ALDH2

Summary

Gene Symbol: ALDH2
Description: aldehyde dehydrogenase 2 family member
Alias: ALDH-E2, ALDHI, ALDM, aldehyde dehydrogenase, mitochondrial, ALDH class 2, acetaldehyde dehydrogenase 2, aldehyde dehydrogenase 2 family (mitochondrial), liver mitochondrial ALDH, nucleus-encoded mitochondrial aldehyde dehydrogenase 2
Species: human
Products:     ALDH2

Top Publications

  1. Sakamoto T, Hara M, Higaki Y, Ichiba M, Horita M, Mizuta T, et al. Influence of alcohol consumption and gene polymorphisms of ADH2 and ALDH2 on hepatocellular carcinoma in a Japanese population. Int J Cancer. 2006;118:1501-7 pubmed
    ..study to examine whether polymorphisms of alcohol dehydrogenase 2 (ADH2) and aldehyde dehydrogenase 2 (ALDH2) modified the HCC risk depending on the amount of alcohol intake...
  2. Hashimoto T, Uchida K, Okayama N, Imate Y, Suehiro Y, Ueyama Y, et al. ALDH2 1510 G/A (Glu487Lys) polymorphism interaction with age in head and neck squamous cell carcinoma. Tumour Biol. 2006;27:334-8 pubmed
    Recent molecular epidemiological studies have revealed a possible association of the acetaldehyde dehydrogenase-2 (ALDH2) 1510 G/A (Glu487Lys) polymorphism with various cancers including head and neck squamous cell carcinoma (HNSCC)...
  3. Zhao H, Liu K, Lei Z, Lei S, Tian Y. Meta-analysis of the aldehyde dehydrogenases-2 (ALDH2) Glu487Lys polymorphism and colorectal cancer risk. PLoS ONE. 2014;9:e88656 pubmed publisher
    A number of studies have explored the association of the aldehyde dehydrogenases-2 (ALDH2) Glu487Lys polymorphism and risk of colorectal cancer; however, the results are inconsistent...
  4. Boonyaphiphat P, Thongsuksai P, Sriplung H, Puttawibul P. Lifestyle habits and genetic susceptibility and the risk of esophageal cancer in the Thai population. Cancer Lett. 2002;186:193-9 pubmed
    The association of lifestyle habits and polymorphism of ADH2 and ALDH2 genes with the risk of esophageal cancer in Thai population was investigated in a hospital-based case-control study: 202 cases and 261 controls...
  5. Takagi S, Iwai N, Yamauchi R, Kojima S, Yasuno S, Baba T, et al. Aldehyde dehydrogenase 2 gene is a risk factor for myocardial infarction in Japanese men. Hypertens Res. 2002;25:677-81 pubmed
    ..missense mutation from glutamic acid (Glu) to lysine (Lys) at codon 487 in an isoenzyme of aldehyde dehydrogenase (ALDH2) with a low Km...
  6. Han H, Wang H, Yin Z, Jiang H, Fang M, Han J. Association of genetic polymorphisms in ADH and ALDH2 with risk of coronary artery disease and myocardial infarction: a meta-analysis. Gene. 2013;526:134-41 pubmed publisher
    ..Meta-analysis showed that mutant genotypes (GA+AA) of the rs671 polymorphism in the ALDH2 gene were associated with increased risk of both CAD and MI (CAD: RR=1.20, 95%CI: 1.03-1.40, P=0.021; MI: RR=1...
  7. Tanaka F, Yamamoto K, Suzuki S, Inoue H, Tsurumaru M, Kajiyama Y, et al. Strong interaction between the effects of alcohol consumption and smoking on oesophageal squamous cell carcinoma among individuals with ADH1B and/or ALDH2 risk alleles. Gut. 2010;59:1457-64 pubmed publisher
    ..Oesophageal squamous cell carcinoma (OSCC) is considered a difficult cancer to cure. The detection of environmental and genetic factors is important for prevention on an individual basis...
  8. Wenzl M, Beretta M, Gorren A, Zeller A, Baral P, Gruber K, et al. Role of the general base Glu-268 in nitroglycerin bioactivation and superoxide formation by aldehyde dehydrogenase-2. J Biol Chem. 2009;284:19878-86 pubmed publisher
    Mitochondrial aldehyde dehydrogenase-2 (ALDH2) plays an essential role in nitroglycerin (GTN) bioactivation, resulting in formation of NO or a related activator of soluble guanylate cyclase...
