Data from a large-scale genetic study has confirmed that alcohol directly causes cancer, reports the University of Oxford. Research with Peking University and the Chinese Academy of Medical Sciences found that accumulation of the carcinogen acetaldehyde among Chinese men with a low-alcohol tolerability gene variant, who still drank regularly, may directly increase cancer risk.
Worldwide, alcohol may cause around three million deaths each year, including more than 400,000 from cancer. With alcohol consumption rising, particularly in rapidly developing countries such as China, there is an urgent need to understand how alcohol affects disease risks in different populations, wrote Oxford in material published on 20 January 2022.
Evidence from Western countries already strongly indicates that alcohol is a direct cause of cancer in the head, neck, oesophagus, liver, colon and breasts.
But it has been difficult to establish whether alcohol directly causes cancer, or if it is linked to possible confounding factors (such as smoking and diet) that could generate biased results. It was also unclear whether alcohol is linked to other types of cancer, including lung and stomach cancers.
To address these unknowns, researchers from Oxford Population Health, Peking University and the Chinese Academy of Medical Sciences in Beijing used a genetic approach by investigating gene variants linked to lower alcohol consumption in Asian populations.
The results were published on 20 January in the International Journal of Cancer.
In Chinese, and other East Asian populations, two common genetic variants (alleles) reduce alcohol tolerability and are strongly associated with lower alcohol intake, because they cause an unpleasant ‘flushing’ effect.
These mutations both disrupt the functioning of enzymes involved in alcohol detoxification, causing the toxic compound acetaldehyde, a Group I carcinogen, to accumulate in the blood.
The first mutation is a loss-of-function mutation in the gene for the enzyme aldehyde dehydrogenase 2 (ALDH2). The second mutation accelerates the activity of alcohol dehydrogenase 1B (ADH1B). Both are common in East Asians but rare in European ancestry populations.
Because these alleles are allocated at birth and are independent of other lifestyle factors (such as smoking), they can be used as a proxy for alcohol intake, to assess how alcohol consumption affects disease risks.
The study team used DNA samples from approximately 150,000 participants – roughly 60,000 men and 90,000 women – in the China Kadoorie Biobank study and measured the frequency of the low-alcohol tolerability alleles for ALDH2 and ADH1B.
The data were combined with questionnaires about drinking habits completed by participants at recruitment and subsequent follow-up visits. The participants were tracked for a median period of 11 years through linkage to health insurance records and death registers.
Since women rarely drink alcohol in China, the main analysis focused on men, a third of whom drank regularly (most weeks in the past year).
Key results
Among the Chinese study population, the frequency of low-alcohol tolerability alleles was 21% for ALDH2 and 69% for ADH1B (compared with <0.01% and ~4% in European ancestry populations).
In men, the low-alcohol tolerability alleles were strongly linked to reduced alcohol consumption, both frequency of drinking and mean alcohol intake.
During the follow-up period, around 4,500 (7.4%) of the men developed cancer.
Men carrying one or two of the low-alcohol tolerability alleles for ADH1B had between 13-25% lower risks of overall cancer and alcohol-related cancers, particularly head and neck cancer, and oesophageal cancer.
Overall, men who carried two copies of the low-alcohol tolerability allele for ALDH2 drank very little alcohol, and had a 14% lower risk of developing any cancer, and a 31% lower risk of developing cancers that have previously been linked to alcohol (cancers of the head and neck; oesophagus, colon, rectum and liver).
Men who drank regularly despite carrying one copy of the low-alcohol tolerability allele for ALDH2 had significantly higher risks of head and neck cancer and oesophageal cancer. For non-drinkers or occasional drinkers, there was no overall association between carrying one copy of the low-alcohol tolerability allele for ALDH2 and increased cancer risk.
The results remained the same when the data were adjusted for other cancer risk factors, such as smoking, diet, physical activity, body mass and family history of cancer.
In women (only 2% of whom drank regularly), these low-alcohol tolerability alleles were not associated with any increased risk of cancer, indicating that the reduced risks for the carriers of these gene variants in men directly resulted from their lower alcohol consumption.
