Mariko Hayashida

East Asian Variant of Aldehyde Dehydrogenase 2 Is Associated With Coronary Spastic Angina Possible Roles of Reactive Aldehydes and Implications of Alcohol Flushing Syndrome

Background— Coronary spastic angina (CSA) is a common disease among East Asians, including Japanese. The prevalence of alcohol flushing syndrome associated with deficient activity of the variant aldehyde dehydrogenase 2 ( ALDH2*2 ) genotype is prevalent among East Asians. We examined whether CSA is associated with the ALDH2*2 genotype in Japanese. Methods and Results— The study subjects consisted of 202 patients in whom intracoronary injection of acetylcholine was performed by angiography on suspicion of CSA (119 men and 83 women; mean age, 66.2±11.4 years). They were divided into CSA (112 patients) and control groups (90 patients). ALDH2 genotyping was performed by the direct application of the TaqMan polymerase chain reaction system on dried whole blood. Clinical and laboratory data were examined using conventional methods. The frequencies of male sex, ALDH2*2 genotype carriers, alcohol flushing syndrome, tobacco smoking, and the plasma level of uric acid were higher ( P <0.001, P <0.001, P <0.001, P <0.001, and P =0.007, respectively) and the plasma high-density lipoprotein cholesterol levels were lower ( P <0.001) in the CSA group than in the control group. The multivariable logistic regression analysis revealed that ALDH2*2 genotype and smoking were significantly associated with CSA ( P <0.001 and P =0.024, respectively). Conclusions— East Asian variant ALDH2*2 genotypes and, hence, deficient ALDH2 activity were associated with CSA in Japanese. These data support further investigation of treatment targeting aldehydes for CSA. # CLINICAL PERSPECTIVE {#article-title-47}Background— Coronary spastic angina (CSA) is a common disease among East Asians, including Japanese. The prevalence of alcohol flushing syndrome associated with deficient activity of the variant aldehyde dehydrogenase 2 (ALDH2*2) genotype is prevalent among East Asians. We examined whether CSA is associated with the ALDH2*2 genotype in Japanese. Methods and Results— The study subjects consisted of 202 patients in whom intracoronary injection of acetylcholine was performed by angiography on suspicion of CSA (119 men and 83 women; mean age, 66.2±11.4 years). They were divided into CSA (112 patients) and control groups (90 patients). ALDH2 genotyping was performed by the direct application of the TaqMan polymerase chain reaction system on dried whole blood. Clinical and laboratory data were examined using conventional methods. The frequencies of male sex, ALDH2*2 genotype carriers, alcohol flushing syndrome, tobacco smoking, and the plasma level of uric acid were higher (P<0.001, P<0.001, P<0.001, P<0.001, and P=0.007, respectively) and the plasma high-density lipoprotein cholesterol levels were lower (P<0.001) in the CSA group than in the control group. The multivariable logistic regression analysis revealed that ALDH2*2 genotype and smoking were significantly associated with CSA (P<0.001 and P=0.024, respectively). Conclusions— East Asian variant ALDH2*2 genotypes and, hence, deficient ALDH2 activity were associated with CSA in Japanese. These data support further investigation of treatment targeting aldehydes for CSA.

Combination Analysis in Genetic Polymorphisms of Drug-Metabolizing Enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A5 in the Japanese Population

The Cytochrome P450 is the major enzyme involved in drug metabolism. CYP enzymes are responsible for the metabolism of most clinically used drugs. Individual variability in CYP activity is one important factor that contributes to drug therapy failure. We have developed a new straightforward TaqMan PCR genotyping assay to investigate the prevalence of the most common allelic variants of polymorphic CYP enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A5 in the Japanese population. Moreover, we focused on the combination of each genotype for clinical treatment. The genotype analysis identified a total of 139 out of 483 genotype combinations of five genes in the 1,003 Japanese subjects. According to our results, most of subjects seemed to require dose modification during clinical treatment. In the near future, modifications should be considered based on the individual patient genotype of each treatment.

