Abstract
There is a genetic difference in sensitivity to alcohol in Orientals, which is known to be mainly due to polymorphisms of alcohol‐metabolizing enzymes such as aldehyde dehydrogenase. Habitual alcohol drinking is a risk factor for hypertension. However, it has not been determined whether individual sensitivity to alcohol influences the relationship between alcohol consumption and blood pressure. In this study, the relationship between amount of alcohol consumption and blood pressure was compared between groups of subjects with low and high sensitivities of circulatory response to alcohol. Sensitivity to alcohol in subjects (306 male workers) was evaluated by a self‐administered questionnaire on symptoms (skin flushing and palpitation) that appear when drinking alcohol. Weight, height and blood pressure were measured. In subjects with high sensitivity to alcohol, systolic blood pressure was significantly higher in the subgroup of moderate‐to‐heavy drinkers (30 g/day or more) than in the subgroups of non‐drinkers and light drinkers (less than 30 g/day). On the other hand, in subjects with low sensitivity to alcohol, systolic blood pressure in the subgroup of non‐drinkers was not significantly different from that in the subgroups of light drinkers and moderate‐to‐heavy drinkers. The amount of daily alcohol consumption was significantly correlated with both systolic and diastolic blood pressures in subjects with high sensitivity to alcohol but not in subjects with low sensitivity to alcohol. Pressor effects of alcohol drinking on blood pressure were significant only in subjects with high sensitivity to alcohol, suggesting that there is a greater risk of development of hypertension from drinking large amounts of alcohol in people with high sensitivity to alcohol.
Introduction
Excessive alcohol consumption is known to be a major risk factor for the development of essential hypertension Citation[1], Citation[2]. Drinking alcohol increases the incidence of stroke Citation[3], and this effect is mainly due to hypertension caused by habitual alcohol drinking Citation[4], Citation[5]. Thus, restriction of ethanol consumption is important for prevention of stroke as well as hypertension. Restriction of ethanol consumption to an amount less than 30 g/day is generally recommended in order to prevent the development of hypertension Citation[6].
Sensitivity to alcohol is different in Orientals from in other races. This difference is mainly due to polymorphism of aldehyde dehydrogenase2 (ALDH2), an enzyme that breaks down acetoaldehyde into acetic acid Citation[7], Citation[8]. Several studies have been carried out to determine whether effects of alcohol drinking on blood pressure and incidence of hypertension are affected by genetic difference of ALDH2. Most studies have shown that the effects of alcohol drinking on blood pressure and incidence of hypertension were not different in subjects with high and low levels of enzymatic activity of ALDH2 Citation[9–12]. Only one study has shown that a higher prevalence of hypertension was observed in subjects showing facial flushing, which indicates high sensitivity to alcohol drinking, than in those without facial flushing Citation[13]. However, there have been only a few studies on the relationship between difference in alcohol sensitivity and effects of drinking on blood pressure. Thus, the purpose of the present study was to determine whether pressor effects of alcohol drinking are affected by alcohol sensitivity of circulatory response. Alcohol sensitivity of subjects was evaluated by using a simple questionnaire on symptoms that appear after drinking alcohol Citation[14].
Methods
Subjects
The subjects were 306 male company workers, aged from 20 to 62 years. The purpose of the present study was explained to the subjects, and all participants of this survey agreed with it. The present study protocol was approved by the ethics committee in Yamagata University School of Medicine. The subjects were divided into two groups by sensitivity to alcohol, as described below, and their profiles are shown in . Histories of the present illness were hypertension (2.8%), peptic ulcer (2.3%), gout (0.6%), dermatitis (1.1%) and arrhythmia (0.6%) in drinkers and hypertension (4.7%), peptic ulcer (3.9%), diabetes mellitus (0.8%), liver dysfunction (0.8%), dermatitis (0.8%) and arrhythmia (0.8%) in non‐drinkers. Thus, the general health status in drinkers and that in non‐drinkers do not seem to be different. In addition to physical measurements, they completed self‐administered questionnaires on alcohol consumption, cigarette smoking and symptoms after drinking alcohol. The subjects were instructed to report their customary drinking frequency (days per week) and average amount (ml) of alcoholic beverages, including beer, sake (rice wine), wine and whisky, on a typical occasion or during a typical day. Mean daily alcohol consumption (g/day) was then calculated. The subjects were further subdivided by mean daily alcohol consumption into three subgroups of non‐drinkers, light drinkers (less than 30 g/day) and moderate‐to‐heavy drinkers (30 g/day or more). The value of 30 g/day was used to separate moderate‐to‐heavy drinkers from light drinkers because JNC VII (the 7th report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, USA) recommends restriction of ethanol consumption to an amount less than 30 g/day in order to prevent development of cardiovascular diseases Citation[6].