  9. Takeuchi F, Yokota M, Yamamoto K, Nakashima E, Katsuya T, Asano H, et al. Genome-wide association study of coronary artery disease in the Japanese. Eur J Hum Genet. 2012;20:333-40 pubmed publisher
    ..12 SNPs were tested; CAD association was replicated and/or verified for 4 (of 12) SNPs from 3 loci: near BRAP and ALDH2 on 12q24 (P=1.6 × 10(-34)), HLA-DQB1 on 6p21 (P=4.7 × 10(-7)), and CDKN2A/B on 9p21 (P=6.1 × 10(-16))...

More Information

Publications134 found, 100 shown here

  1. Li Q, Li H, Wang M, Diao T, Zhou Z, Fang Q, et al. Multi-susceptibility genes associated with the risk of the development stages of esophageal squamous cell cancer in Feicheng County. BMC Gastroenterol. 2011;11:74 pubmed publisher
    ..The genotypes for CYP2E1 G1259C, hOGG1 C326G, MTHFR C677T, MPO G463A, and ALDH2 allele genes were identified in blood samples collected from all participants...
  2. Eom S, Zhang Y, Kim S, Choe K, Lee K, Park J, et al. Influence of NQO1, ALDH2, and CYP2E1 genetic polymorphisms, smoking, and alcohol drinking on the risk of lung cancer in Koreans. Cancer Causes Control. 2009;20:137-45 pubmed publisher
    We investigated the association of genetic polymorphisms of NQO1, ALDH2, CYP2E1, and the combined genotype of these genes on lung cancer risk, and also evaluated the association after stratification by cumulative smoking amounts and ..
  3. Guo Y, Chen L, Bai Y, Li L, Sun J, Zhang G, et al. The ALDH2 Glu504Lys polymorphism is associated with coronary artery disease in Han Chinese: Relation with endothelial ADMA levels. Atherosclerosis. 2010;211:545-50 pubmed publisher
    We studied the association between mitochondrial aldehyde dehydrogenase (ALDH2) Glu504Lys (rs671 or ALDH2*2) polymorphism and coronary artery disease (CAD), and sought to clarify the mechanisms underlying this association...
  4. Matsuo K, Oze I, Hosono S, Ito H, Watanabe M, Ishioka K, et al. The aldehyde dehydrogenase 2 (ALDH2) Glu504Lys polymorphism interacts with alcohol drinking in the risk of stomach cancer. Carcinogenesis. 2013;34:1510-5 pubmed publisher
    The impact of alcohol on the risk of stomach cancer is controversial. Although aldehyde dehydrogenase 2 (ALDH2) Glu504Lys (rs671) polymorphism has a strong effect on acetaldehyde metabolism, little is known about its impact on stomach ..
  5. Beretta M, Gruber K, Kollau A, Russwurm M, Koesling D, Goessler W, et al. Bioactivation of nitroglycerin by purified mitochondrial and cytosolic aldehyde dehydrogenases. J Biol Chem. 2008;283:17873-80 pubmed publisher
    ..of nitroglycerin (GTN) to 1,2-glycerol dinitrate (GDN) and nitrite by mitochondrial aldehyde dehydrogenase (ALDH2) is essentially involved in GTN bioactivation resulting in cyclic GMP-mediated vascular relaxation...
  6. Cao H, Li S, Wu J, Gao C, Su P, Liu Y, et al. Alcohol dehydrogenase-2 and aldehyde dehydrogenase-2 genotypes, alcohol drinking and the risk for stomach cancer in Chinese males. Asian Pac J Cancer Prev. 2010;11:1073-7 pubmed
    To investigate the relationship among alcohol dehydrogenase-2 (ADH2) and aldehyde dehydrogenase-2 (ALDH2) genetic polymorphisms, alcohol consumption, and the susceptibility of stomach cancer in Chinese males...
