New data from a large-scale genetic study led by Oxford Population Health confirms that alcohol directly causes cancer.
Worldwide, alcohol may cause around 3 million deaths each year, including over 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.
Evidence from Western countries already strongly indicates that alcohol is a direct cause of cancer in the head, neck, oesophagus, liver, colon and breast. 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 at the Medical Research Council Population Health Research Unit (MRC PHRU) at the University of Oxford supported a study that used a genetic approach by investigating gene variants linked to lower alcohol consumption in Asian populations. The results have been published today in the International Journal of Cancer. The study also involved researchers from the Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU) at Oxford Population Health, and the Chinese Academy of Medical Sciences, Beijing.
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).
- 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.
Senior researcher Dr Iona Millwood from MRC PHRU 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.’
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.’