Alcohol (Ethanol)

Ethanol acts on the brain largely through the GABA system, the brain's main inhibitory signaling network, and heavy or long-term use disturbs that system in ways linked to dependence and withdrawal [2]. Alcohol use causes about 3 million deaths worldwide each year [2].

Most ethanol is broken down in the liver. Alcohol dehydrogenase (ADH) enzymes oxidize it to acetaldehyde, and aldehyde dehydrogenase (ALDH) enzymes oxidize acetaldehyde to acetate. Other enzymes, such as CYP2E1, handle a small fraction [1]. The mitochondrial enzyme ALDH2 is the main route for clearing acetaldehyde and normally keeps its levels very low [1].

Acetaldehyde matters because it is a mutagen and an animal carcinogen that damages DNA. When it builds up it causes facial flushing, nausea and a fast heartbeat, partly through histamine release [3]. The drug disulfiram, used in alcohol use disorder, works by blocking acetaldehyde clearance on purpose; its label describes blood acetaldehyde levels 5 to 10 times higher than after the same amount of alcohol alone [4]. The ALDH2 variant produces a milder, inherited version of the same effect.

At rs671 the usual G allele codes for glutamic acid at position 504 of the ALDH2 protein (Glu504, the ALDH2*1 form). The A allele codes for lysine (Lys504, ALDH2*2). Older papers number the same change as position 487 [5].

The laboratory evidence is unusually direct. In liver samples from Japanese donors, people with one ALDH2*2 copy had the deficient enzyme pattern, which showed the variant is dominant [5]. When the Lys504 form was made in cells, it produced protein with no enzyme activity, and adding it to cells that already made the normal form pulled their activity down, because ALDH2 works as a four-part complex and the faulty subunits join the normal ones [6]. Heterozygotes have almost no ALDH2 activity detectable in the liver and homozygotes have none [1].

The human consequences follow from this. About 36% of Japanese, Chinese and Korean people flush after drinking, mostly because of ALDH2*2 [3]. In a meta-analysis of 53 studies (9,678 cases and 7,331 controls, mostly East Asian), carrying the Lys504 allele was associated with much lower odds of alcohol abuse or dependence (odds ratio 0.22 for one or two copies against none) [7]. In the China Kadoorie Biobank, these two genes shaped drinking so strongly that genotype-predicted alcohol intake in men ranged from about 4 to 256 g a week, nearly none to about four drinks a day [8].

Less drinking, but higher cancer risk per drink

The flush discourages drinking, but it does not protect people who drink anyway. Heterozygotes had two to three times the acetaldehyde in their saliva of people with normal ALDH2 after a moderate dose of alcohol. Case-control studies in Japan and Taiwan have found odds ratios of 3.7 to 18.1 for squamous cell cancer of the esophagus in heterozygotes who drink, after adjusting for how much they drank; in rural China, where alcohol is a smaller cause of this cancer, the odds ratios were 1.7 to 3.1. ALDH2 deficiency does not change esophageal cancer risk in people who do not drink, and smoking adds to the acetaldehyde in saliva [3]. Among 5,214 Japanese men with alcohol dependence, carrying ALDH2*2 was associated with about 11 times the odds of a history of esophageal cancer and about 9 times the odds of head and neck cancer [9].

The risk pattern is not simply "two copies is worse". People with two copies react so strongly that they cannot drink much. Heterozygotes have a milder reaction, and some develop tolerance to the flush and become regular heavy drinkers, so the cancer risk falls mainly on them [3]. Social pressure matters too: between 1979 and 1992, as drinking became more common in Japanese business life, the share of Japanese alcoholics carrying ALDH2*2 rose from 2.5% to 13% [1].

Allele frequencies are from the 1000 Genomes Project as listed in dbSNP [10]; the last column is calculated from them. Frequencies differ within East Asia, and ALDH2*2 is close to absent outside it.

ADH1B makes the beta subunit of liver alcohol dehydrogenase. At rs1229984 the reference form (ADH1B*1) has arginine at position 48 (Arg48); the variant form (ADH1B*2) has histidine (His48). Older papers call this Arg47His [1]. In dbSNP's forward-strand notation the His48 allele is T and Arg48 is C [11].

The His48 enzyme releases its coenzyme faster and turns over ethanol 70 to 80 times faster than the Arg48 enzyme (350 versus 4 reactions per minute in purified enzyme). Modeled for a whole liver, a man with two His48 copies would have almost eight times the ethanol-oxidizing capacity of a man with two Arg48 copies [1]. That is a calculation, not a measured drinking rate: even among young European Americans, nearly all Arg48/Arg48, real alcohol elimination rates vary about fourfold [1].

