ALDH2 Genotypes Research Articles

Distribution of Alcohol Related ALDH2 Genotypes among Six Ethnic Groups of Nepal

This paper attempts to detect alcohol related ALDH2 genotypes among six ethnic groups of Nepal. The ALDH2*2 allele is rarely found in Caucasians but readily detect in some 50 percent of the Orientals (Mongolians). Altogether 456 blood cum nail samples were collected from six ethnic groups and DNA extraction was carried out by NaI and Phenol-Chloroform methods and finally the samples were subjected to detect the distribution of ALDH2 genotype frequencies by the use of PCR-RFLP method. Allele frequencies were also calculated by the use of Hardy-Weinberg formula for analysis and interpretation. In the case of Nepalese ethnic populations, the ALDH2*2 allele frequency was found to range from the lowest (1%) in the Raute to the highest (8%) in the Gurung through the middle values found in the Chepang (2%) and the Thakali (2.7%), respectively. The prevalence of ALDH2*2 allele in the Dravidian Munda does not rule out its possible genetic admixture with either the Caucasoid or other ethnic groups. ALDH2*2 allele was totally absent in the Caucasoid Chidimar. Therefore, the ALDH2 gene allele frequency demonstrated ethnic distinction. The Chepang showed significant deviation from Hardy-Weinberg expectation.Journal of Institute of Science and Technology, 2014, 19(1): 52-56

Alcohol Dehydrogenase-1B (rs1229984) and Aldehyde Dehydrogenase-2 (rs671) Genotypes Are Strong Determinants of the Serum Triglyceride and Cholesterol Levels of Japanese Alcoholic Men.

BackgroundElevated serum triglyceride (TG) and high-density-lipoprotein cholesterol (HDL-C) levels are common in drinkers. The fast-metabolizing alcohol dehydrogenase-1B encoded by the ADH1B*2 allele (vs. ADH1B*1/*1 genotype) and inactive aldehyde dehydrogenase-2 encoded by the ALDH2*2 allele (vs. ALDH2*1/*1 genotype) modify ethanol metabolism and are prevalent (≈90% and ≈40%, respectively) in East Asians. We attempted to evaluate the associations between the ADH1B and ALDH2 genotypes and lipid levels in alcoholics.MethodsThe population consisted of 1806 Japanese alcoholic men (≥40 years) who had undergone ADH1B and ALDH2 genotyping and whose serum TG, total cholesterol, and HDL-C levels in the fasting state had been measured within 3 days after admission.ResultsHigh serum levels of TG (≥150 mg/dl), HDL-C (>80 mg/dl), and low-density-lipoprotein cholesterol (LDL-C calculated by the Friedewald formula ≥140 mg/dl) were observed in 24.3%, 16.8%, and 15.6%, respectively, of the subjects. Diabetes, cirrhosis, smoking, and body mass index (BMI) affected the serum lipid levels. Multivariate analysis revealed that the presence of the ADH1B*2 allele and the active ALDH2*1/*1 genotype increased the odds ratio (OR; 95% confidence interval) for a high TG level (2.22 [1.67–2.94] and 1.39 [0.99–1.96], respectively), and decreased the OR for a high HDL-C level (0.37 [0.28–0.49] and 0.51 [0.37–0.69], respectively). The presence of the ADH1B*2 allele decreased the OR for a high LDL-C level (0.60 [0.45–0.80]). The ADH1B*2 plus ALDH2*1/*1 combination yielded the highest ORs for high TG levels and lowest OR for a high HDL-C level. The genotype effects were more prominent in relation to the higher levels of TG (≥220 mg/dl) and HDL-C (≥100 mg/dl).ConclusionsThe fast-metabolizing ADH1B and active ALDH2, and especially a combination of the two were strongly associated with higher serum TG levels and lower serum HDL-C levels of alcoholics. The fast-metabolizing ADH1B was associated with lower serum LDL-C levels.

Detection of Single Nucleotide Polymorphism Genotyping by Real-time Polymerase Chain Reaction Coupled with High Specific Invader Assay in Single Tube

