Aldehyde dehydrogenase 2 and head and neck cancer: A meta-analysis implementing a mendelian randomization approach

Alcohol drinkinga thigh doses is a risk factor for head and neck cancer, and exposure to acetaldehyde, the principle metabolite of alcohol, is supposed to account for the increased risk. Individuals homozygous for the *2 variant allele of aldehyde dehydrogenase 2 (ALDH2) are unable tometabolize acetaldehyde, which prevents them from alcohol drinking, whereas *1*2 have 6-fold higher blood acetaldehyde concentration postalcohol consumption with respect to *1*1. Accordingto the concept of Mendelian randomization, because this polymorphism is distributed randomly duringg amete formation, its association with head and neck cancer should be not confounded by smoking. We carried out a meta-analysis of ALDH2 and head and neck cancer searchingfo r relevant studies on Medline and Embase up to January 31, 2008, and investigated the consistency between the expected odds ratio (OR) amongd rinkers from the largest pooled analysis amongne ver smokers and the observed OR from thismeta-analysis by an interaction test. Six studies were selected (945 cases, 2,917 controls). The OR of head and neck cancer among *2*2 was 0.53 [95% confidence interval (95% CI), 0.28-1.00] relative to *1*1 and 1.83 (95% CI, 1.21-2.77) among *1*2. The expected OR for head and neck cancer due to alcohol intake among *1*1 was 1.38 (95% CI, 0.88-2.17) and the observed OR among *1*1 compared with 2*2 from this meta-analysis was 1.88 (95% CI, 1.00-3.57; P for interaction = 0.43). Besides showing the effectiveness of the Mendelian randomization approach, these findings support the theory that alcohol increases head and neck cancer risk through the carcinogenic action of acetaldehyde.