The genetic association with drinking is strong and replicated across ancestries. Among Chinese people in Taiwan, the odds ratio for alcoholism was 0.19 with one His48 copy and 0.12 with two, compared with none [1]. In European and African American case-control studies, His48 was associated with lower odds of alcohol dependence (odds ratio 0.34) and with a lower maximum number of drinks in a day, despite being rare in those groups; the proposed mechanism is a stronger aversive reaction to alcohol [12]. A genome-wide study of 14,904 people with alcohol dependence and 37,944 controls confirmed rs1229984 in people of European ancestry [13]. In a genome-wide study of 15,105 East Asian men, rs1229984 was associated with self-reported flushing, as was ALDH2 rs671 [14].

Two findings temper this. The first is that the cancer data point the other way. Among the Japanese men with alcohol dependence above, the slow Arg48/Arg48 genotype was associated with about 3 times the odds of esophageal cancer and about 2 times the odds of head and neck cancer compared with His48 carriers, and the combination of Arg48/Arg48 with ALDH2*2 was associated with about 35 times the odds of esophageal cancer [9]. Everyone in that study was alcohol dependent, and the reasons for the pattern are not settled, but it means the fast His48 form cannot be described as the higher-harm result. The second is that the evidence that ADH1B alone causes a noticeable flush is much thinner than for ALDH2.

Frequencies are from the 1000 Genomes Project as listed in dbSNP [11]; the last column is calculated from them. In East Asia, His48 is the majority form, so the "Normal Function" Arg48/Arg48 result is the less common one there.

A different ADH1B variant, ADH1B*3 (rs2066702, Arg370Cys), also speeds the enzyme and is found mainly in people of African descent [1]. It reached genome-wide significance for alcohol dependence in African-ancestry participants [13]. Gene2Rx does not read rs2066702, so ADH1B*3 carriers are reported as Normal Function.

Gene2Rx wrote this guideline itself from the research above; no guideline body has published one. The report shows each gene separately. The recommendations are written for a clinician and are restated here in plain language, with the strength the report gives them.

The ALDH2 rows rest on the strongest evidence: a measured loss of enzyme activity and a cancer risk found in many studies. The ADH1B rows rest on a solid link with less drinking and less dependence, but, as explained above, the evidence for a strong reaction from ADH1B alone is thinner, and the "long-term harm" wording fits the cancer data poorly. A Normal Function result in both genes means only that these two variants do not add risk; the general risks of alcohol still apply.

Alcohol is not a prescription drug, but it is widely used, and ALDH2*2 removes most of the enzyme that clears its toxic metabolite. The effect shows as a flush, and the variant's protective link with alcohol dependence is the most widely reproduced association of any single gene with alcoholism [1]. Its link to esophageal cancer in people who drink has been found repeatedly in case-control and prospective studies [3].

Because these genotypes shape how much people drink in East Asian populations, researchers have used them as a natural experiment. In the China Kadoorie Biobank, genotype-predicted alcohol intake was associated with higher blood pressure and a higher risk of stroke, with no sign that moderate drinking protected against stroke [8]. That is part of why the guideline never treats a normal result as a reason to drink.

Many carriers know they flush but not why, or what it means for cancer risk. Some young people treat the flush as a cosmetic problem and take antihistamines to hide it while they keep drinking [3]. A result that names the cause and explains the risk gives people and their clinicians something concrete to talk about. The guideline covers only these two variants because they are the ones with this depth of evidence.

If your report shows ALDH2 Decreased or Poor Function, it is worth telling your clinician, particularly if you drink regularly or used to. Clinicians who see patients with ALDH2 deficiency are advised to know about the esophageal cancer risk, and for patients at high risk, endoscopy for early detection has been suggested [3]. Your clinician can weigh your drinking history, smoking and other factors.

Some medicines block the same pathway. Disulfiram stops acetaldehyde clearance and causes a severe reaction with even small amounts of alcohol, and its label warns that reactions can occur up to 14 days after the last dose [4]. If you are prescribed a medicine that warns against alcohol, follow that warning whatever your genotype.

An ALDH2 result is also relevant to one medicine outside this guideline. ALDH2 helps convert nitroglycerin, used for angina, into its active form, and Lys504 carriers in one Chinese study were less likely to respond to sublingual nitroglycerin [15]. Gene2Rx does not report on nitroglycerin, but a prescriber may want to know.