Table I. Profiles of the groups of subjects with low and high sensitivities of circulatory response to alcohol.
Evaluation of sensitivity to alcohol
A survey on sensitivity to alcohol drinking was performed using a self‐administered questionnaire according to the method of Takeshita & Morimoto Citation[14]. The scoring system for determination of alcohol sensitivity was originally prepared on the basis of results of a stepwise logistic regression analysis to discriminate between the typical homozygote (ALDH2*1/*1) and the atypical heterozygote (ALDH2*1/*2). The questionnaire included three items of questions on symptoms (facial flushing, skin flushing other than facial flushing and palpitation) that appear when drinking alcohol, and the score of each item was determined by the frequency of each symptom as follows: facial flushing: 3.8 (always occurs), 1.1 (sometimes occurs) or 0 (does not occur); flushing elsewhere: 1.6 (always occurs), 1.1 (sometimes occurs) or 0 (does not occur); palpitation: 2.3 (always occurs), 1.3 (sometimes occurs) or 0 (does not occur). The total score was calculated as the score for an alcohol sensitivity screening test (ALST), and the subjects were classified as subjects with low sensitivity and those with high sensitivity to alcohol when the ALST score was ⩽3.1 and >3.1, respectively.
Measurements
After each subject had rested quietly in a sitting position, blood pressure of the right brachial artery was recorded using a mercury sphygmomanometer: Korotkoff's fifth phase was used to define diastolic blood pressure. Weight and height were measured and the body mass index (BMI) was calculated as weight in kilograms divided by the square of height in meters.
Statistics
The data are expressed as means with standard deviations or standard errors in parentheses. Statistical analyses were performed using computer software (SPSS version 9.0J for Windows). The mean levels of each item between the groups were compared using ANOVA and subsequent Student's t‐test after Bonferroni correction. The frequencies of each item between the groups were compared using Fisher's exact probability test. In multiple regression analyses, standardized regression coefficients were calculated. Age, amount of drinking, cigarette smoking, BMI and treatment with anti‐hypertensive drugs were used as explanatory factors in the multiple regression analysis for relationship with blood pressure. A probability (p) value of 0.05 was defined as the limit of statistical significance.
Results
Profiles of the groups of subjects with low and high sensitivities to alcohol
About 40% of the subjects showed high sensitivity to alcohol. The mean amount of daily alcohol consumption was significantly greater in the group of subjects with low sensitivity to alcohol than in the group of subjects with high sensitivity to alcohol (). ALST score was significantly higher (p<0.0001) in non‐drinkers (4.36±0.30) than in drinkers (1.90±0.14). Thus, alcohol sensitivity was higher in non‐drinkers than in drinkers. The mean systolic and diastolic blood pressures as well as BMI were not significantly different between the groups of subjects with low and high sensitivities to alcohol (). The percentage of subjects receiving treatment for hypertension was higher in the group of subjects with high sensitivity to alcohol than in the group of subjects with low sensitivity to alcohol, although the difference was not significant ().
Relationships between ethanol consumption and blood pressure in the groups of subjects with low and high sensitivities to alcohol
In the group of subjects with low sensitivity to alcohol, the mean systolic blood pressure of the moderate‐to‐heavy drinkers was not significantly different from that of the non‐drinkers but was significantly higher than that of the light drinkers (). The mean systolic blood pressure of the light drinkers was slightly lower than that of the non‐drinkers in the group of subjects with low sensitivity to alcohol, although the difference was not significant (). On the other hand, in the group of subjects with high sensitivity to alcohol, the mean systolic blood pressure was significantly higher in the moderate‐to‐heavy drinkers than in the non‐drinkers and light drinkers (). The relationships between amount of alcohol consumption and diastolic blood pressure were similar to the relationships between amount of alcohol consumption and systolic blood pressure, although the differences among subgroups of alcohol consumption were not significant ().