Genetic alcohol sensitivity regulated by ALDH2 and ADH1B polymorphisms is strongly associated with depression and anxiety in Japanese employees

BACKGROUND Although alcohol-related disorders (ARD) have been shown to be accompanied by comorbid depressive and anxiety disorders, and alcohol metabolic enzyme genes, ADH1B and ALDH2 polymorphisms, have been associated with an increased risk of ARD, no studies have been conducted to evaluate the associations between these genetic polymorphisms and anxiety or depression. METHOD A total of 1944 Japanese workers were interviewed regarding their depressive and anxiety disorders, including suicidality, by a brief psychiatric structured interview (MINI). We investigated the relationship of ADH1B rs1229984 and ALDH2 rs671 polymorphism combinations with mental disorder risks. Logistic regression analysis was used to evaluate the associations between those polymorphisms and anxiety/depressive disorders, adjusting for sex, age, and job rank. The degree of alcohol sensitivity was classified into five groups according to the combination of two enzyme genotypes (Group I-V, in order from the lowest alcohol sensitivity). RESULTS Those with ALDH2(*)1/(*)1 and ADH1B(*)1/(*)1 were likely to be at an increased risk of depressive and anxiety disorders as well as ARD. This tendency was more apparent among non-drinkers (OR 9.20, 95% CI 1.66-50.89). No adverse effects of ALDH2 or ADH1B alone were observed with mental disorder risks. Likewise, analyses conducted combining job rank and genetic alcohol sensitivity showed no material associations with such risks. CONCLUSIONS Genetic alcohol sensitivity, especially that with the genotype combination of ALDH2(*)1/(*)1 and ADH1B(*)1/(*)1, was significantly associated with an increased risk of depressive and anxiety disorders as well as ARD.

The ACTN3 Gene is a Potential Biomarker for the Risk of Non-Contact Sports Injury in Female Athletes

Sports injuries can become serious impairments for all athletes. Most notably, female athletes are at higher risk than men for sports injury, for example, anterior cruciate ligament (ACL) disorder. However, there is currently no genetic marker to determine if a female athlete harbors a predisposition for muscle trauma. Hence, we performed single nucleotide polymorphism genotyping of the α-actinin-3 (ACTN3), angiotensin-converting enzyme (ACE), and uncoupling proteins (UCP1, UCP2, and UCP3) in 99 young female athletes who had been injured during a sports activity, and we compared the occurrence of muscle traumas with the genotypes using the chi-square test. For the ACTN3 577R allele, the subjects who had non-contact muscle injury had a marked increase in frequency (p-value=0.0015; odds ratio=2.52). The significant increase in non-contact muscle injury related to ACTN3 577R alleles suggests that ACTN3 is likely to be involved in muscle strain and that non-contact muscle injury might occur due to the presence of this allele. It is crucially important for young female athletes to understand their risk for injury, as they might be able to modify their training program to avoid injury, depending on their specific genetic markers.

East Asian Variant of Aldehyde Dehydrogenase 2 Is Associated With Coronary Spastic Angina

Background— Coronary spastic angina (CSA) is a common disease among East Asians, including Japanese. The prevalence of alcohol flushing syndrome associated with deficient activity of the variant aldehyde dehydrogenase 2 ( ALDH2*2 ) genotype is prevalent among East Asians. We examined whether CSA is associated with the ALDH2*2 genotype in Japanese. Methods and Results— The study subjects consisted of 202 patients in whom intracoronary injection of acetylcholine was performed by angiography on suspicion of CSA (119 men and 83 women; mean age, 66.2±11.4 years). They were divided into CSA (112 patients) and control groups (90 patients). ALDH2 genotyping was performed by the direct application of the TaqMan polymerase chain reaction system on dried whole blood. Clinical and laboratory data were examined using conventional methods. The frequencies of male sex, ALDH2*2 genotype carriers, alcohol flushing syndrome, tobacco smoking, and the plasma level of uric acid were higher ( P <0.001, P <0.001, P <0.001, P <0.001, and P =0.007, respectively) and the plasma high-density lipoprotein cholesterol levels were lower ( P <0.001) in the CSA group than in the control group. The multivariable logistic regression analysis revealed that ALDH2*2 genotype and smoking were significantly associated with CSA ( P <0.001 and P =0.024, respectively). Conclusions— East Asian variant ALDH2*2 genotypes and, hence, deficient ALDH2 activity were associated with CSA in Japanese. These data support further investigation of treatment targeting aldehydes for CSA. # CLINICAL PERSPECTIVE {#article-title-47}Background— Coronary spastic angina (CSA) is a common disease among East Asians, including Japanese. The prevalence of alcohol flushing syndrome associated with deficient activity of the variant aldehyde dehydrogenase 2 (ALDH2*2) genotype is prevalent among East Asians. We examined whether CSA is associated with the ALDH2*2 genotype in Japanese. Methods and Results— The study subjects consisted of 202 patients in whom intracoronary injection of acetylcholine was performed by angiography on suspicion of CSA (119 men and 83 women; mean age, 66.2±11.4 years). They were divided into CSA (112 patients) and control groups (90 patients). ALDH2 genotyping was performed by the direct application of the TaqMan polymerase chain reaction system on dried whole blood. Clinical and laboratory data were examined using conventional methods. The frequencies of male sex, ALDH2*2 genotype carriers, alcohol flushing syndrome, tobacco smoking, and the plasma level of uric acid were higher (P<0.001, P<0.001, P<0.001, P<0.001, and P=0.007, respectively) and the plasma high-density lipoprotein cholesterol levels were lower (P<0.001) in the CSA group than in the control group. The multivariable logistic regression analysis revealed that ALDH2*2 genotype and smoking were significantly associated with CSA (P<0.001 and P=0.024, respectively). Conclusions— East Asian variant ALDH2*2 genotypes and, hence, deficient ALDH2 activity were associated with CSA in Japanese. These data support further investigation of treatment targeting aldehydes for CSA.

