Skip to main content

FAQ

Do white people flush and/or is the variant that makes white people flush the same as the one observed in East Asian people?

Alcohol flushing is also reported in some white populations (e.g., Irish), but the mechanism appears distinct from ALDH2*2. According to Chen et al., reduced ALDH2 activity affects “an estimated 120 million people of non-East Asian genetic ancestry” (Chen et al., 2020). The alcohol flushing response observed in white populations are of shorter duration and lower intensity compared to East Asian populations. There is conflicting evidence as to whether the alcohol flushing response is caused by an increased in blood acetaldehyde (Chan, 1986; Ward et al., 1994). White alcohol flushing is linked to low ALDH1 activity rather than the ALDH2 deficiency common in East Asian populations (Ward et al., 1994). There is little to no evidence as to whether the variant observed in white populations is associated with the same diseases and/or disease incidence observed with ALDH2*2 in East Asian populations.

Where did the ALDH2*2 allele come from and why do more East Asian people have this allele?

Studies show the ALDH2*2 variant became common in East Asian populations fairly quickly, over the last 2,000 to 3,000 years, because it was favored by natural selection (Luo et al., 2009; Field et al., 2016; Chen et al., 2022). Strong selection signals co-occur with the alcohol dehydrogenase 1B (ADH1B) gene, another gene involved in alcohol metabolism, pointing to pressures related to how the body handles alcohol and possibly diet (Okada et al., 2018; Chen et al., 2022). The increase corresponds with the spread of rice domestication, when fermented drinks and new dietary shifts became more common (Wang et al., 2016; Zhu et al., 2021; Chen et al., 2022). The ALDH2*2 variant may have been favored by natural selection for several reasons: (1) people with ALDH2*2 may drink alcohol less because they experience noxious symptoms associated with alcohol flushing, which could lower alcohol-related liver disease (Park et al., 2014; Chen et al., 2022); some studies also suggest protection against infections like tuberculosis, and geographic correlations linking ALDH2*2 with hepatitis B raise similar ideas (Lin & Cheng, 2002; Chen et al., 2022). Population biobank studies suggest protection from certain cardiovascular outcomes (e.g., atrial flutter, ischemic stroke), which could have modestly favored variant carriers (Sakaue et al., 2021; Chen et al., 2022). Although the exact cause has not been identified, most likely, several factors worked together.

Why do East Asians in East Asian countries have lower disease incidence than their counterparts in America?

Specific comparative data between East Asians in their countries of origin and East Asian Americans are limited. Generally, some aldehyde associated diseases are higher in East Asians in their countries of origin, and some are higher in East Asian Americans in the U.S. Unfortunately, the aggregation of Asian American data can obscure meaningful variations between ethnic groups. For example, one study found significant differences in the prevalence of diabetes, hypertension, coronary artery disease, obesity, and smoking across different Asian subgroups (Gordon et al., 2019). It is because of this and a combination of lifestyle (e.g., diet, smoking), environmental (e.g., pollution), cultural (e.g., alcohol consumption habits), and healthcare factors that it is challenging to answer this question.

Does the disease incidence still happen when you have the variant without long-term alcohol consumption?

It is challenging to find a study population that has abstained from alcohol prior to the study and will continue to do so long enough to observe disease incidence. However, some animal research studies have found that disease incidence is higher in those with the variant compared to those without the variants (Chang et al., 2023).

Outside knowing that I have this variant, why should I get genetic testing (GT) and/or why shouldn’t I?

Why some may wish to pursue GT:

  • Individuals may seek GT to understand their risk for alcohol-related conditions, such as esophageal cancer and cardiovascular disease.
    • Healthcare providers may recommend GT to tailor medical advice and interventions based on genetic predisposition.
  • Knowledge of their genotype could encourage lifestyle changes, such as reducing alcohol consumption and improving dietary choices.
  • Individuals may want to understand potential genetic risks for their children.

Why some may NOT pursue GT:

  • Learning about genetic risks may cause anxiety or stress.
  • Fear of stigma related to drinking behaviors or perceptions in social settings.
  • GT may not be covered by insurance and/or be expensive, inconvenient.
  • Some individuals may feel that the knowledge would not significantly impact their daily lives or health decisions.
  • Concerns about genetic data being used by insurance companies or employers.
    • See Genetic Information Nondiscrimination Act of 2008 (GINA): It prohibits health insurers from using genetic information to determine eligibility, coverage, or premiums and prevents employers from using genetic data for hiring, firing, or promotion decisions. However, GINA does not apply to life, disability, or long-term care insurance. Its goal is to encourage individuals to pursue GT without fear of discrimination.