  7. Nakamura Y, Amamoto K, Tamaki S, Okamura T, Tsujita Y, Ueno Y, et al. Genetic variation in aldehyde dehydrogenase 2 and the effect of alcohol consumption on cholesterol levels. Atherosclerosis. 2002;164:171-7 pubmed
    ..We examined the interaction between the aldehyde dehydrogenase type 2 (ALDH2), alcohol intake, and HDL levels in 826 men and 1295 women in a rural town in Japan...
  8. Larson H, Weiner H, Hurley T. Disruption of the coenzyme binding site and dimer interface revealed in the crystal structure of mitochondrial aldehyde dehydrogenase "Asian" variant. J Biol Chem. 2005;280:30550-6 pubmed
    Mitochondrial aldehyde dehydrogenase (ALDH2) is the major enzyme that oxidizes ethanol-derived acetaldehyde. A nearly inactive form of the enzyme, ALDH2*2, is found in about 40% of the East Asian population...
  9. Perez Miller S, Hurley T. Coenzyme isomerization is integral to catalysis in aldehyde dehydrogenase. Biochemistry. 2003;42:7100-9 pubmed
    ..Our data suggest that the presence of magnesium may lead to selection of particular conformations and speed isomerization of the reduced cofactor following hydride transfer. ..
  10. Xu F, Chen Y, Xue L, Li R, Zhang H, Bian Y, et al. Role of aldehyde dehydrogenase 2 Glu504lys polymorphism in acute coronary syndrome. J Cell Mol Med. 2011;15:1955-62 pubmed publisher
    This study aimed to investigate the association of the aldehyde dehydrogenase 2 (ALDH2) Glu504Lys polymorphism, which exists in 30-50% of East Asians, and risk of acute coronary syndrome (ACS)...
  11. Yamada Y, Sun F, Tsuritani I, Honda R. Genetic differences in ethanol metabolizing enzymes and blood pressure in Japanese alcohol consumers. J Hum Hypertens. 2002;16:479-86 pubmed
    ..polymorphisms in ethanol metabolizing enzymes, such as alcohol dehydrogenase-2 (ADH2), aldehyde dehydrogenase-2 (ALDH2) and cytochrome P450-2E1 (CYP2E1)...
  12. Xu F, Chen Y, Lv R, Zhang H, Tian H, Bian Y, et al. ALDH2 genetic polymorphism and the risk of type II diabetes mellitus in CAD patients. Hypertens Res. 2010;33:49-55 pubmed publisher
    ..In this study, we investigated the relationship between Glu504Lys polymorphism in the acetaldehyde dehydrogenase 2 (ALDH2) gene, a key enzyme of alcohol metabolism, and the risk of having T2DM in Chinese Han CAD ..
  13. Wu C, Kraft P, Zhai K, Chang J, Wang Z, Li Y, et al. Genome-wide association analyses of esophageal squamous cell carcinoma in Chinese identify multiple susceptibility loci and gene-environment interactions. Nat Genet. 2012;44:1090-7 pubmed publisher
    ..54×10(-7) to PG×E=3.23×10(-2)). We confirmed the known association of the ALDH2 locus on 12q24 to ESCC, and a joint analysis showed that drinkers with both of the ADH1B and ALDH2 risk alleles ..
  14. Hiraki A, Matsuo K, Wakai K, Suzuki T, Hasegawa Y, Tajima K. Gene-gene and gene-environment interactions between alcohol drinking habit and polymorphisms in alcohol-metabolizing enzyme genes and the risk of head and neck cancer in Japan. Cancer Sci. 2007;98:1087-91 pubmed
    ..The genetic polymorphisms aldehyde dehydrogenase2 (ALDH2) Glu487Lys and alcohol dehydrogenase 2 (ADH2) His47Arg, which have a strong impact on alcohol metabolism, are ..
  15. Takeuchi F, Isono M, Nabika T, Katsuya T, Sugiyama T, Yamaguchi S, et al. Confirmation of ALDH2 as a Major locus of drinking behavior and of its variants regulating multiple metabolic phenotypes in a Japanese population. Circ J. 2011;75:911-8 pubmed
    ..associate with drinking behavior in stage 1, among which rs671 (a Glu-to-Lys substitution at position 504) in the ALDH2 gene showed the strongest association (odds ratio (OR)=0.16, P=3.6×10(-211) in the joint analysis)...