Abstract A method was developed for genotyping of single nucleotide polymorphism (SNP) by real-time polymerase chain reaction (PCR) coupled with high specific invader assay. The concentrations of flap endonuclease 1 (FEN1 enzyme) and wild type detection probe were optimized to reduce the background signal. Under the optimal conditions including 1×buffer, 250 μM dNTPs, 0.5 μM each PCR primer, 0.05 μM invasive oligo probe, 0.125 μM wild detection probe, 0.5 μM mutant detection probe, 0.25 μM each fluorescence resonance energy transfer (FRET) probe, 1 U Taq DNA polymerase, 1.5 U FEN1, and approximate 40-200 ng of genomic DNA, the background signals of wild-type sample and mutant-type sample were dramatically decreased and the background interference to the esults was thus eliminated. The reaction program was initial denaturation at 95 °C for 3 min, followed by 10 cycles (95 °C for 20 s, 67 °C for 60 s, 70 °C for 30 s) and 35 cycles (95 °C for 20 s, 63 °C for 60 s, read the fluorescence signal, 70 °C for 30 s). In the experiment, a total of 21 cases of ALDH2*2, 19 cases of CYP2C19*2 and 19 cases of CYP2C19*3 were analyzed by the established method, and the results showed that the genotypes of ALDH2*2 were 10 cases of GG homozygote, 8 cases of GA heterozygote and 3 cases of AA homozygote; the genotypes of CYP2C19*2 were 9 cases of GG homozygote, 8 cases of GA heterozygote and 2 cases of AA homozygote; and the genotypes of CYP2C19*3 were 18 cases of GG homozygote and 1 case of GA heterozygote. These results were consistent with the detection results by pyrosequencing. The established method was specific, simple, short time-consuming and low cost, and could be used for SNP genotyping with no-pollution in single tube.

Associations between ALDH2 and ADH1B Genotypes and Ethanol-Induced Cutaneous Erythema in Young Japanese Women

The purpose of this study was to identify associations between ALDH2 and ADH1B genotypes and ethanol-induced cutaneous erythema and assess the accuracy of an ethanol patch test in young Japanese women. The subjects were 942 female Japanese university students. They were given an ethanol patch test and examined for ethanol-induced cutaneous erythema both immediately after removing the patch and 10 minutes after removing the patch. A saliva sample was used to determine the ALDH2 and ADH1B genotype of each subject by realtime PCR. The sensitivity and specificity of erythema immediately after removing the patch as the marker for the presence of inactive ALDH2 were 69.6% and 87.7%, respectively, and the sensitivity and specificity of erythema 10 minutes after removing the patch were 85.2% and 85.1%, respectively. The sensitivity of erythema after 10 minutes was markedly lower in the ADH1B*1/*1 carriers than in the ADH1B*2 carriers (8.3% vs. 89.7%, p<0.0001), and the specificity was significantly higher in the ADH1B*1/*1 carriers than in the ADH1B*2 carriers (96.9% vs. 84.3%, p<0.05). Overall, both sensitivity and specificity were satisfactorily high, but having the ADH1B*1/*1 genotype prevented a positive reaction for inactive ALDH2 and caused false-negative results. The data also suggested that having the ADH1B*2/*2 genotype caused a positive reaction in subjects with the ALDH2*1/*1 genotype. Despite these exceptions, the ethanol patch test has enough accuracy and can be used easily to subjects who don't drink alcohol. This is a valuable tool for improving the health literacy of younger generation subjects.

Genetic alcohol sensitivity regulated by ALDH2 and ADH1B polymorphisms as indicator of mental disorders in Japanese employees.

Alcohol-related disorders (ARD) have been shown to be accompanied by a variety of other comorbid mental disorders. This study evaluated the associations between a variety of mental disorders and genetic alcohol sensitivity. A total of 1944 Japanese workers were interviewed regarding their mental disorders by the Mini-International Neuropsychiatric Interview (M.I.N.I.). We investigated the relationship of ADH1B rs1229984 and ALDH2 rs671 polymorphisms' combination with mental disorder risks. Logistic regression analysis was used to evaluate the associations between those polymorphisms and mental disorders, adjusting for sex, age, and job rank. The degree of alcohol sensitivity was classified into five groups according to the combination of ADH1B and ALDH2 genotypes (Group I-V in order starting from the lowest alcohol sensitivity). Those with ALDH2 *1/*1 and ADH1B *1/*1 or with ALDH2 *1/*1 and ADH1B *1/*2,*2/*2 (low sensitivity) were significantly or nearly significantly associated with an increased risk of ARD compared with those with ALDH2 *1/*2 and ADH1B *1/*2,*2/*2 as a reference. Those with ALDH2 *1/*1 and ADH1B *1/*1 were also likely to be at an increased risk of any mental disorder except ARD, as well as disorders without comorbid ARD. This tendency was more apparent among women (OR 11.94, 95% CI 0.73-195.63) and non-drinkers (OR 5.43, 95% CI 1.05-28.23). The genotype combination of ALDH2 *1/*1 and ADH1B *1/*1 is significantly associated with an increased risk of any mental disorder, especially ARD. Non-drinkers or women with ALDH2 *1/*1 and ADH1B *1/*1 are likely to suffer from any mental disorder except ARD.