The significantly greater risks seen in men carrying the low-alcohol tolerability ALDH2 gene variant who still drank regularly suggests that greater accumulation of acetaldehyde may directly increase cancer risk.
Lead researcher Dr Pek Kei (Becky) Im from Oxford Population Health said: “These findings indicate that alcohol directly causes several types of cancer, and that these risks may be increased further in people with inherited low alcohol tolerability who cannot properly metabolise alcohol.”
Senior researcher Dr Iona Millwood from Oxford Population Health said: “Our 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 large subset of the population.”
Study details
Alcohol metabolism genes and risks of site-specific cancers in Chinese adults: An 11-year prospective study
Pek Kei Im, Ling Yang, Christiana Kartsonaki, Yiping Chen, Yu Guo, Huaidong Du, Kuang Lin, Rene Kerosi, Alex Hacker, Jingchao Liu, Canqing Yu, Jun Lv, Robin G Walters, Liming Li, Zhengming Chen, Iona Y Millwood and the China Kadoorie Biobank (CKB) Collaborative Group
Author affiliations: Oxford University, Peking University, Chinese Academy of Medical Sciences, and the China Kadoorie Biobank
First published by Cancer Genetics and Epigenetics on 20 January 2022.
Abstract
Two genetic variants that alter alcohol metabolism, ALDH2-rs671 and ADH1B-rs1229984, can modify oesophageal cancer risk associated with alcohol consumption in East Asians, but their associations with other cancers remain uncertain. ALDH2-rs671 G>A and ADH1B-rs1229984 G>A were genotyped in 150,722 adults, enrolled from 10 areas in China during 2004 to 2008.
After 11 years' follow-up, 9,339 individuals developed cancer. Cox regression was used to estimate hazard ratios (HRs) for site-specific cancers associated with these genotypes, and their potential interactions with alcohol consumption. Overall, the A-allele frequency was 0.21 for ALDH2-rs671 and 0.69 for ADH1B-rs1229984, with A-alleles strongly associated with lower alcohol consumption.
Among men, ALDH2-rs671 AA genotype was associated with HR of 0.69 (95% confidence interval: 0.53-0.90) for IARC alcohol-related cancers (n = 1900), compared to GG genotype. For ADH1B-rs1229984, the HRs of AG and AA vs GG genotype were 0.80 (0.69-0.93) and 0.75 (0.64-0.87) for IARC alcohol-related cancers, 0.61 (0.39-0.96) and 0.61 (0.39-0.94) for head and neck cancer (n = 196) and 0.68 (0.53-0.88) and 0.60 (0.46-0.78) for oesophageal cancer (n = 546).
There were no significant associations of these genotypes with risks of liver (n = 651), colorectal (n = 556), stomach (n = 725) or lung (n = 1135) cancers. Among male drinkers, the risks associated with higher alcohol consumption were greater among ALDH2-rs671 AG than GG carriers for head and neck, oesophageal and lung cancers (Pinteraction < .02).
Among women, only 2% drank alcohol regularly, with no comparable associations observed between genotype and cancer.
These findings support the causal effects of alcohol consumption on upper aerodigestive tract cancers, with ALDH2-rs671 AG genotype further exacerbating the risks.
What's new?
Alcohol consumption has been increasing among men in China, and is a major contributor to the total cancer burden. Two genetic variants that alter alcohol metabolism are associated with oesophageal cancer risk in East Asians. Do these variants also play a role in other cancers, or influence the effect of alcohol on cancer risk?
In this large Chinese study, the authors found that certain genotypes were associated with reduced upper aero-digestive tract cancer risk, and that one of the variants may exacerbate the effects of alcohol on several cancers.
See also from the MedicalBrief archives
Large 10-year genetic study finds no protective benefits to light drinking
WHO: 5,000 fewer lives a year lost to cancer if Europe ups alcohol tax
Alcohol consumption linked to 4% of global cancer cases – WHO study
No amount of alcohol is good for the heart – World Heart Federation
Stopping smoking before 45 can wipe out 87% of lung cancer risk