Table II. Relationships of alcohol drinking with blood pressure and BMI in the subjects with low and high sensitivities of circulatory response to alcohol.
Relationships between ethanol consumption and BMI in the groups of subjects with low and high sensitivities to alcohol
Alcohol consumption did not have a significant effect on BMI in either the group of subjects with low sensitivity to alcohol or the group of subjects with high sensitivity to alcohol ().
Multiple regression analysis of the relationships between ethanol consumption and blood pressure in the groups of subjects with low and high sensitivities to alcohol
shows the results of multiple regression analysis of correlations between blood pressure and various items, including amount of daily ethanol consumption. In the group of subjects with high alcohol sensitivity, amount of ethanol consumption was significantly correlated with both systolic and diastolic blood pressures after adjustment for age, BMI and treatment for hypertension, whereas the relationship between amount of ethanol consumption and blood pressure was not significant in the group of subjects with low alcohol sensitivity. Age and BMI were significantly correlated with systolic and diastolic blood pressures in both groups of subjects with low and high alcohol sensitivities. Since the percentage of subjects who had been treated with anti‐hypertensive drugs was low, the standardized regression coefficients were hardly affected by removal of subjects receiving treatment for hypertension in the multiple regression analysis.
Table III. Results of multiple regression analysis of the relationships of blood pressure with various items, including amount of drinking, in the groups of subjects with low and high sensitivities of circulatory response to alcohol.
There was no difference between the percentage of smokers in the group of subjects with low sensitivity to alcohol and that in the group of subjects with high sensitivity (). In multiple regression analysis using smoking, age, BMI and treatment for hypertension as explanatory variables, the standardized regression coefficients between amount of ethanol consumption and blood pressure were significant in the group of subjects with high alcohol sensitivity [systolic blood pressure, 0.268 (p = 0.001); diastolic blood pressure, 0.165 (p = 0.046)] but were not significant in the group of subjects with low alcohol sensitivity [systolic blood pressure, 0.106 (p = 0.162); diastolic blood pressure, 0.097 (p = 0.204)]. Thus, the association between amount of ethanol consumption and blood pressure in the group of subjects with high sensitivity to alcohol was independent of habitual smoking.
Discussion
This study is, to the best of our knowledge, the first one showing a difference in the effects of alcohol drinking on blood pressure in subjects with low sensitivity and high sensitivity to alcohol as evaluated by acute alcohol‐induced symptoms after drinking, such as skin flushing and palpitation. In the group of subjects with high sensitivity to alcohol, the systolic blood pressure was significantly higher in moderate‐to‐heavy drinkers than in non‐drinkers, but this effect of drinking was not observed in subjects with low sensitivity to alcohol. Moreover, the amount of alcohol consumption was significantly related to blood pressure in the subjects with high sensitivity to alcohol but not in the subjects with low sensitivity to alcohol. Thus, pressor effects of moderate‐to‐heavy drinking were observed only in the subjects with high sensitivity to alcohol.