Screening of susceptibility genes and multi-gene risk analysis in gastric cancer.

The aim of the study was to explore the relations between the genetic polymorphism and the susceptibility to the gastric cancer in Chinese Han population, and to analyze the multi-genes risk in the development of gastric carcinoma. A case-control study of 1:1 matching was performed on 564 individuals with primary gastric carcinoma in Nanjing, China. The genotypes of CYP2E1, GSTMl, GSTTl, NAT2, ALDH2, MTHFR, XRCCl, IL-1β, VDR, and TNF were detected by molecular biological techniques (PCR-RFLP and AS-PCR). Sole gene and gene-gene interactions were analyzed using Logistic regression model. The effect of multi-genes on gastric carcinoma was analyzed using multi-gene risk analysis model, which focused on the effect of multi-gene interaction on the development of gastric carcinoma. The genotypes involved in the susceptibility of gastric carcinoma were CYP2E1(c1/c1), NAT2M1(T/T), NAT2M2(A/A), XRCC1194(T/T), NAT2 phenotype (slow acetylator), MTHFR1298(A/C), and VDR TaqI(T/T), respectively. Multi-gene risk analysis model was introduced to analyze the effect of these genes on the gastric carcinoma. The results showed that there was a strong relation between odds ratio (OR) value of polygene combination and the gene frequency. With the increase of susceptibility gene frequency, the risk distribution curve of gastric carcinoma would shift to a more dangerous phase and exhibit a quantitative relation. Our results demonstrated that the OR of each gene can be utilized as an index to assess the effect of multiple susceptible genes on the occurrence of gastric carcinoma.

P-24 * GENE-GENE INTERACTION OF ALCOHOL METABOLIZING HEPATIC ENZYME GENE AND MU-OPIOID RECEPTOR GENE IN KOREAN PATIENTS WITH ALCOHOL DEPENDENCE

Introduction. Many previous studies tried to find etiologic genes of alcohol dependence. Among these genes, alcohol metabolizing hepatic enzyme genes (ADH2 and ALDH2) and mu-opioid receptor gene (OPRM1) have become a great interest recently. Accordingly, our purpose is to investigate gene-gene interaction of alcohol metabolizing hepatic enzyme gene and mu-opioid receptor gene in the Korean male and female patients with alcohol dependence. Methods. The subjects were 241 male alcohol-dependent patients, 60 female alcohol-dependent patients, 79 male normal controls, and 59 female normal controls. The frequencies of the ADH2 (1/1 and 2+), ALDH2 (1/1 and 2+), and OPRM1 All8G (A/A and G+) genotypes were investigated in male and female alcohol-dependent patients and the normal control group. Results. In female alcohol-dependent patients, who has ADH2 1/1 genotype, OPRM1 G+ genotype frequencies were significantly higher than the female normal control group. Furthermore, OPRM1 G+ genotype frequencies were significantly higher in the female alcohol-dependent patients who have ALDH2 2+ genotype, compared to the female normal control group. Conclusion. G+ genotype frequency in OPRM1 was higher only in female alcoholics, who had low activity of ADH2 or ALDH2. These results suggest that the cause of drinking in women is strongly related to inducing reward.

Effect of the allelic variant of alcohol dehydrogenase ADH1B*2 on ethanol metabolism.

It has been known that ADH1B*2 allele has a protective effect against the development of alcohol dependence. However, the protection mechanism is still unknown. We investigated whether ADH1B gene polymorphism affects ethanol (EtOH) metabolism. In a parent study, we conducted a randomized crossover trials on 24 healthy male subjects who were selected by genotyping: 12 with ALDH2*1/*1 (active form) and 12 with ALDH2*1/*2 (inactive form). In the present study, the 24 subjects were reclassified into 2 groups of 11 with ADH1B*1/*2 and 13 with ADH1B*2/*2 according to the ADH1B genotypes. Each subject was administered 1 of 3 doses of EtOH (0.25, 0.5, 0.75 g/kg) or a placebo in 4 trials. After the administration of alcohol, blood EtOH and acetaldehyde concentrations were measured 9 times over 4 hours. In the case of EtOH, the area under the concentration-time curve from 0 to 4 hours (AUC0-4 ) and the peak blood concentration of EtOH (Cmax ) in subjects with ADH1B*2/*2 were significantly higher than those in subjects with ADH1B*1/*2 at all 3 dosages before stratifying by ALDH2 genotype. However, after stratifying by ALDH2 genotype, a statistically significant difference between ADH1B*2/*2 and ADH1B*1/*2 was found only at the 0.5 g/kg dosage regardless of ALDH2 genotype. In the case of acetaldehyde, the AUC0-4 and Cmax of acetaldehyde of ADH1B*2/*2 after administration of 0.25 g/kg alcohol and the AUC0-4 of acetaldehyde of ADH1B*2/*2 at 0.5 g/kg were significantly higher than corresponding values of ADH1B*1/*2 only in the group of ALDH2*1/*2. Our findings indicate that the blood EtOH concentrations of ADH1B*2/*2 group are higher than those of ADH1B*1/*2 group regardless of ALDH2 genotype, and the blood acetaldehyde concentrations of ADH1B*2/*2 are also higher than those of ADH1B*1/*2 only in the ALDH2*1/*2 group. To our knowledge, this is the first report to demonstrate the association of ADH1B*2 allele with blood EtOH and acetaldehyde levels in humans, and these results suggest that higher blood EtOH and acetaldehyde concentrations in ADH1B*2/*2 may constitute the mechanism of protection against alcoholism by ADH1B*2/*2.

