Alcohol and coronary artery calcification: an investigation using alcohol flushing as an instrumental variable.

Background: We examined whether alcohol flushing could be used as an instrumental variable (IV) and investigated the effect of alcohol consumption on coronary calcification using alcohol flushing status as an IV. Methods: We analysed cross-sectional data from 24 681 Korean adults (20 696 men and 3985 women) who had been administered a questionnaire assessing alcohol consumption and alcohol flushing, as well as a coronary artery calcium (CAC) measurement. The associations of alcohol flushing status with potential confounders and alcohol consumption were examined. We employed two-stage predictor substitution methodology for the IV analysis. Results: The prevalence of alcohol flushing did not differ depending on gender, education, household income, cigarette smoking or physical activity. Balanced levels of confounders were observed between alcohol flushers and non-flushers. Alcohol flushing was closely related to alcohol consumption and levels of liver enzymes. In men, a doubling in alcohol consumption was associated with increased odds of coronary calcification in both the IV analysis [odds ratio (OR) of CAC scores of 1 or over = 1.11; 95% confidence interval (CI) = 1.03-1.20) and the multivariable regression analysis (OR = 1.04; 95% CI = 1.01-1.07). For cardiovascular risk factors, the IV analysis showed a positive association between alcohol consumption and blood pressure and high-density lipoprotein-cholesterol. Conclusions: Alcohol flushing can be used as an IV in studies evaluating the health impact of alcohol consumption, especially in East Asian countries. Through such an analysis, we found that increased alcohol consumption was associated with an increased risk of subclinical coronary atherosclerosis.

[Harlequin syndrome in a melanoderm patient]. / Syndrome d'Arlequin chez un patient mélanoderme.

INTRODUCTION: Harlequin's syndrome is a neurological disorder due to a dysfunction of the sympathetic innervation of the face. It has been rarely reported in the literature. The authors report one case occurring in a melanoderm patient. OBSERVATION: A 38-year-old melanoderm man, without any history of surgery or neck trauma, consulted for a strictly right unilateral facial hyperhidrosis. Clinical and radiological investigations concluded to an idiopathic Harlequin's syndrome. Therapeutic abstention was proposed because of non-invalidating symptoms. DISCUSSION: Harlequin's syndrome is a rare sudoral and vaso-motor disorder. On dark skin, flush and erythrosis may be subtle and the diagnosis less obvious. Etiologies are varied but essentially idiopathic. Its association with others dysautonomic facial syndromes is possible. Main differential diagnosis is the Frey's syndrome. Treatment is not clearly codified.

Flushing response modifies the association of alcohol consumption with markers of glucose metabolism in Japanese men and women.

BACKGROUND: Influences of alcohol use on glucose metabolism may depend on alcohol flushing response. We investigated the effect of alcohol flushing response on the associations between alcohol consumption and markers of glucose metabolism in Japanese men and women. METHODS: The subjects were 979 employees (885 men and 94 women), aged 18 to 69 years, of a manufacturing company in Japan. Flushing response and alcohol consumption were determined using a self-administered questionnaire. Homeostasis model assessment-insulin resistance (HOMA-IR) and homeostasis model assessment for ß-cell function (HOMA-ß) were computed using fasting plasma glucose and insulin. For each group of flushers and nonflushers, multiple regression analysis was used to estimate means of fasting plasma glucose, hemoglobin A1c (HbA1c), and HOMAs for each category of alcohol consumption, with adjustments for potential confounders. RESULTS: In flushers, alcohol consumption was associated with HbA1c levels in a U-shaped manner, with the lowest HbA1c levels being observed at an alcohol consumption level of 23.0 to <34.5 g ethanol/d (p for quadratic trend = 0.002). In nonflushers, alcohol consumption was linearly and inversely associated with HbA1c levels (p for linear trend = 0.001). Decreases in HbA1c were more evident among flushers compared with nonflushers at moderate alcohol consumption levels (p for interaction = 0.049). An increase of fasting glucose associated with highest alcohol consumption was observed in both flushers and nonflushers. A statistically significant decrease in HOMA-IR with increasing alcohol consumption was observed in flushers (p for trend = 0.007), whereas HOMA-IR levels slightly decreased at higher alcohol consumption in nonflushers. HOMA-ß similarly decreased with increasing alcohol consumption in both flushers and nonflushers (both p for trend < 0.001). CONCLUSIONS: The results suggest that the alcohol flushing response may improve glucose metabolism and insulin resistance at moderate alcohol use levels in apparently healthy Japanese adults.

