Harmful alcohol use is a major contributor to the global burden of disease and mortality. However, there is also a widely held belief, mainly based on findings from prospective studies, that moderate alcohol drinking may be beneficial for cardiovascular disease (CVD). Using East Asian specific genetic variants that strongly affect alcohol metabolism, CKB has, for the first time, reliably refuted any apparent protective effects of moderate drinking on stroke.
We have also demonstrated clearly that drinking alcohol is associated with increased mortality and morbidity risks from a wide range of diseases in the Chinese population. As well as increasing risks of several cancers, cardiovascular and chronic liver diseases, and all-cause mortality, and affecting mental health and wellbeing, we have shown that alcohol is associated with over 60 diseases, including many not previously established to be related to alcohol by the World Health Organization (WHO).
Drinking alcohol has a long tradition in China but for cultural reasons it is more frequent in men than women, with about a third of CKB men, and only 2% of women, drinking regularly at baseline (IJE 2013). Regular alcohol consumption also varied substantially by geographical region, ranging from less than 10% of men in Gansu to more than 50% in Sichuan and Harbin. Most alcohol was consumed as spirits, with strong spirits preferred in rural areas, and most drinking took place at mealtimes. Heavy drinking episodes with a large amount of alcohol drunk in a session were common, particularly on special occasions.
Over about ten years between ~2004-2014, harmful patterns of drinking had increased, particularly among younger men, in line with nationwide trends (BMC Public Health 2019). Similar to other populations, heavy alcohol drinking among Chinese men tends to be associated with high levels of smoking and other unhealthy behaviours and risk factors. Problem drinking indicators, such as being unable to stop drinking or to work due to drinking, or experiencing ‘the shakes’ when stopping, were reported by nearly 10% of CKB men (Addiction 2019). These problems were associated with stressful life events, poor sleep patterns, low life satisfaction, and symptoms of depression and anxiety.
Over many decades, epidemiological studies have shown moderate alcohol intake to be associated with a lower risk of CVD, including ischaemic heart disease (IHD), stroke, and certain other conditions, compared with not drinking. However, it is uncertain whether these relationships are causal, as moderate alcohol intake is often associated with other favourable health factors such as higher socio-economic status and some people who do not drink any alcohol may have underlying health problems. In conventional observational analyses, it is difficult to fully account for these factors, leading to potentially biased results. Indeed, in CKB participants, as in many other studies in Western populations, we observed a typical J-shaped association of alcohol drinking with risk of CVD, with those who reported drinking moderately (ie one to two drinks a day) having the lowest risk (Lancet 2019).
In Chinese and other East Asian populations, alcohol tolerability is strongly affected by two common genetic variants in the ALDH2 and ADH1B genes which disrupt the metabolism of alcohol and cause the characteristic East Asian flushing response to alcohol (BMC Genomics 2023). Alcohol drinking patterns are also affected by other genetic variants, with several thousand identified in multi-ancestry genome-wide meta-analyses (Nature 2022). These genetic variants provide a unique opportunity to assess the causal effects of alcohol on a range of health outcomes, particularly the so-called beneficial effects of moderate alcohol drinking on CVD.
We used a genetic approach which mimics a randomised trial (known as Mendelian randomisation) among 60,000 men and 90,000 women with information on the genetic variants in ALDH2 and ADH1B which affect alcohol tolerability. There was a 60-fold difference in mean alcohol intake between men carrying two copies of the ALDH2 variant who drank very little, and those with no copies of either variant who drank up about two drinks a day on average. Women drank little alcohol regardless of their genotypes, which allowed us to assess whether any associations with disease were due to the effects of the genotypes on alcohol or to other effects of the genotypes.