The interplay between alcohol consumption, oral hygiene, ALDH2 and ADH1B in the risk of head and neck cancer

Alcohol consumption is an established risk factor for head and neck cancer (HNC). The major carcinogen from alcohol is acetaldehyde, which may be produced by humans or by oral microorganisms through the metabolism of ethanol. To account for the different sources of acetaldehyde production, the current study examined the interplay between alcohol consumption, oral hygiene (as a proxy measure for the growth of oral microorganisms), and alcohol-metabolizing genes (ADH1B and ALDH2) in the risk of HNC. We found that both the fast (*2/*2) and the slow (*1/*1+ *1/*2) ADH1B genotypes increased the risk of HNC due to alcohol consumption, and this association differed according to the slow/non-functional ALDH2 genotypes (*1/*2+ *2/*2) or poor oral hygiene. In persons with the fast ADH1B genotype, the HNC risk associated with alcohol drinking was increased for those with the slow/non-functional ALDH2 genotypes. For those with the slow ADH1B genotypes, oral hygiene appeared to play an important role; the highest magnitude of an increased HNC risk in alcohol drinkers occurred among those with the worst oral hygiene. This is the first study to show that the association between alcohol drinking and HNC risk may be modified by the interplay between genetic polymorphisms of ADH1B and ALDH2 and oral hygiene. Although it is important to promote abstinence from or reduction of alcohol drinking to decrease the occurrence of HNC, improving oral hygiene practices may provide additional benefit.

Effects of ALDH2∗2 on alcohol problem trajectories of Asian American college students.

The variant aldehyde dehydrogenase allele, ALDH2∗2, consistently has been associated with protection against alcohol dependence, but the mechanism underlying this process is not known. This study examined growth trajectories of alcohol consumption (frequency, average quantity, binge drinking, maximum drinks) and problems over the college years and then tested whether the ALDH2 genotype mediated or moderated the relationship between alcohol consumption and problems. Asian American college students (N = 433) reported on their drinking behavior in their first year of college and then annually for 3 consecutive years. Alcohol consumption and problems increased over the college years for both those with and without ALDH2∗2, but having an ALDH2∗2 allele was associated with less of an increase in problems over time. A mediation model was supported, with ALDH2∗2 group differences in problems fully accounted for by differences in frequency of binge drinking. Findings also supported a moderation hypothesis: All four alcohol consumption variables were significant predictors of subsequent alcohol problems, but these relationships were not as strong in those with ALDH2∗2 as in those without ALDH2∗2. Our findings suggest that the interplay between ALDH2∗2 and drinking-related problems is complex, involving both mediation and moderation processes that reduce the likelihood of developing problems via reduction of heavy drinking as well as by altering the relationship between alcohol consumption and problems. Results of this longitudinal study provide evidence that what seems like a relatively straightforward effect of a diminished ability to metabolize alcohol on drinking behavior is actually dependent on behavior and developmental stage.