  16. Matsuo K, Rossi M, Negri E, Oze I, Hosono S, Ito H, et al. Folate, alcohol, and aldehyde dehydrogenase 2 polymorphism and the risk of oral and pharyngeal cancer in Japanese. Eur J Cancer Prev. 2012;21:193-8 pubmed publisher
    ..Aldehyde dehydrogenase 2 (ALDH2) gene polymorphism is known to interact with alcohol consumption...
  17. Amamoto K, Okamura T, Tamaki S, Kita Y, Tsujita Y, Kadowaki T, et al. Epidemiologic study of the association of low-Km mitochondrial acetaldehyde dehydrogenase genotypes with blood pressure level and the prevalence of hypertension in a general population. Hypertens Res. 2002;25:857-64 pubmed
    In Japanese and other Asians, the prevalence of genetically decreased mitochondrial aldehyde dehydrogenase (ALDH2) activity is higher than in Caucasians...
  18. Beretta M, Sottler A, Schmidt K, Mayer B, Gorren A. Partially irreversible inactivation of mitochondrial aldehyde dehydrogenase by nitroglycerin. J Biol Chem. 2008;283:30735-44 pubmed publisher
    Mitochondrial aldehyde dehydrogenase (ALDH2) may be involved in the biotransformation of glyceryl trinitrate (GTN), and the inactivation of ALDH2 by GTN may contribute to the phenomenon of nitrate tolerance...
  19. Tsuchihashi Makaya M, Serizawa M, Yanai K, Katsuya T, Takeuchi F, Fujioka A, et al. Gene-environmental interaction regarding alcohol-metabolizing enzymes in the Japanese general population. Hypertens Res. 2009;32:207-13 pubmed publisher
    ..001) with drinking behavior was observed for ADH1B Arg47His (rs1229984) and ALDH2 Glu487Lys (rs671) polymorphisms...
  20. Hashimoto Y, Nakayama T, Futamura A, Omura M, Nakarai H, Nakahara K. Relationship between genetic polymorphisms of alcohol-metabolizing enzymes and changes in risk factors for coronary heart disease associated with alcohol consumption. Clin Chem. 2002;48:1043-8 pubmed
    ..The ADH2 genotype was determined by PCR and subsequent digestion with MaeIII. The ALDH2 genotype was determined based on amplified product length polymorphisms...
  21. Oikawa T, Iijima K, Koike T, Uno K, Horii T, Iwai W, et al. Deficient aldehyde dehydrogenase 2 is associated with increased risk for esophageal squamous cell carcinoma in the presence of gastric hypochlorhydria. Scand J Gastroenterol. 2010;45:1338-44 pubmed publisher
    In Orientals, deficient aldehyde dehydrogenase 2 (ALDH2) is associated with an increased risk for esophageal squamous cell carcinoma (ESCC)...
  22. Hiura Y, Tabara Y, Kokubo Y, Okamura T, Miki T, Tomoike H, et al. A genome-wide association study of hypertension-related phenotypes in a Japanese population. Circ J. 2010;74:2353-9 pubmed
    ..AC was influenced by the functional polymorphism in ALDH2, which affected BP levels in men...
  23. Ding J, Li S, Cao H, Wu J, Gao C, Su P, et al. Polymorphisms of alcohol dehydrogenase-2 and aldehyde dehydrogenase-2 and esophageal cancer risk in Southeast Chinese males. World J Gastroenterol. 2009;15:2395-400 pubmed
    To evaluate the impact of alcohol dehydrogenase-2 (ADH2) and aldehyde dehydrogenase-2 (ALDH2) polymorphisms on esophageal cancer susceptibility in Southeast Chinese males...
  24. Hao P, Chen Y, Wang J, Wang X, Zhang Y. Meta-analysis of aldehyde dehydrogenase 2 gene polymorphism and Alzheimer's disease in East Asians. Can J Neurol Sci. 2011;38:500-6 pubmed
    The association of genetic polymorphism of mitochondrial aldehyde dehydrogenase 2 (ALDH2) and Alzheimer's disease (AD) has been controversial and has been investigated only in several small-sample studies...
  25. Doser T, Turdi S, Thomas D, Epstein P, Li S, Ren J. Transgenic overexpression of aldehyde dehydrogenase-2 rescues chronic alcohol intake-induced myocardial hypertrophy and contractile dysfunction. Circulation. 2009;119:1941-9 pubmed publisher
    ..impact of altered acetaldehyde metabolism through systemic transgenic overexpression of aldehyde dehydrogenase-2 (ALDH2) on chronic alcohol ingestion-induced myocardial damage...