Relationships among alcohol consumption, facial flushing response, and metabolic syndrome in healthy men.

PURPOSE: It is believed that alcohol has an intimate connection with metabolic syndrome (MS). However, the role of facial flushing after alcohol consumption in this relationship has not yet been well known. We explored the relationship between weekly alcohol consumption, risk of MS, and the flushing response. METHODS: The subjects were 1823 Korean adult males (305 nondrinkers, 540 flushers, 978 nonflushers) who had undergone a comprehensive medical check-up at Chungnam National University Hospital. We excluded the cases with the history of hypertension, diabetes, dyslipidemia, or who had taken medication in the previous month. After controlling for age, body mass index, exercise status, and smoking history, we used a logistic regression analysis to calculate the risk of MS with drinks per week in flushers and nonflushers as compared with nondrinkers. RESULTS: The risk of MS in flushers was significantly increased with alcohol consumption >4 drinks (4-16 drinks: odds ratio [OR] 1.93; >16 drinks: OR 2.20). However, in nonflushers, the risk of MS was increased in those consuming >16 drinks (OR 2.02). CONCLUSIONS: Our results suggest that the threshold for MS from alcohol consumption is lower in flushers than in nonflushers.

Influence of drinking alcohol on atherosclerotic risk in alcohol flushers and non-flushers of Oriental patients with type 2 diabetes mellitus.

AIMS: Facial flushing caused by alcohol drinking is a typical symptom of high sensitivity to alcohol in orientals. We investigated whether drinking alcohol influences atherosclerotic risk factors in alcohol flushers and non-flushers in patients with diabetes mellitus. METHODS: A cross-sectional study was performed using 225 subjects with type 2 diabetes. Sensitivity to alcohol was surveyed by a questionnaire on facial flushing. Subjects were divided into three groups by average amount of alcohol drinking (non-drinkers; light drinkers: <140 g/week; heavy drinkers: 140 g/week or more). RESULTS: Systolic blood pressure and blood HDL cholesterol were significantly higher in heavy drinkers than in non-drinkers. There were no significant differences in body mass index, blood pressure, blood total cholesterol, HDL cholesterol, uric acid, fibrinogen and sialic acid levels in flushers and non-flushers. In alcohol flushers, diastolic blood pressure and HDL cholesterol in heavy drinkers were significantly higher than those in non-drinkers, and systolic blood pressure was significantly higher in heavy drinkers than in non-drinkers and light drinkers. On the other hand, blood pressure and HDL cholesterol in non-flushers were not significantly different among non-, light and heavy drinkers. Serum total cholesterol was not significantly different among the three drinking groups both in flushers and non-flushers. CONCLUSIONS: Blood pressure and HDL cholesterol are more prone to be affected by drinking in flushers than in non-flushers, suggesting that alcohol sensitivity evaluated by flushing response due to drinking alcohol should be taken into account when the effects of alcohol drinking on atherosclerotic risk factors are considered in oriental patients with type 2 diabetes mellitus.

Aldehyde dehydrogenase 2 genotypes, alcohol flushing symptoms and drinking patterns in Thai men.