EPA-0382 – Genetic alcohol sensitivity as an indicator of mental disorders

Objective To evaluate the association between genetic alcohol sensitivity ( ADH1B and ALDH2 polymorphisms) and mental disorders. Method A total of 1945 prefectural civil servants were screened and interviewed regarding their mental disorders by the Mini-International Neuropsychiatric Interview. The mental disorders include major depressive disorder, dysthymia, suicidal risk, manic episode, panic disorder, agora phobia, social phobia, specific phobia, obsessive-compulsive disorder, general anxiety disorder, alcohol dependence/abuse, substance dependence/abuse, anorexia nervosa, anorexia bulimia, and PTSD. Genomic DNA was extracted from blood samples. TaqMan? SNP genotyping assays were used for the following (gene, SNP, assay ID): ADH1B , rs1229984, C_2688467_20; ALDH2 , rs671, C_11703892_10. Logistic regression analysis was used to evaluate those genetic polymorphisms and mental disorders adjusting for sex, age, and job rank. Results Alcohol sensitivity was genetically classified into five domains according to the combination of ADH1B and ALDH2 genotypes (type A, B, C, D and E). Preliminary analysis using 497 samples showed that low alcohol sensitivity (type A and B combined) was significantly associated with alcohol dependence/abuse (OR 2.71, 95% CI 1.44-5.10) compared to high sensitivity (type C, D, and E combined). Low alcohol sensitivity also showed non-significant modest association with any mental disorders except alcohol-related disorders (OR 1.99, 95% CI 0.72-5.48). Conclusions Low alcohol sensitivity might be associated with mental disorders, especially with alcohol-related disorders. Since the analysis has not been finished yet, the complete results will be shown in the congress.

Blood Ethanol Levels of Nonabstinent Japanese Alcoholic Men in the Morning After Drinking and Their ADH1B and ALDH2 Genotypes

Genetic polymorphisms of alcohol dehydrogenase-1B (ADH1B, rs1229984) and aldehyde dehydrogenase-2 (ALDH2, rs671) affect ethanol (EtOH) metabolism and susceptibility to alcoholism. We evaluated associations between ADH1B/ALDH2 genotypes and the blood EtOH levels of 805 Japanese alcoholic men in the morning after they had drunk within the previous 34 h. Age-adjusted usual alcohol consumption did not differ according to ADH1B/ALDH2 genotypes. Higher blood EtOH levels persisted for longer periods in the ADH1B*1/*1 carriers (n = 246) than in the ADH1B*2 carriers (n = 559). Blood EtOH levels did not differ by ALDH2 genotype. The blood EtOH levels ≥ 0.3 mg/ml (criterion for drunk driving in Japanese law) were observed (40% vs. 14-17%, P < 0.0001) in a higher proportion of the ADH1B*1/*1 carriers than of the ADH1B*2 carriers after a 12.1-to-18-h interval since the last drink. Multivariate analyses showed that the EtOH levels heightened by 0.500 mg/ml in the presence of ADH1B*1*1 and by 0.248 mg/ml in the presence of cirrhosis, and lowered by 0.120 mg/ml per 10-year age increase, by 0.087 mg/ml per 10-kg body-weight increase and by 0.673 mg/ml per 10-h interval since the last drink. The odds ratio (95% confidence interval) for an EtOH level ≥ 0.3 mg/ml was 3.44 (2.34-5.04) in the presence of ADH1B*1/*1, 2.01 (1.28-3.14) in the presence of cirrhosis, 0.59 (0.49-0.71) per 10-year age increase, 0.80 (0.68-0.95) per 10-kg body-weight increase and 0.10 (0.07-0.15) per 10-h interval since the last drink. The longer-than-expected EtOH lingering in the blood of the ADH1B*1/*1 alcoholics may exacerbate alcohol-related problems, including drunk driving.

Telomere Shortening in the Esophagus of Japanese Alcoholics: Relationships with Chromoendoscopic Findings, ALDH2 and ADH1B Genotypes and Smoking History

Chromoendoscopy with Lugol iodine staining provides important information on the development of squamous cell carcinoma (SCC). In particular, distinct iodine-unstained lesions (DIULs) larger than 10 mm show a high prevalence in high-grade intraepithelial neoplasia. It has also been reported that inactive ALDH2*1/*2 and less-active ADH1B*1/*1, and smoking, are risk factors for esophageal SCC. We previously examined telomere shortening in the esophageal epithelium of alcoholics, and suggested a high prevalence of chromosomal instability in such individuals. In the present study, we attempted to analyze telomere lengths in 52 DIULs with reference to both their size and multiplicity, ALDH2 and ADH1B genotypes, and smoking history. Patients with DIULs <10 mm (n = 42) had significantly longer telomeres than those with DIULs ≥10 mm (n = 10, p = 0.008). No significant differences in telomere length were recognized between the ALDH2 and ADH1B genotypes (ALDH2 active/inactive = 35/17, ADH1B active/inactive = 32/20; p = 0.563, 0.784, respectively) or among four groups of patients divided according to smoking history (never-, ex-, light, and heavy smokers = 3, 6, 21, and 22 patients, respectively; p = 0.956). Patients without multiple DIULs (n = 17) had significantly longer telomeres than patients with multiple DIULs (n = 35, p = 0.040). It is suggested that alcoholism reduces telomere length in the esophagus, irrespective of genotype or smoking habit. Telomere shortening may not generate cancer directly, but may create conditions under which SCC can develop more easily, depending on subsequent exposure to carcinogens.