We demonstrated for the first time that alcohol intake uniformly increases the risk of stroke, with no apparent protective effects of moderate drinking for stroke and stroke types (Lancet 2019). Consuming one to two drinks a day was associated with 12% higher risk of stroke (9% for ischaemic stroke and 18% for haemorrhagic stroke). Our findings implied that among men, alcohol was responsible for about 8% of ischaemic strokes and 16% of intracerebral haemorrhages. Moreover, there was no clear causal effect of alcohol on ischaemic heart disease risk, contrary to a U-shaped association in conventional observational analyses. However, the number of IHD events was much smaller compared with stroke, and further research is still needed to clarify this. Similar patterns of risk were seen for cardiovascular deaths (Lancet Public Health 2023). We have also shown that alcohol intake was associated with a higher burden of carotid plaque and atherosclerosis among Chinese men (Atherosclerosis 2023).
Cancer accounts for a high proportion of deaths attributed to alcohol use, and the International Agency for Research on Cancer (IARC) has concluded that alcohol is causally related to certain cancer types. In CKB, we have shown that alcohol intake is associated with higher risks of cancers of the oesophagus, mouth and throat, liver, colon-rectum, gallbladder and lung, with relative risks per 40 g/day ranging from 1.98 for oesophageal cancer to 1.25 for lung cancer (Int J Cancer 2021). Alcohol was also associated with higher risks of liver cirrhosis, and both non-alcoholic fatty liver disease and alcoholic liver disease (BMC Medicine 2021). We showed that given the amount consumed certain drinking patterns may further exacerbate risk, for example, daily drinking was particularly harmful for oesophageal cancer and alcoholic liver disease, and drinking outside of meal times was particularly harmful for liver cancer, liver cirrhosis and alcoholic liver disease. In a study validating findings from UK Biobank, we showed a similar interaction between diabetes and heavy episodic drinking to increase risk of alcohol-related liver cirrhosis (Nature Communications 2023). Alcohol was also found to interact with hot tea consumption to increase risk of oesophageal cancer (Ann Intern Med 2018).
Genetic variants which affect alcohol tolerability were associated with lower risks of certain cancers, providing evidence that alcohol intake is a cause of cancer (Int J Cancer 2022). Men with one or two copies of the ADH1B variant had 13-25% lower risks of overall cancer and alcohol-related cancers, particularly head and neck cancer, and oesophageal cancer. Men with two copies of the low tolerability ALDH2 variant 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. However, men who drank alcohol regularly despite carrying one variant copy of ALDH2 had higher risks of head and neck and oesophageal cancers (Int J Cancer 2018), suggesting that the greater accumulation of alcohol’s metabolite acetaldehyde may directly increase the risk of these cancers.
In a landmark study of the health effects of alcohol use, we showed that alcohol consumption was associated with higher risks of 61 out of 207 diseases studied in Chinese men, including 33 not previously established by WHO to be alcohol-related (Nature Medicine 2023). Collectively, there was strong evidence that these 61 alcohol-disease associations were causal, including the 33 not previously related to alcohol. These included cataract and gout, where genetic analyses showed that risks increased by about 20% and two-fold, respectively, for each four drinks per day higher intake. We are continuing this phenome-wide evaluation of the health effects of alcohol in the UK Biobank population. We are also investigating, in further detail, the associations of alcohol with certain important diseases such as diabetes, cardiovascular and respiratory diseases, and mental health.
Alcohol may affect health through multiple biological pathways, and our current work is using proteomics, metabolomics and other biomarker measurements to help understand the mechanisms of action of alcohol and its role in causing disease. This will help understand disease aetiology, and could lead to identification of potential drug targets for the treatment and prevention of alcohol-related diseases.
Impact of research
Alcohol drinking accounts for an estimated three million annual deaths globally, with the associated disease burden projected to increase still further. In China, alcohol consumption has been increasing steadily, with striking increases in per capita consumption over recent decades. Research in CKB has, and will continue to provide reliable nationwide evidence in China about the hazards of alcohol. Our evidence has informed public health policies in China and other countries including alcohol guidelines for the National Health and Medical Research Council of Australia.