On the other hand, several studies have consistently demonstrated that the difference in ALDH2 genotypes, which is known to cause alcohol sensitivity in Orientals, including Japanese, does not modulate the relationship between alcohol consumption and blood pressure or prevalence of hypertension Citation[9–12]. The reason for the discrepancy in the conclusions of the studies using ALDH genotypes and the present study is not known, but one possible reason is the difference in methods for evaluation of alcohol sensitivity in the above studies (acute symptoms of alcohol intoxication vs ALDH2 genotypes). In fact, Itoh et al. Citation[13], using a questionnaire method, have shown that the prevalence of hypertension was higher in subjects who showed the symptom of facial flushing after drinking than in subjects without flushing. However, Higuchi et al. Citation[15] reported two types of flushing reactions: a fast‐onset flushing evoked by one drink of alcohol or less, due to a deficiency of ALDH2, and slow‐onset flushing produced after at least two drinks, which was not associated with inactive ALDH2. Alcohol sensitivity is also affected by differences in other enzymes such as alcohol dehydrogenase2 (ADH2) Citation[16]. Several studies have recently been carried out on the relationships of ADH2 genotypes with blood pressure, but the results of these studies are inconsistent. Hashimoto et al. Citation[17] found that the probability of having systolic blood pressure in the highest one‐third of the distribution was significantly greater in subjects homozygous for the high‐activity subunit (ADH22/22) than in subjects homozygous for the low‐activity subunit (ADH21/21). On the other hand, Saito et al. Citation[18] reported that the relationship between alcohol consumption and diastolic blood pressure was stronger in men with ADH21/21 than in men with ADH21/22 or ADH22/22, whereas the strength of the relationship between alcohol consumption and blood pressure was similar in different ALDH2 genotype groups. Yamada et al. Citation[19] reported that there was no significant influence of ADH2 genotypes on blood pressure. Thus, further studies are needed to determine whether ADH2 genotypes influence effects of alcohol drinking on blood pressure. The mechanisms underlying the difference in alcohol sensitivity in Orientals also still remains to be clarified. In addition, studies on pressor effects of alcohol drinking in different flushing types would be of interest.
The amount of alcohol consumed by drinkers with low sensitivity to alcohol is generally greater than that consumed by drinkers with high sensitivity. This may cause a difference in impacts on the relationship between alcohol consumption and blood pressure. However, in the subjects of the present study, the mean amounts of alcohol consumed by moderate‐to‐heavy drinkers are not different between the subjects with low and high sensitivities to alcohol. This may be a merit in the present study for evaluation of the influence of alcohol sensitivity on the alcohol–blood pressure relationship. One limitation of the present study is that genotypes of ALDH2 and ADH2 were not determined. More detailed surveys are needed to elucidate the relationship between polymorphisms of alcohol metabolism and blood pressure as well as symptoms of acute alcohol intoxication. Another limitation of the present study is related to the self‐reported data for estimation of individual alcohol consumption. There might have been under‐reporting by habitual drinkers, which is generally more frequent in subjects with low sensitivity to alcohol, because of a larger amount of alcohol consumption. With this possible bias of under‐reporting, the amount of alcohol consumption reported in the subgroup of moderate‐to‐heavy drinkers would be smaller than the true amount of alcohol consumption, and the impact of alcohol‐induced pressor action in subjects with low sensitivity to alcohol would therefore be greater than that in subjects with high sensitivity to alcohol. However, in subjects with low sensitivity to alcohol, mean blood pressure was not significantly different in the groups of non‐drinkers and moderate‐to‐heavy drinkers. Therefore, this bias may not alter the conclusion of the present study.
In the group of subjects with low sensitivity of circulatory response to alcohol, light drinkers showed slightly but not significantly lower blood pressure than that in non‐drinkers. In general, even habitual light drinking is known to cause elevation of blood pressure in Japanese, whereas the sensitivity of blood pressure to light drinking was reportedly lower in Caucasians than in Japanese Citation[20]. Habitual light drinking has also been reported to even lower blood pressure in Caucasian women Citation[21–23]. Our recent study showed that the sensitivity of blood pressure to light drinking depends on age: habitual light drinking causes elevation of blood pressure in elderly people but not in young people Citation[24]. This may explain the present results showing no significant difference between blood pressures of non‐drinkers and light drinkers, because the subjects of the present study were relatively young, with a mean age of about 40 years. Further studies on the relation of alcohol sensitivity to pressor effects of alcohol drinking that include elderly subjects and take into account ethnic differences would be of interest. The differences between blood pressure levels in the groups in the present study were small and thus prospective studies on relationships of alcohol sensitivity with blood pressure and incidence of hypertension are needed to confirm the present findings. The mechanism of alcohol‐induced hypertension still remains to be clarified, although there are several hypotheses, such as increased sympathetic activity Citation[25], Citation[26], increased secretion of cortisol Citation[27], increased arterial reactivity Citation[28], Citation[29], induction of insulin resistance Citation[30], decreased vascular magnesium content Citation[31] and increased activity of renin–angiotensin system Citation[32]. It is also still not clear whether acetoaldehyde or ethanol is mainly involved in the development of hypertension in alcohol consumers. Thus, further studies on the basic mechanism of alcohol‐induced hypertension are also needed to explain the causal relationship between alcohol sensitivity and hypertension. Only male subjects were used in the present study as well as in the study by Itoh et al. Citation[13], which showed a significant relationship between alcohol flushing and prevalence of hypertension. Women are generally more prone to be affected by alcohol drinking. Thus, the relationship between alcohol sensitivity and blood pressure in women should also be investigated.
