Screening for acetaldehyde dehydrogenase 2 genotype in alcohol-induced asthma by using the ethanol patch test

To identify the pharmacological effectiveness of cyanamide, 144 alcoholics treated with cyanamide were subjected to a test that used an acetaldehyde dehydrogenase (ALDH) inhibitor, the ethanol patch test, which is considered to be a good indicator of ALDH2 phenotype. We placed 100 microl of 70% ethanol on a lint pad and, as a control, placed the same volume of distilled water on a second pad. The ethanol patch test was performed on 144 alcoholics more than 2 weeks after abstinence from alcohol before and after treatment with cyanamide for 1 week. The dose of cyanamide was increased up to 150 mg until the patch test yielded a positive result. In the ethanol patch test, 36 alcoholics (25.0%) gave a positive result before treatment with cyanamide and might have been ALDH2(1)/2(2) heterozygotes. Among 108 alcoholics who were not positive, the distribution of the cyanamide dose that yielded a positive ethanol patch test result was 30 mg in 42 cases (38.9%), 50 mg in 33 cases (30.6%), 70 mg in 5 cases (4.6%), 100 mg in 6 cases (5.6%), and 150 mg in 2 cases (1.9%). Prevalence of liver cirrhosis was significantly higher in alcoholics who showed a positive ethanol patch test result at doses of less than 50 mg cyanamide than those at doses more than 70 mg (p = 0.029). The prevalence of adverse effects was significantly higher in alcoholics who showed a positive ethanol patch test result at doses of more than 70 mg than at doses of less than 50 mg cyanamide (p = 0.002). The ethanol patch test is a useful method for identifying pharmacological effectiveness of cyanamide and may reduce the prevalence of side effects in cyanamide-treated alcoholics.

High/low alcohol tolerance is determined by genetic polymorphisms of ADH2 and ALDH2. Currently, operators conduct ethanol patch testing for assessment of alcohol tolerance in a subjective manner; therefore, the test results may vary among individuals. The present study was designed to verify the reliability of ethanol patch testing, with a focus on changes in skin color due to seasons. Two operators were assigned to perform ethanol patch tests, and alcohol-related genetic polymorphisms were evaluated to verify the results. The study included 129 healthy students from Utsunomiya University (age range: 21-24 years). These students were selected because they met the eligibility criteria for the study (all necessary information had to be available, i.e. results for all questionnaire items and patch tests, as well as genetic analysis). Alcohol-related genes tested in this study were ADH2 and ALDH2. During the ethanol patch tests, two operators examined the subjects' cutaneous reactions immediately after lint pad had been removed from their skin, and at 10 min after removal. Ethanol patch test to the subjects was performed twice: once in summer and once in winter. We also administered a questionnaire to assess the students' views on alcohol and drinking habits. According to the cutaneous reactions examined at 10 min, there was significant concordance between the results of ethanol patch tests and ALDH2 genetic polymorphisms. The results of the patch tests performed by the 2 operators (A and B) in summer showed that the concordance rate between the operators was 93.8% (κ coefficient: 0.889; 95% confidence interval: 0.815-0.962, p<0.001) for the cutaneous reactions at 10 min after lint pad removal. Moreover, the same operator's data showed that the concordance rate between the results of the summer and winter patch tests was 70% or higher. These findings suggest that ethanol patch testing is a reliable assay of alcohol tolerance, although the results may be influenced by seasons and individual operator subjectivity. Therefore, during ethanol patch tests, it is important to take into account test conditions such as the time of year and skin color, and to evaluate the results comprehensively.

Alpha-Lipoic Acid Protects Against Pressure Overload-induced Heart Failure &lt;i&gt;via&lt;/i&gt; ALDH2-Dependent Nrf1-FUNDC1 Signaling

Acetaldehyde dehydrogenase 2 deficiency exacerbates cardiac fibrosis by promoting mobilization and homing of bone marrow fibroblast progenitor cells