Effect of alcohol and aldehyde dehydrogenase gene polymorphisms on alcohol-associated hypertension: the Guangzhou Biobank Cohort Study

The effects of alcohol dehydrogenase (ADH) 2 and aldehyde dehydrogenase (ALDH) 2 genotypes on the alcohol–blood pressure association are unclear. We examined the association of ADH2 or ALDH2 genotypes with blood pressure in older Chinese men. Based on the Guangzhou Biobank Cohort Study (GBCS), 4792 men with valid ADH2, ALDH2 genotypes were included, and genotyping of rs1229984 ADH2 and rs671 ALDH2 (AA, AG/GA or GG) was performed using a Sequenom Mass-Array platform. Information on socio-demographics and lifestyle factors, including alcohol use, was obtained from a questionnaire, and blood pressure was measured. Among alcohol drinkers, systolic and diastolic blood pressure (SBP and DBP) and mean arterial pressure (MAP) were highest for men with the GG ADH2 genotype (136.6, 77.9 and 97.5 mm Hg, respectively), followed by those with the (AA/AG ADH2+GG ALDH2) genotype (133.4, 77.6 and 96.2 mm Hg, respectively) and then the (AA/AG ADH2+AA/AG ALDH2) genotype (SBP=132.6, DBP=76.6 and MAP=95.2 mm Hg) (P for trend ranged 0.025–0.035). After adjustment for potential confounders, as well as frequency or amount of alcohol use, men with the GG ADH2 genotype were more likely to have hypertension (odds ratio (OR)=1.62, 95% confidence interval 1.15–2.28) as were men with the (AA/AG ADH2+AA/AG ALDH2) genotype (OR=1.40, 95% confidence interval 1.01–1.96) compared with men with the (AA/AG ADH2+GG ALDH2) genotype). ADH2 or ALDH2 genotypes were unrelated to hypertension among those who never drink alcohol. ADH2 genotype influences blood pressure and risk of hypertension among male alcohol drinkers, suggesting that the hypertensive effect of alcohol is due to ethanol rather than acetaldehyde.

Association of the ALDH1A1*2 Promoter Polymorphism With Alcohol Phenotypes in Young Adults With or Without ALDH2*2

Prior studies suggest a possible association of a promoter polymorphism in the ALDH1A1 gene ( ALDH1A1*2 ) with alcohol use or dependence. The aim of this study was to examine the association of ALDH1A1*2 with drinking behaviors in Asian young adults and to examine ALDH2 genotype as a potential moderator of these associations. Asian young adults (n = 951) were recruited from 2 college sites for studies of genetic associations with alcohol use behavior. Participants completed comprehensive background questionnaires on demographics and drinking behavior. Fingertip blood samples were obtained for DNA extraction and analysis. Participants with the ALDH2*1/*2 genotype reported significantly lower levels (frequency and quantity) of drinking within the last 90 days, fewer numbers of heavy drinking episodes within the last 90 days, and lower lifetime maximum consumption levels compared with ALDH2*1/*1 participants. There were no significant main effects of ALDH1A1*2 on any drinking variables, nor was there a significant interaction between ALDH2 and ALDH1A1 genotypes on drinking outcomes. The association of ALDH2*2 with reduced alcohol consumption replicates previous findings across numerous studies. Although ALDH1A1*2 was not associated with drinking levels, the lack of an ALDH1A1*2 effect in ALDH2*2 individuals is consistent with the only other study that has examined these associations in East Asian populations.

