Increasing trend in the prevalence of alcohol‐sensitive individuals with alcohol use disorder over the past 40 years

The inactive form of aldehyde dehydrogenase-2 allele (ALDH2*2 (rs671, Glu487Lys)) is present in approximately 40% of the East Asians including Japanese but rarely found in other ethnics.1 ALDH2*2 leads to high blood acetaldehyde concentrations which cause various discomforting symptoms; therefore, ALDH2*2 careers have been considered unlikely to develop alcohol use disorder (AUD). However, our project to examine ALDH2 genotypes in patients with AUD started in 1979 and reported that the prevalence of ALDH2*2 carriers with AUD was significantly increasing through three independent years (1979, 1986, and 1992, n = 1500).2 Thereafter, we continued alcohol-sensitivity genotyping (i.e., ALDH2 and alcohol dehydrogenase-1B (ADH1B)) for patients with AUD on their first admission between 1996–2019. This study was approved by the Ethics Committee of Kurihama Medical and Addiction Center, Japan (Approval ID: G37) (Supporting Text S1). The patients gave informed consent, and their anonymity was preserved. The study was conformed to the provisions of the Declaration of Helsinki. In total, 8805 male patients with AUD were enrolled, and 1358 (15.3%) were found to carry an ALDH2*2 allele (Fig. 1 and Table S1). An increasing trend in the prevalence of ALDH2*2 carriers were steadily and robust (TJT = 186.00, P = 0.01) (Fig. 1). This trend has been consistent over the past 40 years synthesizing with our previous literature.2 There were no associations between the prevalence of ALDH2*2 carriers and average age or prevalence of an ADH1B*2 allele among ALDH2*2 carriers (Table S2). The distribution of ADH1B genotypes among ALDH2*2 carriers were in accordance with the Hardy–Weinberg equilibrium (χ2 = 52.83, P < 0.01). Moreover, we found four cases who were homozygous for ALDH2*2 very recently (one (2013), two (2015), and one (2019)), which are theoretically further less likely to develop AUD than those with heterozygotes. To our knowledge, three cases with ALDH2*2/*2 have been reported to date.3, 4 However, one had comorbid major depressive disorder,4 and two were accidentally identified to carry ALDH2*2/*2 and meet the criteria for AUD in a cross-sectional study of students but not in treatment.3 In contrast, we found the first four patients with ALDH2*2/*2 suffering from AUD without any comorbidity. They showed a similar course in developing AUD: (i) they had not been able to drink alcohol at all because of discomforting symptoms for the first few years after starting drinking; (ii) they were getting used to alcohol through social drinking with low alcoholic beverages (3–9%) i.e., ready-to-drinks (RTDs); and (iii) they became able to drink as much as 20 drinks/day (i.e., 200 g of ethanol) before admission (Supporting Text S2). Socio-cultural factors have long been suggested to break the strong genetic barrier against AUD,2, 5 and the four ALDH2*2/*2 carriers may provide some clues to this phenomenon; social drinking and RTDs may play a crucial role in breaking the genetic protection against AUD. Many Japanese people have experienced their first drink together with their friends or senior colleagues. To get along with them, alcohol-sensitive individuals often choose sweet and easy-to-drink RTDs and perhaps some homemade drinks, particularly with a lower range of alcohol, which may work as a “gateway drug” and gradually lead them to shift to higher alcoholic beverages such as spirits. Moreover, the decreased stigma for getting treatment, increased accessibility to treatment, and societal pressure to drink might as well be considered as environmental factors. Such drinking culture may familiarize alcohol-sensitive persons with alcohol, and even overcome the genetic protection of the higher acetaldehyde by ALDH2*2/*2. This speculation from these small case descriptions seems consistent with the sales data of RTDs on a national level. Interestingly, while the overall consumption of alcohol has gradually declined, that of liqueurs mostly consisting of RTDs has substantially increased for the past 20 years (Table S1),6 and the prevalence of AUD is also on the rise (1.6% (2003), 3.4% (2016)).7, 8 In addition, the prevalence of ALDH2*2 carriers admitted to our center showed significant associations with consumptions of total alcohol and liqueurs as well as the liqueurs/total alcohol ratio (Table S2). These facts suggest that the distribution of ALDH2 phenotypes among patients with AUD has been changing recently. This study had a limitation. Clinical characteristics relevant to the development of AUD, including preferences about alcoholic beverages and illness severity and duration were lacking. Although such socio-cultural factors among Japanese cannot be necessarily extrapolated to other populations, physicians are advised to be aware that any environmental situations could trigger the onset of developing AUD even among genetically alcohol-sensitive individuals. This notion is especially relevant in the light of reported increased drinking in the COVID-19 pandemic environment.9 This study was supported by a research grant from Suntory Holdings Limited. The funding source had no role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. FU has received fellowship grants from Discovery Fund, Nakatani Foundation, and the Canadian Institutes of Health Research (CIHR); and consultant fee from VeraSci, and Uchiyama Underwriting within the past 3 years. HU has received grants from Eisai, Otsuka Pharmaceutical, Dainippon-Sumitomo Pharma, Mochida Pharmaceutical, Meiji-Seika Pharmaceutical, and Novartis; speaker's honoraria from Otsuka Pharmaceutical, Eli Lilly, Shionogi, Pfizer, Yoshitomi Yakuhin, Dainippon-Sumitomo Pharma, Meiji-Seika Pharma, MSD, and Janssen Pharmaceutical; and advisory panel payments from Dainippon-Sumitomo Pharma within the past 3 years. YY has received grants from Ministry of Health, Labor and Welfare, and Japan Agency for Medical Research and Development; and personal fees from Otsuka Pharmaceutical Company Limited, and Nippon Shinyaku Company Limited within the past 3 years. HN has received grants from Japan Agency for Medical Research and Development, and Japan Health and Labor Sciences within the past 3 years. SM has received grants from Asahi Quality & Innovations, Ltd.; personal fees from EA Pharma, Ono Yakuhin, Otsuka Pharmaceutical, and Yoshitomi Yakuhin within the past 3 years. MK, AY, TY, and MI have nothing to disclose. Table S1. Characteristics of patients with AUD who were first admitted to our center, and the amount of consumption of total alcoholic beverages and liqueurs in Japan between 1996 and 2019. Table S2. Spearman's correlation analyses between the yearly prevalence of ALDH2*2 carriers admitted to our center and covariates. Supporting Text S1. Methods. Supporting Text S2. Case descriptions. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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