Antisocial alcoholism is related to dopamine and serotonin which are catalyzed by monoamine oxidase A (MAOA) and acetaldehyde dehydrogenase 2 (ALDH2). The objective of this study is to determine whether the interaction between the MAOA and the ALDH2 genes is associated with subjects with antisocial personality disorder (ASPD) having alcoholism. A total of 294 Han Chinese men in Taiwan including 132 ASPD with alcoholism (Antisocial ALC) and 162 without alcoholism (Antisocial Non-ALC) were recruited in this study. Alcohol dependence and ASPD were diagnosed according to DSM-IV criteria. Genotypes of ALDH2 and MAOA-uVNTR were determined using PCR-RFLP. A significant difference of ALDH2 polymorphisms (p = 3.39E-05), but not of MAOA, was found among the 2 study groups. However, only after the stratification of the MAOA-uVNTR (variable number of tandem repeat located upstream) 3-repeat, a significant association between Antisocial Non-ALC and ALDH2*1/*2 or *2/*2 genotypes was shown (p = 1.46E-05; odds ratio = 3.913); whereas stratification of MAOA-uVNTR 4-repeat revealed no association. Multiple logistic regression analysis further revealed significant interaction of MAOA and ALDH2 gene in antisocial ALC (odds ratio = 2.927; p = 0.032). The possible interaction of MAOA and ALDH2 gene is associated with Antisocial ALC in Han Chinese males in Taiwan. However, the protective effects of the ALDH2*2 allele against alcoholism might disappear in subjects with ASPD and carrying MAOA-uVNTR 4-repeat allele in the Han Chinese male population.

Fluoropyrimidine-based chemotherapy is extensively used for the treatment of solid cancers, including colorectal cancer. However, fluoropyrimidine-driven toxicities are a major problem in the management of the disease. The grade and type of the toxicities depend on demographic factors, but substantial inter-individual variation in fluoropyrimidine-related toxicity is partly explained by genetic factors. The aim of this study was to investigate the effect of dihydropyrimidine dehydrogenase (DPYD), thymidylate synthase (TYMS), and methylenetetrahydrofolate reductase (MTHFR) polymorphisms in colorectal cancer patients. Eighty-five patients who were administered fluoropyrimidine-based treatment were included in the study. The DPYD, TYMS and MTHFR polymorphisms were scanned by a next generation Sequenom MassARRAY. Fluoropyrimidine toxicities were observed in 92% of all patients. The following polymorphisms were detected: DPYD 85T>C (29.4% heterozygote mutants, 7.1% homozygote mutants), DPYD IVS 14+1G>A (1.2% heterozygote mutants), TYMS 1494del TTAAAG (38.4% heterozygote mutants, 24.7% homozygote mutants), MTHFR 677C>T (43.5% heterozygote mutants, 9.4% homozygote mutants) and MTHFR 1298A>C (8.2% heterozygote mutants, 2.4% homozygote mutants). A statistically significant association was demonstrated between MTHFR 677C>T and fluoropyrimidine-related toxicity (p value = 0.007). Furthermore, MTHFR 1298A>C was associated with hematopoietic toxicity (p value = 0.008). MTHFR polymorphisms may be considered as related factors of fluoropyrimidine toxicity and may be useful as predictive biomarkers for the determination of the colorectal cancer patients who can receive the greatest benefit from fluoropyrimidine-based treatments.

In Japan there are many people who are intolerant to alcohol. Known as flushers, they do not genetically have low Km acetaldehyde dehydrogenase (AlDH2). Flushers are judged easily and accurately by the alcohol patch test. An ethanol patch test carried out on agricultural and fishing populations in Japan showed that approx. 40% were deficient in AlDH2. A questionnaire survey of the drinking behavior of many people showed significant differences between the normal AlDH2 and AlDH2-deficient groups. The normal group drinks positively and actively, while the deficient group drinks negatively and passively. As a result, there were significant differences in subjective and objective symptoms that result from drinking between the two groups: More frequent hangovers, abnormal physical conditions and higher KAST scores were seen in the normal group, and health examination showed higher values in liver function tests, including γ-GTP, and higher levels of blood pressure, HDL-cholesterol (HDL-C), etc., in the normal AlDH2group.It may be very useful for prevention of alcohol-related health disorders to help Mongoloid peoples, such as the Japanese, recognize whether their AlDH2 is normal or deficient, which is as determined by the ethanol patch test.