Why do some pursue single gene vs panel genetic testing (GT)?

Why some may pursue single gene GT:

  • If a person has a strong family history or symptoms of a specific genetic condition, often associated with one gene, testing a single gene can provide a clear answer.
  • Single gene tests are usually less expensive compared to comprehensive panel testing.
  • Some insurers may cover single gene testing but not broader panels.
  • A single result is sometimes easier to interpret and manage clinically. Some patients may also prefer to NOT know their status for additional genes. Depending on the patient, this may or may not be the most optimal form of genetic healthcare.

Why some may pursue pane GT:

  • Panel testing can detect mutations across multiple genes associated with similar symptoms or conditions. It reduces the need for sequential testing when multiple genes could be implicated.
  • In cases of genetic heterogeneity, panels increase the chance of finding a pathogenic variant.
    • Genetic heterogeneity means that the same disease or condition can be caused by changes in different genes. In other words, different people might have different genetic reasons for having the same health problem.
  • Panels can provide a broader understanding of potential risks beyond the initially suspected condition.

The cost of GT varies widely based on the type and complexity of the test. Prices can range from under $100 to more than $2000. DTC GT is usually cheaper than clinical GT, even with some insurance coverage. Some tests may require follow-up consultations, genetic counseling, or additional GT, which can add to the overall expense. Consult with a healthcare provider or genetic counselor to determine the most appropriate test and understand the associated costs and potential insurance coverage.

Does the type of alcohol you drink (e.g., beer, sake, baijiu, etc.) matter when it comes to flushing?

Yes, the type of alcohol consumed can influence the severity of alcohol flushing reactions, although the underlying cause, acetaldehyde buildup due to ALDH2 deficiency, remains the same for East Asian populations. Stronger drinks contain higher concentrations of ethanol, leading to faster acetaldehyde buildup, which can cause a more intense flushing reaction. Some alcoholic beverages contain congeners, which are byproducts of fermentation (e.g., tannins in red wine, methanol in whiskey). These can exacerbate flushing symptoms by increasing the body’s metabolic burden (National Institute on Alcohol Abuse and Alcoholism, n.d.-a). Drinking larger quantities in a short period can overwhelm the body’s ability to metabolize acetaldehyde, intensifying flushing. Some alcoholic beverages include histamines and sulfites (e.g., wine), which can trigger additional flushing and allergic-like reactions (National Institute on Alcohol Abuse and Alcoholism, n.d.-b).

Is the alcohol flushing responses an allergic reaction?

No, the alcohol flushing response is not an allergic reaction. It is a metabolic reaction caused by a deficiency or reduced activity of the ALDH2 enzyme. On the other hand, an alcohol allergy is rare and involves an immune system reaction to ethanol itself or ingredients in alcoholic beverages, such as grains, sulfites, or histamines (Thermo Fisher Scientific, n.d.). Symptoms of an allergic reaction can include swelling, difficulty breathing, and severe gastrointestinal distress – some of which are also observed in the alcohol flushing response. Although, both the alcohol flushing response and alcohol allergy release histamines (National Institute on Alcohol Abuse and Alcoholism, n.d.-b).

References

Chan A. W. (1986). Racial differences in alcohol sensitivity. Alcohol and alcoholism (Oxford, Oxfordshire), 21(1), 93–104.

Chang, Y. C., Lee, H. L., Yang, W., et al. (2023). A common East-Asian ALDH2 mutation causes metabolic disorders and the therapeutic effect of ALDH2 activators. Nat Commun, 14, 5971. https://doi.org/10.1038/s41467-023-41570-6

Chen, C. H., Ferreira, J. C. B., Joshi, A. U., Stevens, M. C., Li, S. J., Hsu, J. H., Maclean, R., Ferreira, N. D., Cervantes, P. R., Martinez, D. D., Barrientos, F. L., Quintanares, G. H. R., & Mochly-Rosen, D. (2020). Novel and prevalent non-East Asian ALDH2 variants; Implications for global susceptibility to aldehydes’ toxicity. EBioMedicine, 55, 102753. https://doi.org/10.1016/j.ebiom.2020.102753