This result is about alcohol, so there is no prescription to change. If you take a medicine for alcohol use disorder or any other condition, do not start, stop or change it on the basis of a genetic result without talking to your prescriber.

Gene2Rx reads two positions. Each is measured directly or inferred by imputation from nearby markers, and the result reflects only those positions. It does not read ADH1B*3, the ALDH1A1 gene or other variants that affect alcohol breakdown, and it does not include the many genes that each add a small amount to the risk of alcohol use disorder [13]. Consumer arrays (23andMe, AncestryDNA, MyHeritage) are not clinical-grade tests, and their raw data is labeled not for medical use.

A normal result says nothing about whether alcohol is safe for you. Alcohol use disorder, liver disease, cancer and harm from intoxication happen to people with every genotype. Most of the research on these variants comes from East Asian men, and the ALDH2 cancer findings come mainly from Japan and Taiwan.

I flush when I drink but my ALDH2 result is normal. Why?

The ADH1B variant has also been linked to flushing [14], and genes this report does not read may contribute. Flushing can have non-genetic causes as well, so it is worth mentioning to your clinician.

Do antihistamines or other remedies for the flush make drinking safer?

No. Hiding the redness does not change how fast acetaldehyde is cleared, and the cancer risk described above comes from acetaldehyde, not from the flush [3].

Can I build up tolerance?

Some ALDH2 heterozygotes do become tolerant to the flush, but acetaldehyde still builds up, and these are the people in whom the cancer risk has been found [3]. People with two ALDH2*2 copies are generally unable to drink much at all.

1. Edenberg HJ. The genetics of alcohol metabolism: role of alcohol dehydrogenase and aldehyde dehydrogenase variants. Alcohol Res Health (2007). Pathway, enzyme kinetics, and odds ratios by ADH1B and ALDH2 genotype.
2. Dharavath RN et al. GABAergic signaling in alcohol use disorder and withdrawal: pathological involvement and therapeutic potential. Front Neural Circuits (2023). How ethanol acts in the brain and its global burden.
3. Brooks PJ et al. The alcohol flushing response: an unrecognized risk factor for esophageal cancer from alcohol consumption. PLoS Med (2009). Flushing prevalence, acetaldehyde exposure and esophageal cancer risk in ALDH2 deficiency.
4. Disulfiram tablets: prescribing information. DailyMed. Acetaldehyde accumulation and the disulfiram-alcohol reaction.
5. Crabb DW et al. Genotypes for aldehyde dehydrogenase deficiency and alcohol sensitivity. The inactive ALDH2(2) allele is dominant. J Clin Invest (1989). Genotype and enzyme activity in human liver.
6. Xiao Q et al. The aldehyde dehydrogenase ALDH2*2 allele exhibits dominance over ALDH2*1 in transduced HeLa cells. J Clin Invest (1995). How the inactive subunit suppresses the normal enzyme.
7. Li D, Zhao H, Gelernter J. Strong protective effect of the aldehyde dehydrogenase gene (ALDH2) 504lys (*2) allele against alcoholism and alcohol-induced medical diseases in Asians. Hum Genet (2012). Meta-analysis of 53 studies.
8. Millwood IY et al. Conventional and genetic evidence on alcohol and vascular disease aetiology: a prospective study of 500 000 men and women in China. Lancet (2019). Genotype-predicted drinking, blood pressure and stroke.
9. Yokoyama A, Yokoyama T. History of alcohol-related cancers and ADH1B/ALDH2 genotypes in a large Japanese cohort of male patients with alcohol dependence. Cancer Med (2026). Cancer odds by ADH1B and ALDH2 genotype in 5,214 men.
10. dbSNP: rs671 (ALDH2). Allele frequencies, including 1000 Genomes populations.
11. dbSNP: rs1229984 (ADH1B). Allele frequencies, including 1000 Genomes populations.
12. Bierut LJ et al. ADH1B is associated with alcohol dependence and alcohol consumption in populations of European and African ancestry. Mol Psychiatry (2012). The His48 association outside East Asia.
13. Walters RK et al. Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders. Nat Neurosci (2018). rs1229984 in European and rs2066702 in African ancestry.
14. Cho Y et al. Genetic influences on alcohol flushing in East Asian populations. BMC Genomics (2023). Genome-wide study of self-reported flushing.
15. Li Y et al. Mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys polymorphism contributes to the variation in efficacy of sublingual nitroglycerin. J Clin Invest (2006). ALDH2 and nitroglycerin response.