874 Is Idiopathic Pancreatitis (Acute, Recurrent Acute and Chronic) in Children Genetically Predisposed?

ism of them is also relevant to pancreatic steatosis in alcoholics. Objective: to find out the possible genetic background of alcohol-induced pancreatic steatosis in alcoholics by analyzing genetic polymorphism in ADH2 and ALDH2. Methods: 163 alcoholic male aged 20~70 years with a normal body mass index were recruited into this study. The alcoholics were defined as the drinkers with an alcohol intake of >80g/day, a duration of >5 years, and abstinence from alcohol within 2 years. They received magnetic resonance scanning in the epigastric region by using double-echo chemical shift magnetic resonance technique. PCRrestriction fragment length polymorphism was used for ADH2 and ALDH2 genotype detection. The drinkers with pancreatic fat content higher than 4.2%, 8.0% in alcoholics younger and older than 50 years respectively were diagnosed as alcohol-induced pancreatic steatosis. This study was approved by the Chinese Clinical Trial Registry Clinical Trial Ethics Committee (registration number:ChiCTR-CCH-00000147) and the Ethics Committee of West China Hospital of Sichuan University. And it conformed to the principles of the Declaration of Helsinki of the World Medical Association. Informed consent was obtained from each participant before enrollment. Results: The distribution of the different ADH2 and ALDH2 genotypes among the 163 alocholics closely conformed to expected Hardy-Weinberg frequencies (p>0.05). In drinkers, compared with ADH2*2/*2 carriers, ADH2*1/*1 carriers showed a significantly elevated risk of developing pancreatic steatosis ( 50 years, OR=5.34). No association was found between ALDH2 genotypes and risk of pancreatic steatosis. Conclusion: In drinkers, ADH2*l/*1 carriers had a significantly higher risk to develop alcohol-induced pancreatic steatosis. ADH2*1/*1 genotypemay be related to alcoholinduced pancreatic steatosis.

The acute effects of ethanol and acetaldehyde on physiological responses after ethanol ingestion in young healthy men with different ALDH2 genotypes

Background. This study investigated the acute effects of ethanol and acetaldehyde on physiological responses in healthy men according to ALDH2 genotype by measuring them directly in human blood. Methods. Twenty-four men, 12 with the ALDH2*1/*1 genotype and 12 with the ALDH2*1/*2 genotype, were selected. In a double-blind placebo-controlled crossover design, each subject was administered one of three doses of ethanol (0.25, 0.5 or 0.75 g/kg) or a placebo on four separate occasions. The blood ethanol concentration (BEC), blood acetaldehyde concentration (BAAC) and physiological responses including facial redness, pulse rate and systolic and diastolic blood pressures were assessed. Results. Significant differences were observed in the physiological responses between the ALDH2*1/*2 and ALDH2*1/*1 groups. Significant gene effects were observed for pulse rate and facial flushing (F-values = 62.344; p values < 0.001 and F-values = 7.062; p values = 0.010, respectively, by repeated-measures analysis of variance), which were significantly greater in subjects with the ALDH2*1/*2 genotype. In a linear regression analysis, BAAC significantly predicted increased facial redness at 30 minutes (adjusted R: 0.209; p values < 0.001) and pulse rate at 30, 60, 90 and 120 minutes (adjusted R: 0.454, 0.490, 0.428 and 0.193, respectively; all p values < 0.001), whereas BEC was not associated with any physiological response measure at any time. Conclusions. Facial redness and pulse rate after ethanol ingestion were significantly higher in the ALDH2*1/*2 genotype, and were significantly associated with blood acetaldehyde concentrations. The acute effects of ethanol on the physiological responses were mediated mainly by acetaldehyde, the active metabolite of ethanol, rather than by ethanol itself.

Breath Alcohol Elimination Rate and Widmark Factor Derived from Breath Alcohol Concentration in Chinese and Indians in Singapore

To determine the breath alcohol elimination rate (AER) and Widmark factor derived from the maximum breath alcohol concentration (r(peak BrAC)) in Chinese and Indians in Singapore, and to evaluate the contribution of genetic and non-genetic factors to variability of AER and r(peak BrAC). A total of 180 subjects ingested a vodka-orange juice mixture, together with a standardized meal and underwent a series of BrAC measurements. Significant inter-ethnic differences in AER and r(peak BrAC) were observed in females and males, respectively. Alcohol dehydrogenase 1B (ADH1B) and acetaldehyde dehydrogenase (ALDH2) genotypes were identified as significant predictors for AER among males, accounting for 8.5% (P = 0.048) and 23.4% (P < 0.001) of the variance, respectively. ADH1B genotype was identified as a significant predictor for r(peak BrAC) among males, accounting for 17.1% of the variance (P = 0.001). In females, however, none of the genotypes were found to be significant predictors for breath AER, and r(peak BrAC). ALDH2 and/or ADH1B genotypes in males, but not in females, appear to contribute, albeit modestly, to variability in AER and r(peak BrAC). The median AER in Chinese males, Indian males, Chinese females and Indian females is 6.6 μg dl(-1) h(-1) [99% confidence interval (CI), 5.6-7.5 μg dl(-1) h(-1)], 6.2 μg dl(-1) h(-1) (99% CI, 5.5-7.0 μg dl(-1) h(-1)), 8.6 μg dl(-1) h(-1) (99% CI, 7.4-9.7 μg dl(-1) h(-1)) and 7.4 μg dl(-1 )h(-1) (99% CI, 6.2-8.4 μg dl(-1) h(-1)), respectively. The median r(peak BrAC) in Chinese males, Indian males, Chinese females and Indian females is 0.0229 (99% CI, 0.0216-0.0268), 0.0209 (99% CI, 0.0190-0.0237), 0.0214 (99% CI, 0.0185-0.0254) and 0.0199 (99% CI, 0.0187-0.0227), respectively.