In conclusion, sensitivity to alcohol affected the relationship between alcohol drinking and blood pressure, and alcohol consumption was significantly related to blood pressure only in subjects with high sensitivity to alcohol, suggesting that there is a greater risk of development of hypertension from consumption of large amounts of alcohol in people with high sensitivity to alcohol.
Acknowledgements
This work was supported by a grant for scientific research from the Ministry of Education, Science and Culture of Japan (No. 15590538) and the Grant of the Yamagata University 21st Century COE program.
References
- Klatsky A. L. Alcohol and hypertension. Clin Chim Acta 1996; 246: 91–105
- Kawasaki T., Uezono K., Sanefuji M., Utsunomiya H., Fujino T., Kanaya S. A 17‐year follow‐up study of hypertensive and normotensive male university students in Japan. Hypertens Res 2003; 26: 445–452
- Hillbom M. Alcohol consumption and stroke: Benefits and risks. Alcoholism Clin Exp Res 1998; 22((7 Suppl))352S–358S
- MacMahon S. Alcohol consumption and hypertension. Hypertension 1987; 9: 111–121
- Marmot M. G., Elliott P., Shipley M. J., Dyer A. R., Ueshima H., Beevers D. G. Alcohol and blood pressure: The INTERSALT study. Brit Med J 1994; 308: 1263–1267
- Chobanian A. V., Bakris G. L., Black H. R., Cushman W. C., Green L. A., Izzo J. L., Jr. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003; 42: 1206–1252
- Goedde H. W., Harada S., Agarwal D. P. Racial differences in alcohol sensitivity: A new hypothesis. Hum Genet 1979; 51: 331–334
- Harada S., Agarwal D. P., Goedde H. W. Aldehyde dehydrogenase deficiency as cause of facial flushing reaction to alcohol in Japanese. Lancet 1981; 2: 982
- Okayama A., Ueshima H., Yamakawa M., Kita Y. Low‐Km aldehyde dehydrogenase deficiency does not influence the elevation of blood pressure by alcohol. J Hum Hypertens 1994; 8: 205–208
- Tsuritani I., Ikai E., Date T., Suzuki Y., Ishizaki M., Yamada Y. Polymorphism in ALDH2‐genotype in Japanese men and the alcohol–blood pressure relationship. Am J Hypertens 1995; 8: 1053–1059
- Takagi S., Baba S., Iwai N., Fukuda M., Katsuya T., Higaki J. The aldehyde dehydrogenase 2 gene is a risk factor for hypertension in Japanese but does not alter the sensitivity to pressor effects of alcohol: The Suita study. Hypertens Res 2001; 24: 365–370
- Amamoto K., Okamura T., Tamaki S., Kita Y., Tsujita Y., Kadowaki T. Epidemiologic study of the association of low‐Km mitochondrial acetaldehyde dehydrogenase genotypes with blood pressure level and the prevalence of hypertension in a general population. Hypertens Res 2002; 25: 857–864
- Itoh T., Matsumoto M., Nakamura M., Okada A., Shirahashi N., Hougaku H. Effects of daily alcohol intake on the blood pressure differ depending on an individual's sensitivity to alcohol: Oriental flushing as a sign to stop drinking for health reasons. J Hypertens 1997; 15: 1211–1217
- Takeshita T., Morimoto K. Development of a questionnaire method to discriminate between typical and atypical genotypes of low Km aldehyde dehydrogenase in a Japanese population. Alcoholism Clin Exp Res 1998; 22: 1409–1413
- Higuchi S., Parrish K. M., Dufour M. C., Towle L. H., Harford T. C. The relationship between three subtypes of the flushing response and DSM‐III alcohol abuse in Japanese. J Stud Alcohol 1992; 53: 553–560