The drinking behavior, alcohol-induced facial flushing and ALDH2 genotypes were determined in 283 Thai men comprising 85 who were alcohol-dependent, 62 hazardous/harmful drinkers and 136 non-drinkers or infrequent drinkers. A structured interview questionnaire, containing the 'tri-level' method and the Alcohol-Use Disorders and Associated Disabilities Schedule, was used to determine the quantity of drinking and the number of alcohol-related adverse experiences. The study revealed the mutant ALDH2*2 allele in 44 (15.5%) subjects. The risks of being alcohol-dependent and of having hazardous/harmful drinking were lower in individuals with heterozygous ALDH2*1/*2, compared with homozygous ALDH2*1/*1 [relative probability ratios (95% CI) 0.14 (0.05-0.41) and 0.23 (0.08-0.61), respectively]. Eighty percent of those who were heterozygous and 28% of those who were homozygous ALDH2*1 reported flush symptoms after drinking alcohol. Twenty-nine percent of homozygous ALDH2*1 individuals, but only 9% of heterozygous subjects, drank almost everyday (24-30 days/month). Similarly, higher percentages of people drinking beyond the safety limit (>60 g/day) and having alcohol-related problems were observed in homozygous ALDH2*1 compared with heterozygous individuals: 32% vs. 5% and 27% vs. 12%, respectively. Overall, the study supports the role of the mutant ALDH2*2 allele in preventing high alcohol consumption and the development of alcohol dependence in a Thai population.

An examination of ALDH2 genotypes, alcohol metabolism and the flushing response in Native Americans.

OBJECTIVE: The study was designed to examine the relationship between aldehyde dehydrogenase (ALDH2) genotype and the flushing response in a population of Native Americans. METHOD: Objective measures of the flushing response were obtained by monitoring skin temperature, heart rate, blood pressure, as well as blood alcohol concentrations, in flushing and nonflushing Native Americans (n = 105) as well as in Oriental (n = 15) and white (n = 15) control subjects following a dose of alcohol (0.2 or 0.4 gm/kg). ALDH genotypes were determined via polymerase chain reaction followed by hybridization to 32P or biotin-labeled allele-specific oligonucleotide probes. RESULTS: There were no ALDH2 mutations detectable in Native Americans reporting the flushing response, nor any objective evidence of an Oriental-like response to alcohol. The rate of alcohol metabolism was shown to be the same among whites, Native flushers and Native nonflushers. CONCLUSIONS: The results demonstrate that the flushing reaction experienced by Native Americans appears to be milder and less unpleasant than the "Oriental" flushing reaction, with little effect on drinking frequency and amount. In addition, the flushing is not mediated by the ALDH2 mutation or elevated blood acetaldehyde. A critical analysis of the discrepancies in the literature regarding alcohol metabolism in Native Americans is provided.

Alcohol flushing, patch test, and ADH and ALDH genotypes in Brazilian ethnic groups.

Self reports of flushing reaction after drinking, cutaneous sensitivity to alcohol (patch test), and genotypic determination of ADH2, ADH3, and ALDH2 were studied in 53 Brazilian volunteers of different ethnic groups. Genotypes were determined using single-strand conformation polymorphism in discontinuous buffer electrophoresis. Analysis of the results indicated several cases of a reported flushing reaction among ALDH2 1/1 individuals, while all but 2 cases of ALDH2 heterozygotes reported a flushing reaction. The latter subjects also had a negative result in the patch test. These preliminary results indicate that variability in the facial flushing reaction to alcohol seems to be a phenomenon resulting not only from the presence of a deficient ALDH2*2 allele, but also from other polymorphisms of alcohol-metabolizing enzymes.

Alcohol flushing, patch test, and ADH and ALDH genotypes in Brazilian ethnic groups

Self reports of flushing reaction after drinking, cutaneous sensitivity to alcohol (patch test), and genotypic determination of ADH2, ADH3, and ALDH2 were studied in 53 Brazilian volunteers of different ethnic groups. Genotypes were determined using single strand conformation polymorphism in discontinous buffer electrophoresis. Analysis of the results indicated several cases of a reported flushing reaction among ALDH2 1/1 individuals, while all but 2 cases of ALDH2 heterozygotes reported a flushing reaction. The latter subjects also had negative result in the patch test. These preliminary results indicate that variability in the facial flushing reaction to alcohol seems to be a phenomenon resulting not only from the presence of a deficient ALDH2*2 allele, but also from other polymorphism of alcohol-metabolizing enzymes

Improved methods for genotype determination at the ALDH2 locus using PCR by introducing the MBOII recognition site or conducting secondary PCR.