Response to Letter Regarding Article, “East Asian Variant of Aldehyde Dehydrogenase 2 Is Associated With Coronary Spastic Angina: Possible Roles of Reactive Aldehydes and Implications of Alcohol Flushing Syndrome”

We appreciate Brugaletta and colleagues for their interest in our article.1 In their opinion, it cannot be excluded that endothelial dysfunction contributes to vasospasm, being a confounding variable in the diagnosis of coronary spastic angina (CSA) by the acetylcholine test, and that use of ergonovine instead of acetylcholine could differentiate between CSA and vasospasm caused by endothelial dysfunction. Coronary spasm can be induced by various methods, including intracoronary injection of acetylcholine, ergonovine, histamine, or dopamine; hyperventilation; alcohol ingestion; cold pressure test; physical exercise; and mental stress.2 Various factors therefore may be involved in the pathogenesis of coronary spasm. However, it is generally accepted that hyperreactivity of coronary vascular smooth muscle is the common underlying mechanism of coronary spasm.2,3 The precise mechanisms underlying the hyperreactivity of coronary smooth muscle, however, …

Depression, Alcoholism, and Genetic Alcohol Sensitivity Regulated by ALDH2 and ADH1B Polymorphisms among Japanese Community-Dwelling Adults

Background: Although strong association between drinking and depression as well as alcohol-related disorders (ARD) has been reported, the relationship between potential ability to drink (genetic alcohol sensitivity) and depression or ARD is unclear. Genetic alcohol sensitivity is regulated by two alcohol metabolic enzyme genes, ADH1B and ALDH2 polymorphisms. We have already evaluated the association between depression and these polymorphisms in Japanese white-collar workers. Current study expanded this issue on community-dwelling relatively older adults.

East Asian Variant of Aldehyde Dehydrogenase 2 Is Associated With Coronary Spastic AnginaCLINICAL PERSPECTIVE

Background— Coronary spastic angina (CSA) is a common disease among East Asians, including Japanese. The prevalence of alcohol flushing syndrome associated with deficient activity of the variant aldehyde dehydrogenase 2 ( ALDH2*2 ) genotype is prevalent among East Asians. We examined whether CSA is associated with the ALDH2*2 genotype in Japanese. Methods and Results— The study subjects consisted of 202 patients in whom intracoronary injection of acetylcholine was performed by angiography on suspicion of CSA (119 men and 83 women; mean age, 66.2±11.4 years). They were divided into CSA (112 patients) and control groups (90 patients). ALDH2 genotyping was performed by the direct application of the TaqMan polymerase chain reaction system on dried whole blood. Clinical and laboratory data were examined using conventional methods. The frequencies of male sex, ALDH2*2 genotype carriers, alcohol flushing syndrome, tobacco smoking, and the plasma level of uric acid were higher ( P <0.001, P <0.001, P <0.001, P <0.001, and P =0.007, respectively) and the plasma high-density lipoprotein cholesterol levels were lower ( P <0.001) in the CSA group than in the control group. The multivariable logistic regression analysis revealed that ALDH2*2 genotype and smoking were significantly associated with CSA ( P <0.001 and P =0.024, respectively). Conclusions— East Asian variant ALDH2*2 genotypes and, hence, deficient ALDH2 activity were associated with CSA in Japanese. These data support further investigation of treatment targeting aldehydes for CSA. # CLINICAL PERSPECTIVE {#article-title-47}Background— Coronary spastic angina (CSA) is a common disease among East Asians, including Japanese. The prevalence of alcohol flushing syndrome associated with deficient activity of the variant aldehyde dehydrogenase 2 (ALDH2*2) genotype is prevalent among East Asians. We examined whether CSA is associated with the ALDH2*2 genotype in Japanese. Methods and Results— The study subjects consisted of 202 patients in whom intracoronary injection of acetylcholine was performed by angiography on suspicion of CSA (119 men and 83 women; mean age, 66.2±11.4 years). They were divided into CSA (112 patients) and control groups (90 patients). ALDH2 genotyping was performed by the direct application of the TaqMan polymerase chain reaction system on dried whole blood. Clinical and laboratory data were examined using conventional methods. The frequencies of male sex, ALDH2*2 genotype carriers, alcohol flushing syndrome, tobacco smoking, and the plasma level of uric acid were higher (P<0.001, P<0.001, P<0.001, P<0.001, and P=0.007, respectively) and the plasma high-density lipoprotein cholesterol levels were lower (P<0.001) in the CSA group than in the control group. The multivariable logistic regression analysis revealed that ALDH2*2 genotype and smoking were significantly associated with CSA (P<0.001 and P=0.024, respectively). Conclusions— East Asian variant ALDH2*2 genotypes and, hence, deficient ALDH2 activity were associated with CSA in Japanese. These data support further investigation of treatment targeting aldehydes for CSA.