- Harada S., Misawa S., Agarwal D. P., Goedde H. W. Liver alcohol dehydrogenase and aldehyde dehydrogenase in the Japanese: Isozyme variation and its possible role in alcohol intoxication. Am J Hum Genet 1980; 32: 8–15
- Hashimoto Y., Nakayama T., Futamura A., Omura M., Nakarai H., Nakahara K. Relationship between genetic polymorphisms of alcohol‐metabolizing enzymes and changes in risk factors for coronary heart disease associated with alcohol consumption. Clin Chem 2002; 48: 1043–1048
- Saito K., Yokoyama T., Yoshiike N., Date C., Yamamoto A., Muramatsu M. Do the ethanol metabolizing enzymes modify the relationship between alcohol consumption and blood pressure?. J Hypertens 2003; 21: 1097–1105
- Yamada Y., Sun F., Tsuritani I., Honda R. Genetic differences in ethanol metabolizing enzymes and blood pressure in Japanese alcohol consumers. J Hum Hypertens 2002; 16: 479–486
- Klag M. J., Moore R. D., Whelton P. K., Sakai Y., Comstock G. W. Alcohol consumption and blood pressure: A comparison of native Japanese to American men. J Clin Epidemiol 1990; 43: 1407–1414
- Klatsky A. L., Friedman G. D., Siegelaub A. B., Gerard M. J. Alcohol consumption and blood pressure Kaiser‐Permanente Multiphasic Health Examination data. N Engl J Med 1977; 296: 1194–1200
- Criqui M. H., Wallace R. B., Mishkel M., Barrett‐Connor E., Heiss G. Alcohol consumption and blood pressure. The lipid research clinics prevalence study. Hypertension 1981; 3: 557–565
- Witteman J. C., Willett W. C., Stampfer M. J., Colditz G. A., Kok F. J., Sacks F. M. Relation of moderate alcohol consumption and risk of systemic hypertension in women. Am J Cardiol 1990; 65: 633–637
- Wakabayashi I., Kobaba‐Wakabayashi R. Effects of age on the relationship between drinking and atherosclerotic risk factors. Gerontology 2002; 48: 151–156
- Saunders J. B., Beevers D. G., Paton A. Factors influencing blood pressure in chronic alcoholics. Clin Sci (Lond) 1979; 57(Suppl 5)295s–298s
- Potter J. F., Bannan L. T., Saunders J. B., Ingram M. C., Beevers D. G. Blood pressure and pressor mechanisms during alcohol withdrawal. J Hypertens 1983; Suppl 1((2))97–99
- Rivier C., Imaki T., Vale W. Prolonged exposure to alcohol: Effect on CRF mRNA levels, and CRF‐ and stress‐induced ACTH secretion in the rat. Brain Res 1990; 520: 1–5
- Hatake K., Wakabayashi I., Kakishita E., Taniguchi T., Ouchi H., Sakaki N. Inhibitory effect of ethanol on endothelium‐dependent vascular responsiveness. Eur J Pharmacol 1989; 168: 277–283
- Vasdev S., Sampson C. A., Prabhakaran V. M. Platelet‐free calcium and vascular calcium uptake in ethanol‐induced hypertensive rats. Hypertension 1991; 18: 116–122
- Metz R., Berger S., Mako M. Potentiation of the plasma insulin response to glucose by prior administration of alcohol. An apparent islet‐priming effect. Diabetes 1969; 18: 517–522
- Altura B. M., Zhang A., Cheng T. P., Altura B. T. Ethanol promotes rapid depletion of intracellular free Mg in cerebral vascular smooth muscle cells: Possible relation to alcohol‐induced behavioral and stroke‐like effects. Alcohol 1993; 10: 563–566
- Ibsen H., Christensen N. J., Rasmussen S., Hollnagel H., Damkjaer Nielsen M., Giese J. The influence of chronic high alcohol intake on blood pressure, plasma noradrenaline concentration and plasma renin concentration. Clin Sci (Lond) 1981; 61(Suppl 7)377s–379s