Abstract 8093: Inorganic Nitrite Induces Second-Window Preconditioning in Healthy Volunteers

Background Inorganic nitrite has been shown to induce preconditioning in a variety of animal and tissue models. Work from our group has shown that nitrite can induce periconditioning in a human model of ischemia-reperfusion injury, which is influenced by ALDH2 genotype. We investigated whether systemic inorganic nitrite infusion, given 24 hours before the onset of ischemia, protects human forearm endothelium from ischemia-reperfusion injury in unselected healthy volunteers. Methods 12 healthy volunteers were randomised to 2 groups. Inorganic nitrite or saline placebo was given intravenously at a dose of 1 mcg/kg/min for 10 minutes, 24 hours before the onset of studies. Venous occlusion plethysmography, using escalating doses of intra-arterial acetylcholine, was used to measure forearm endothelial function before and 15 minutes after 20 minutes of total forearm ischemia. Results Ischemia-reperfusion injury caused significant endothelial dysfunction in those that had received a placebo infusion (n=5, p&lt;0.05). Conversely, the group that received systemic nitrite 24 hours before study were protected from IR injury (p=0.78 for a difference pre- and post-ischemia). Discussion This study shows, for the first time in man, that a simple cost-effective intervention has potential to prevent injury in situations where significant ischemia-reperfusion injury is predictable, such as in cardiac surgery. More speculatively, this mechanism may be involved in the health benefits of a diet containing nitrite-rich green leafy vegetables. This result invites further study in the form of clinical trials.

An association study between polymorphism of alcohol dehydrogenase (ADH1B), aldehyde dehydrogenase (ALDH2), cytochrome (CYP4502E1), Catechol-O- Methyltransferase (COMT) and 5-hydroxytryptamine transporter (5-HTT) genes in Yunnan Han population with alcohol dependence

Alcohol dependence (AD) is a complex disease resulting from the inheritance of several susceptible genes and multiple environmental determinants. The aim of thisstudy was to identify the genetic risk factors which include alcohol metabolizing genes and neurotransmitter related genes for alcoholism in Yunnan Han population. Eight allelic variants of five genes were genotyped from 332 Yunnan Han individuals (including 118 alcohol-dependent patients (DSM-IV criteria) and 214 controls) using PCR-RFLP method. Those polymorphic sites included alcohol dehydrogenase (ADH1B), aldehyde dehydrogenase (ALDH2), cytochrome P-4502E1 (CYP2E1) PstI, Catechol-O-Methyltransferase (COMT) rs2075507 (5’region), rs737865 (intron1), rs4680 (Val158Met), rs165599 (3’region) and serotonin transporter (5-HTTLPR). Both genotype and allele frequencies of ALDH2 and CYP4502E1 as well as the allele frequency of ADH1B gene differed significantly between AD group and control group. The proportion of ALDH2 *1/*2 genotype and *2 allele was significantly smaller in patients than that in controls (χ2 = 6.554, p = 0.038; χ2 = 4.906, p = 0.027), while the proportion of c2 allele of CYP4502E1 was significantly higher (χ2 = 4.410, p = 0.036). Compared with the controls, the frequencies of the 5-HTTLPR L/L genotype and COMT rs737865 C/C genotype were significantly lower in AD group. Twelve COMT haplotypes (rs2075507, rs737865, rs4680 and rs165599) defined as H1 to H12 were obtained in this major minority population. The prevalence of the haplotype H1 ‘‘A-C-A-A’’ was significantly greater in alcoholics than the prevalence in their respective control group. There were no significant differences in the genotype frequencies of the COMT rs2075507, rs4680 and rs165599 polymorphisms between alcoholics and controls. COMT rs2075507 and rs737865 polymorphisms were in complete linkage disequilibrium in Han population of Yunnan Province. This study indicates that polymorphisms of ADH1B, ALDH2, CYP4502E1, COMT and 5-HTT were significantly associated with AD in Han majority. The ADH1B *2, ALDH2 *2 alleles, 5-HTTLPR L/L genotype and C/C genotype of the COMT rs737865 polymorphism had an important role in reducing the risk of AD while the c2 allele of CYP4502E1 increased the risk of AD. Therefore, the A-C-A-A haplotype may be a dangerous factor leading to AD. Key words: Yunnan Han population, polymorphism, alcohol dependence, genetic risk factor.