East Asian Variant of Aldehyde Dehydrogenase 2 Is Associated With Coronary Spastic AnginaCLINICAL PERSPECTIVE: Possible Roles of Reactive Aldehydes and Implications of Alcohol Flushing Syndrome

Background— Coronary spastic angina (CSA) is a common disease among East Asians, including Japanese. The prevalence of alcohol flushing syndrome associated with deficient activity of the variant aldehyde dehydrogenase 2 ( ALDH2*2 ) genotype is prevalent among East Asians. We examined whether CSA is associated with the ALDH2*2 genotype in Japanese. Methods and Results— The study subjects consisted of 202 patients in whom intracoronary injection of acetylcholine was performed by angiography on suspicion of CSA (119 men and 83 women; mean age, 66.2±11.4 years). They were divided into CSA (112 patients) and control groups (90 patients). ALDH2 genotyping was performed by the direct application of the TaqMan polymerase chain reaction system on dried whole blood. Clinical and laboratory data were examined using conventional methods. The frequencies of male sex, ALDH2*2 genotype carriers, alcohol flushing syndrome, tobacco smoking, and the plasma level of uric acid were higher ( P <0.001, P <0.001, P <0.001, P <0.001, and P =0.007, respectively) and the plasma high-density lipoprotein cholesterol levels were lower ( P <0.001) in the CSA group than in the control group. The multivariable logistic regression analysis revealed that ALDH2*2 genotype and smoking were significantly associated with CSA ( P <0.001 and P =0.024, respectively). Conclusions— East Asian variant ALDH2*2 genotypes and, hence, deficient ALDH2 activity were associated with CSA in Japanese. These data support further investigation of treatment targeting aldehydes for CSA. # CLINICAL PERSPECTIVE {#article-title-47}Background— Coronary spastic angina (CSA) is a common disease among East Asians, including Japanese. The prevalence of alcohol flushing syndrome associated with deficient activity of the variant aldehyde dehydrogenase 2 (ALDH2*2) genotype is prevalent among East Asians. We examined whether CSA is associated with the ALDH2*2 genotype in Japanese. Methods and Results— The study subjects consisted of 202 patients in whom intracoronary injection of acetylcholine was performed by angiography on suspicion of CSA (119 men and 83 women; mean age, 66.2±11.4 years). They were divided into CSA (112 patients) and control groups (90 patients). ALDH2 genotyping was performed by the direct application of the TaqMan polymerase chain reaction system on dried whole blood. Clinical and laboratory data were examined using conventional methods. The frequencies of male sex, ALDH2*2 genotype carriers, alcohol flushing syndrome, tobacco smoking, and the plasma level of uric acid were higher (P<0.001, P<0.001, P<0.001, P<0.001, and P=0.007, respectively) and the plasma high-density lipoprotein cholesterol levels were lower (P<0.001) in the CSA group than in the control group. The multivariable logistic regression analysis revealed that ALDH2*2 genotype and smoking were significantly associated with CSA (P<0.001 and P=0.024, respectively). Conclusions— East Asian variant ALDH2*2 genotypes and, hence, deficient ALDH2 activity were associated with CSA in Japanese. These data support further investigation of treatment targeting aldehydes for CSA.