (P = 0.042). In conclusion, this case-control study showed a significantly increased risk of SCCHN in subjects with the ADH2 Arg/Arg and ALDH2 Glu/Lys polymorphisms in a Japanese population. In addition, our results also demonstrated that this risk was associated with significant gene-gene interactions between ADH2 and ALDH2 polymorphisms, as well as gene-environment interactions between these polymorphisms and alcohol drinking.

MeSH terms

  • Alcohol Dehydrogenase / genetics
  • Alcoholism / epidemiology*
  • Alcoholism / genetics*
  • Aldehyde Dehydrogenase / genetics
  • Aldehyde Dehydrogenase, Mitochondrial
  • Amino Acid Substitution
  • Arginine
  • Carcinoma, Squamous Cell / epidemiology
  • Carcinoma, Squamous Cell / genetics
  • Environment*
  • Genes*
  • Head and Neck Neoplasms / epidemiology*
  • Head and Neck Neoplasms / genetics*
  • Histidine
  • Humans
  • Japan / epidemiology
  • Polymorphism, Genetic
  • Polymorphism, Single Nucleotide
  • Reference Values
  • Risk Factors
  • Smoking / epidemiology


  • Histidine
  • Arginine
  • ADH1B protein, human
  • Alcohol Dehydrogenase
  • ALDH2 protein, human
  • Aldehyde Dehydrogenase
  • Aldehyde Dehydrogenase, Mitochondrial