  26. Oelze M, Knorr M, Schell R, Kamuf J, Pautz A, Art J, et al. Regulation of human mitochondrial aldehyde dehydrogenase (ALDH-2) activity by electrophiles in vitro. J Biol Chem. 2011;286:8893-900 pubmed publisher
    ..The Trx/TrxR system may play an important role in this process because it not only prevents inhibition of ALDH-2 but is also inhibited by the ALDH-2 substrate 4-hydroxynonenal. ..
  27. Saito K, Yokoyama T, Yoshiike N, Date C, Yamamoto A, Muramatsu M, et al. Do the ethanol metabolizing enzymes modify the relationship between alcohol consumption and blood pressure?. J Hypertens. 2003;21:1097-105 pubmed
    ..and blood pressure (alcohol-BP relationship) differs among individuals with different aldehyde dehydrogenase-2 (ALDH2) genotypes, but few studies have examined the association with alcohol dehydrogenase-2 (ADH2), and those have ..
  28. Dickson P, James M, Heath A, Montgomery G, Martin N, Whitfield J, et al. Effects of variation at the ALDH2 locus on alcohol metabolism, sensitivity, consumption, and dependence in Europeans. Alcohol Clin Exp Res. 2006;30:1093-100 pubmed
    The low-activity variant of the aldehyde dehydrogenase 2 (ALDH2) gene found in East Asian populations leads to the alcohol flush reaction and reduces alcohol consumption and risk of alcohol dependence (AD)...
  29. Ding J, Li S, Wu J, Gao C, Zhou J, Cao H, et al. Alcohol dehydrogenase-2 and aldehyde dehydrogenase-2 genotypes, alcohol drinking and the risk of primary hepatocellular carcinoma in a Chinese population. Asian Pac J Cancer Prev. 2008;9:31-5 pubmed
    To investigate the relationship of alcohol dehydrogenase-2 (ADH2) and aldehyde dehydrogenase-2 (ALDH2) genotypes as well as alcohol drinking to the susceptibility of primary hepatocellular carcinoma (HCC)...
  30. Matsuo K, Wakai K, Hirose K, Ito H, Saito T, Suzuki T, et al. A gene-gene interaction between ALDH2 Glu487Lys and ADH2 His47Arg polymorphisms regarding the risk of colorectal cancer in Japan. Carcinogenesis. 2006;27:1018-23 pubmed
    ..Genetic polymorphisms, aldehyde dehydrogenase (ALDH2) Glu487Lys and alcohol dehydrogenase 2 (ADH2) His47Arg, which have a strong impact on alcohol metabolism, are ..
  31. Yin G, Kono S, Toyomura K, Moore M, Nagano J, Mizoue T, et al. Alcohol dehydrogenase and aldehyde dehydrogenase polymorphisms and colorectal cancer: the Fukuoka Colorectal Cancer Study. Cancer Sci. 2007;98:1248-53 pubmed
    ..The present case-control study was conducted to determine the influence of ADH2, ADH3 and ALDH2 polymorphisms in Fukuoka, Japan, with 685 incident cases of histologically confirmed colorectal adenocarcinomas ..
  32. Wenzl M, Beretta M, Griesberger M, Russwurm M, Koesling D, Schmidt K, et al. Site-directed mutagenesis of aldehyde dehydrogenase-2 suggests three distinct pathways of nitroglycerin biotransformation. Mol Pharmacol. 2011;80:258-66 pubmed publisher
    ..underlying reduction of nitroglycerin (GTN) to nitric oxide (NO) by mitochondrial aldehyde dehydrogenase (ALDH2), we generated mutants of the enzyme lacking the cysteines adjacent to reactive Cys302 (C301S and C303S), the ..
  33. Yokoyama A, Kato H, Yokoyama T, Igaki H, Tsujinaka T, Muto M, et al. Esophageal squamous cell carcinoma and aldehyde dehydrogenase-2 genotypes in Japanese females. Alcohol Clin Exp Res. 2006;30:491-500 pubmed
    Aldehyde dehydrogenase-2 (ALDH2) is the key enzyme for elimination of acetaldehyde, an established animal carcinogen produced after drinking...