Chen, C.-H., Kraemer, B. R., & Mochly-Rosen, D. (2022). ALDH2 variance in disease and populations. Disease Models & Mechanisms, 15(6). https://doi.org/10.1242/dmm.049601

Field, Y., Boyle, E. A., Telis, N., Gao, Z., Gaulton, K. J., Golan, D., Yengo, L., Rocheleau, G., Froguel, P., Mccarthy, M. I., et al. (2016). Detection of human adaptation during the past 2000 years. Science, 354, 760–764. https://doi.org/10.1126/science.aag0776

Gordon, N. P., Lin, T. Y., Rau, J., & Lo, J. C. (2019). Aggregation of Asian-American subgroups masks meaningful differences in health and health risks among Asian ethnicities: an electronic health record based cohort study. BMC Public Health, 19(1), 1551. https://doi.org/10.1186/s12889-019-7683-3

Lin, Y.-P. and Cheng, T. J. (2002). Why can’t Chinese Han drink alcohol? Hepatitis B virus infection and the evolution of acetaldehyde dehydrogenase deficiency. Med. Hypotheses 59, 204–207. https://doi.org/10.1016/S0306-9877(02)00253-0

Luo, H.-R., Wu, G.-S., Pakstis, A. J., Tong, L., Oota, H., Kidd, K. K., & Zhang, Y.-P. (2009). Origin and dispersal of atypical aldehyde dehydrogenase ALDH2⁎487Lys. Gene, 435(1), 96–103. https://doi.org/10.1016/j.gene.2008.12.021

National Institute on Alcohol Abuse and Alcoholism. (n.d.-a). Hangovers. National Institutes of Health. Retrieved from https://www.niaaa.nih.gov/publications/brochures-and-fact-sheets/hangovers

National Institute on Alcohol Abuse and Alcoholism. (n.d.-b). Alcohol flush reaction: Does drinking alcohol make your face red? National Institutes of Health. Retrieved from https://www.niaaa.nih.gov/publications/alcohol-flush-reaction-does-drinking-alcohol-make-your-face-red

Okada, Y., Momozawa, Y., Sakaue, S., Kanai, M., Ishigaki, K., Akiyama, M., Kishikawa, T., Arai, Y., Sasaki, T., Kosaki, K., et al. (2018). Deep whole-genome sequencing reveals recent selection signatures linked to evolution and disease risk of Japanese. Nat. Commun. 9, 1631. https://doi.org/10.1038/s41467-018-03274-0

Park, S. K., Park, C. S., Lee, H.-S., Park, K. S., Park, B. L., Cheong, H. S. and Shin, H. D. (2014). Functional polymorphism in aldehyde dehydrogenase-2 gene associated with risk of tuberculosis. BMC Med. Genet. 15, 40. https://doi.org/10.1186/1471-2350-15-40

Sakaue, S., Kanai, M., Tanigawa, Y., Karjalainen, J., Kurki, M., Koshiba, S., Narita, A., Konuma, T., Yamamoto, K., Akiyama, M., et al. (2021). A cross-population atlas of genetic associations for 220 human phenotypes. Nat. Genet. 53, 1415–1424. https://doi.org/10.1038/s41588-021-00931-x

Thermo Fisher Scientific. (n.d.). Alcohol intolerance: Symptoms, causes, and management. Retrieved from https://www.thermofisher.com/allergy/us/en/living-with-allergies/understanding-allergies/alcohol-intolerance.html

Wang, L.-X., Wen, S., Wang, C.-C., Zhou, B. and Li, H. (2016a). Molecular adaption of alcohol metabolism to agriculture in East Asia. Quat. Int. 426, 187–194. https://doi.org/10.1016/j.quaint.2016.03.008

Ward, R. J., McPherson, A. J. S., Chow, C., Ealing, J., Sherman, D. I. N., Yoshida, A., & Peters, T. J. (1994). Identification and characterisation of alcohol-induced flushing in Caucasian subjects. Alcohol and Alcoholism, 29(4), 433–438. https://doi.org/10.1093/oxfordjournals.alcalc.a045562

Zhu, C., Talhelm, T., Li, Y., Chen, G., Zhu, J., & Wang, J. (2021). Relationship between rice farming and polygenic scores potentially linked to agriculture in China. R. Soc. Open Sci. 8, 210382. https://doi.org/10.1098/rsos.210382