Two convenient methods for determining the ALDH2 genotype using PCR were devised. The first method for distinguishing ALDH2(1) and ALDH2(2) alleles was conducted by introducing a single base change into an oligonucleotide primer for PCR, which produced the MboII recognition site for ALDH2(1) but not for ALDH2(2). The second method was conducted with a secondary PCR using allele-specific primers. Both methods have enabled us to easily determine the genotype of the ALDH2 locus without using isotopes. By applying these methods, the genotype of 112 Japanese individuals was determined. The frequency of ALDH2(1) was estimated to be 0.75 and that of ALDH2(2) was to be 0.25.

Cutaneous vasomotor sensitivity to ethanol and acetaldehyde: subtypes of alcohol-flushing response among Chinese.

A cutaneous test has been applied in examination of the flushing response to ethanol and acetaldehyde in 402 Chinese of Han ethnicity. Using this noninvasive method, five response subtypes have been observed: (A) fast flushing to both ethanol and acetaldehyde; (B) fast flushing only to ethanol but not to acetaldehyde; (C) slow flushing to ethanol only; (D) no response either to ethanol or to acetaldehyde; (E) vasoconstriction to ethanol, or to both ethanol and acetaldehyde. A total of 94% in subtype (A) are reported to be flushers, while only 25% was reported in subtype (D). Other physiological responses, such as tachycardia, dizziness, headache, drowsiness, and nausea are less frequent after alcohol ingestion. The recent history of consumption of alcohol of the subjects in different subtypes was also obtained. Although alcohol-induced flushing is thought to be a deterrent factor to heavy consumption of alcohol, the frequency of drinking of alcoholic beverages was not found to be different between flushers and nonflushers.

Genetic or cultural determinants of drinking: a study of embarrassment at facial flushing among Japanese and Japanese-Americans.

Facial flushing after the ingestion of alcohol is common among Asians. Flushers are genetically less able to tolerate alcohol than nonflushers and are less likely to become alcoholics. This study examined whether lower consumption of alcohol among flushers was correlated with cultural factors such as embarrassment over flushing as well as with biological factors among Japanese in Japan and Japanese-Americans using data from a joint Japan-U.S. collaborative survey. Eight hundred forty-six Japanese and 737 Japanese-American current drinkers with known flushing status were studied. The mean alcohol intake differed significantly between groups: (1) habitat--Japanese versus Japanese-Americans, (2) flushing status--flushers versus nonflushers, and (3) embarrassment about flushing. Among men, ethnicity was the major determinant of alcohol consumption, followed by flushing status and embarrassment about flushing. Among women, differences were not significant. Lower alcohol consumption by flushers than by nonflushers has been attributed to differences in physiological reactions to alcohol. However, this study demonstrated that cultural factors such as embarrassment also contribute to lower alcohol consumption by flushers. The lack of interaction between habitat and flushing status and between habitat and embarrassment status suggests that flushing status and embarrassment status associated with drinking levels are independent of habitat.

Familial transmission of alcohol consumption and the flushing response to alcohol in three Oriental groups.

Multivariate path analysis was used to examine the etiologies of variation and covariation of flushing after alcohol use in nuclear families of Korean, Taiwanese, Japanese and Caucasian ancestries. Phenotypic variances and covariances were partitioned into familial (additive genetic and common family environment) and environmental components. Although alcohol consumption and flushing varied greatly among the different groups, familialities, estimated from components of mother, father and at least one child, were remarkably similar. The familialities for flushing were 0.48 for Japanese, 0.56 for Koreans and 0.35 for Taiwanese; flushing is infrequent in Caucasians and thus was not analyzed. Familialities were lower for consumption, but like flushing, were consistent across ethnic groups (Japanese, 0.27; Koreans, 0.24; Taiwanese, 0.15; Caucasians, 0.28). The genetic correlation between flushing and alcohol consumption was high. Thus, to the extent that flushing influences alcohol consumption, the covariance is most likely genetic.