Differences in the activities of resveratrol and ascorbic acid in protection of ethanol-induced oxidative DNA damage in human peripheral lymphocytes

&#x0D; Background and Objective: CYP1A1 gene, which has role in carcinogenic metabolisms, is also detected in pterygium tissue. The aim of the study is to determine the polymorphisms of CYP1A1 m2 (rs1048943) and m4 (rs1799814) gene and its correlation with clinical variant of the pterygium.&#x0D; Methods: DNA isolation was performed from blood sample of 80 pterygium patients consisting of 40 inflammatory and 40 non-inflammatory pterygium. Genotyping of rs1048943 SNP AG (m2) in the CYP1A1 gene was performed using Alel Specific Polymerase Chain reaction (AS-PCR) and rs1048943) SNP Genotyping was performed using PCR. Polymorphism results are characterized as wild type (AA), mutant homozygote (GG), and mutant heterozygote (AG).&#x0D; Results: CYP1A1 m2 and m4 gene polymorphism consist of wild type (AA), mutant homozygote (GG), and mutant heterozygote (AG). Both CYP1A1 m2 and m4 genes polymorphism of both groups of inflammatory and non-inflammatory pterygium was mostly consist of wild type polymorphism, followed by the mutant heterozygote polymorphism. The wild type polymorphism was found to be higher in inflammatory pterygium, meanwhile the mutant heterozygote was found to be higher in non-inflammatory pterygium.&#x0D; Conclusion: There were differences in CYP1A1 m2 and m4 gene polymorphism in both pterygium group, but none has been shown to be statistically associated with the clinical variant of the pterygium.

To observe the changes in NLR family pyrin domain containing 3 (NLRP3) inflammasome in a rat model of diabetes-induced lung injury, and investigate the effect of low-dose ethanol on the production of NLRP3 inflammasome. The type I diabetic mellitus (DM) rat model was established, and the rats were divided into four groups: normal control group (CON group), low-dose ethanol group (EtOH group), diabetes group (DM group) and DM+EtOH group. The rats were fed for 6 and 12 weeks, respectively. The ratio of lung wet weight/body weight (lung/body coefficient) was calculated, and the changes of pulmonary morphology and fibrosis were observed by HE and Masson staining. The changes in pulmonary ultra-structure were examined by electron microscopy. The expressions of mitochondrial acetaldehyde dehydrogenase 2 (ALDH2) and NLRP3 inflammasome key factors, NLRP3, ASC and caspase-1 proteins were detected by western blot. Compared with the CON group, the lung/body coefficient was increased (P<0.05), lung fibrosis occurred, ALDH2 protein expression was decreased, and NLRP3, ASC and caspase-1 protein expressions were increased in the DM rats (P<0.05). Compared with the DM group, the lung/body coefficient and fibrosis degree were decreased, ALDH2 protein expression was increased (P<0.05), and NLRP3, ASC and caspase-1 protein expressions were decreased in the DM+EtOH group (P<0.05). Hence, low-dose ethanol increased ALDH2 protein expression and alleviated diabetes-induced lung injury by inhibiting the production of NLRP3 inflammasome.

Anaphylaxis to 6-α-methylprednisolone in an eight-year-old child

A genetic epidemiological case-control study on aldehyde dehydrogenase 2 (ALDH2) genotype and male probable alcohol use disorders (AUD) was performed in Khon Kaen province, northeast Thailand. One hundred and twenty-four of cases (probable AUD) were obtained from male villagers aged 18-65 years using the modified Michigan Alcoholism Screening Test-Thai version. The same number of controls were selected, being matched with the cases in terms of age (+/-4 years) within the same village. Marital status, education history and past or present histories of physical illnesses were essentially the same for the cases and the controls. All of the cases and 85.5% of the controls were current drinkers, and the cases tended to drink significantly more often than the controls. Genomic DNA was extracted from fingernails and ALDH2 genotypes were determined by polymerase chain reaction technique and digested by Ksp 632I. The ALDH2 genotypes of the cases and the controls were not significantly different: 90.3% versus 91.1% normal homozygote; 8.1% versus 8.9% heterozygote; and 1.6% versus 0.0% mutant homozygote, respectively. Among the normal homozygote, the daily amount of alcohol intakes of the cases were significantly larger than that of the controls (56.2+/-40.6g vs. 8.1+/-14.1 g), the same was found among the ALDH2 deficient (55.9+/-43.4 vs. 2.2+/-5.8 g). Multivariate analysis based on the conditional logistic regression model showed no significant association of AUD with ALDH2 genotype, marital status, education history, or past history of injury, however, occupation and daily amount of alcohol intake were found to be significantly associated with AUD (OR = 10.72, 95% CI = 1.15-99.99, P = 0.037, and OR = 1.12, 95% CI = 1.06-1.18, P = 0.000, respectively). Non-farmers showed 10.7 times larger risk of developing AUD compared to farmers, and the subjects had three times more chance of developing AUD for each increase of 10 g of the daily amount of alcohol intake.

