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A pair of common genetic variants that alter alcohol metabolism -- ADH1B-rs1229984 and ALDH2-rs671 -- were associated with a lower risk of cancer in men, especially head and neck and esophageal cancers, according to a large prospective study from China.

Among men with the AG and AA genotypes, the ADH1B-rs1229984 variant was significantly associated with a 13-16% lower risk of any cancer and a 20-25% lower risk for alcohol-related cancer when compared to men with the GG genotype, reported Iona Millwood, DPhil, of the University of Oxford in England, and colleagues.

For the ALDH2-rs671 variant, only the AA genotype was associated with lower risk versus the GG genotype, 14% lower for any cancer and 31% lower for alcohol-related cancers such as head and neck, esophageal, colon, rectal, and liver cancers, according to the findings in the .

"These genetic variants, which are randomly allocated at conception and usually independent of other lifestyle exposures, can be used as instruments for alcohol intake to help assess the likely causal effects of alcohol consumption on disease risks," the authors wrote. "These findings support the causal effects of alcohol consumption on upper aerodigestive tract cancers, with ALDH2-rs671 AG genotype further exacerbating the risks."

Millwood and colleagues noted that only 2% of women in their study population drank alcohol regularly, with no comparable associations observed between genotype and cancer.

For their study, the authors used DNA samples from approximately 150,000 study participants (median age 52.1 years, 60% men) and measured the frequency of the genetic variants for ALDH2 and ADH1B. They also used questionnaires about drinking habits completed by participants at recruitment and subsequent follow-up visits. The participants were tracked through linkage to health insurance records and death registers.

The overall A-allele frequency was 0.21 (range by area 0.13-0.29) for ALDH2-rs671 and 0.69 (range 0.64-0.74) for ADH1B-rs1229984, with a generally higher frequency in southern areas for both variants. Both ALDH2-rs671 and ADH1B-rs1229984 were associated with the prevalence of current regular drinking and mean alcohol intake in men.

During a median follow-up of 11.2 years, 9,339 of the study participants (4,509 men, 4,830 women) developed cancer.

For the ADH1B-rs1229984 variant, men with the AG and AA genotypes had lower risk for overall and alcohol-related cancers versus those with the GG genotype:

• AG, overall cancer: HR 0.87 (95% CI 0.78-0.96)
• AA, overall cancer: HR 0.84 (95% CI 0.76-0.93)
• AG, alcohol-related cancer: HR 0.80 (95% CI 0.69-0.93)
• AA, alcohol-related cancer: HR 0.75 (95% CI 0.64-0.87)

This lower risk with ADH1B-rs1229984 versus the GG genotype was driven by upper aerodigestive tract cancers, specifically:

• AG, head and neck cancer: HR 0.61 (95% CI 0.39-0.96)
• AA, head and neck cancer: HR 0.61 (95% CI 0.39-0.94)
• AG, esophageal cancer: HR 0.68 (95% CI 0.53-0.88)
• AA, esophageal cancer: HR 0.60 (95% CI 0.46-0.78)

For the ALDH2-rs671 variant, men with the AA genotype had a lower risk of cancer overall (HR 0.86, 95% CI 0.73-1.00) and of alcohol-related cancers (HR 0.69, 95% CI 0.53-0.90) compared to those with the GG genotype.

And compared to the GG genotype, men with this ALDH2-rs671 variant and the AG genotype had significantly higher risks for head and neck cancer (HR 1.35, 95% CI 0.86-2.13) and oesophageal cancer (HR 2.07, 95% CI 1.58-2.71) if they were regular drinkers at any point.

Millwood's group said there were no differences in the results after adjusting for other cancer risk factors, such as smoking, diet, physical activity, body mass index, and family history.

No significant associations between the two variants and genotypes were seen with regard to risk for liver, colorectal, stomach, and lung cancers.

"The study reinforces the need to lower population levels of alcohol consumption for cancer prevention, especially in China where alcohol consumption is increasing despite the low alcohol tolerability among a subset of the population," the team wrote.

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