A possible pathogenic polymorphism in the gene for the G subunit of the glycogen-associated regulatory form of protein phosphatase 1 (PP1 G subunit), causing an Asp-to-Tyr substitution at codon 905 (Asp905Tyr), has been reported to be associated with insulin resistance and hypersecretion of insulin in the white population. Since marked heterogeneity has been reported in the association of mutations of candidate genes with essential hypertension between Japanese and other ethnic groups, we investigated the association of Asp905Tyr with essential hypertension in Japanese subjects. The frequency of the Tyr allele in Japanese control subjects (0.70) was much higher than that in the Danish population (0.10, P<1x10(-8)), indicating that the Tyr allele, previously reported as a rare variant in white subjects, is a common allele in our population. The genotype distribution in Japanese hypertensive patients (n=109; Asp/Asp=0.09, Asp/Tyr=0.39, Tyr/Tyr=0.52) was not significantly different (chi2=0.7, df=2, P>.6) from that in normotensive control subjects (n=148; Asp/Asp=0.12, Asp/Tyr=0.36, Tyr/Tyr=0.52). Among subjects with different PP1 G subunit genotypes, there was no difference in blood pressure, serum cholesterol, plasma glucose and insulin levels, and glucose disposal rate estimated by the euglycemic hyperinsulinemic clamp test. These data indicate that the Asp905Tyr polymorphism of the PP1 G subunit is not associated with essential hypertension, nor with insulin resistance and/or hyperinsulinemia in Japanese patients with essential hypertension, suggesting that the polymorphism plays little if any role in susceptibility to insulin resistance or hypertension.

Iron-deficiency anemia (IDA) is the most common form of anemia. Iron replacement therapy is an effective treatment, but oral and previously available intravenous (IV) formulations in Japan have disadvantages such as side effects, immunogenic reactions, low dose per tablet/vial, and the need for continuous administration. Ferric carboxymaltose (FCM), which overcomes these limitations, is widely used as an IV iron preparation outside of Japan. In this single-center, open-label, single-dose escalation study, we investigated the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of FCM in Japanese subjects. Twenty-four Japanese IDA patients, diagnosed by hemoglobin, serum ferritin, and transferrin saturation, were assigned in equal groups to the 100, 500, 800, and 1000mg iron dose arms. All subjects completed the study without important protocol deviations. Mean total serum iron concentrations showed a rapid, dose-dependent increase after FCM injection, reaching a maximum within 1h. Mean reticulocyte counts significantly increased in all arms, suggesting improved hematopoietic function. Fourteen of 24 subjects experienced adverse events, but these were neither serious nor led to drug interruption. The PK/PD and safety profiles were similar in Japanese and European subjects. Ferric carboxymaltose is safe for administration in Japanese patients with IDA.

Background: Cervical cancer incidence rate in Bangladesh is 15.9 and age-standardized incidence rate is 19.2 (rates per 1,00,000 women per year). Polymorphisms of different genes have been affirmed to be associated with cervical cancer. Our prime purpose is to observe whether CYP3A4*1B polymorphisms are related with increasing cervical cancer risk in Bangladeshi population. The compilation of precise clinical information allows the clarity of different clinical phenotypes, which play a vital role in genetic studies of cervical cancer. Methods: The study was a case-control study carried out between patients and volunteers matched by age, sex, height, weight and smoking status. Daly’s chemical method was used to isolate genomic DNA from venous blood. The demographic variables of cases and controls were put side by side using chi-square tests and Student’s t tests. Results: Odds ratio and 95 % confidence interval were assigned to estimate the risk of cervical cancer. CYP3A4*1B polymorphisms and cervical cancer risk do not show any considerable relationship. The polymorphic frequencies of CYP3A4*1B allele (normal homozygote, heterozygote and mutant homozygote ) in cervical cancer were 60%, 40% and 0% respectively; frequencies in control were 66.67%, 33.33% and 0% respectively (p<0.05). Finally, we conclude that CYP3A4*1B polymorphisms is not associated in susceptibility to developing cervical cancer, at least in Bangladeshi population. Conclusions: In brief, the consequences of our study demonstrated that CYP3A4*1B polymorphism is not allied in susceptibility to develop cervical cancer, at least in Bangladeshi women.