  34. Sangrajrang S, Sato Y, Sakamoto H, Ohnami S, Khuhaprema T, Yoshida T. Genetic polymorphisms in folate and alcohol metabolism and breast cancer risk: a case-control study in Thai women. Breast Cancer Res Treat. 2010;123:885-93 pubmed publisher
    ..Twenty-seven single nucleotide polymorphisms (SNPs) in the MTR, MTRR, MTHFR, TYMS, ADH1C, ALDH2, GSTP1, NAT1, NAT2, CYP2E1 DRD2, DRD3, and SLC6A4 were genotyped...
  35. Yang S, Wang H, Li X, Du H, Zheng C, Chen H, et al. Genetic polymorphisms of ADH2 and ALDH2 association with esophageal cancer risk in southwest China. World J Gastroenterol. 2007;13:5760-4 pubmed
    To evaluate the impact of alcohol dehydrogenase 2 (ADH2) and aldehyde dehydrogenase 2 (ALDH2) polymorphisms on esophageal cancer risk...
  36. Perez Miller S, Younus H, Vanam R, Chen C, Mochly Rosen D, Hurley T. Alda-1 is an agonist and chemical chaperone for the common human aldehyde dehydrogenase 2 variant. Nat Struct Mol Biol. 2010;17:159-64 pubmed publisher
    In approximately one billion people, a point mutation inactivates a key detoxifying enzyme, aldehyde dehydrogenase (ALDH2)...
  37. Wang Y, Ji R, Wei X, Gu L, Chen L, Rong Y, et al. Esophageal squamous cell carcinoma and ALDH2 and ADH1B polymorphisms in Chinese females. Asian Pac J Cancer Prev. 2011;12:2065-8 pubmed
    Alcohol dehydrogenase-IB (ADH1B) and aldehyde dehydrogenase-2 (ALDH2) are the key enzymes for elimination of ethanol and acetaldehyde, the latter being an established animal carcinogen produced after drinking...
  38. Choi I, Kee B, Son H, Ham B, Yang B, Kim S, et al. Genetic polymorphisms of alcohol and aldehyde dehydrogenase, dopamine and serotonin transporters in familial and non-familial alcoholism. Eur Neuropsychopharmacol. 2006;16:123-8 pubmed
    ..healthy men were tested for the genetic polymorphisms of alcohol dehydrogenase 2 (ADH2), aldehyde dehydrogenase 2 (ALDH2), serotonin transporter (5-HTT) and dopamine transporter (DAT1)...
  39. Lu R, Ko H, Lee J, Lin W, Huang S, Wang T, et al. No alcoholism-protection effects of ADH1B*2 allele in antisocial alcoholics among Han Chinese in Taiwan. Alcohol Clin Exp Res. 2005;29:2101-7 pubmed
    suggested that the genetic variation at ADH1B and ALDH2 influences the risk of alcoholism. The ADH1B*2 and ALDH2*2 alleles had been thought to be protective against alcoholism...
  40. Seitz H, Meier P. The role of acetaldehyde in upper digestive tract cancer in alcoholics. Transl Res. 2007;149:293-7 pubmed
    ..It has been clearly shown in Asians that individuals carrying the acetaldehyde dehydrogenase 2*2 (ALDH2*2) allele have a significantly increased cancer risk when they consume alcohol...
  41. Zintzaras E, Stefanidis I, Santos M, Vidal F. Do alcohol-metabolizing enzyme gene polymorphisms increase the risk of alcoholism and alcoholic liver disease?. Hepatology. 2006;43:352-61 pubmed
    ..The present meta-analysis underscores significant associations of ADH2*1, ADH3*2, and ALDH2*1 alleles and the risk of alcoholism (OR = 1.89 [95% CI 1.56-2.28], 1.32 [95% CI 1.12-1.57], and 4.35 [95% CI 3...
  42. Cai L, You N, Lu H, Mu L, Lu Q, Yu S, et al. Dietary selenium intake, aldehyde dehydrogenase-2 and X-ray repair cross-complementing 1 genetic polymorphisms, and the risk of esophageal squamous cell carcinoma. Cancer. 2006;106:2345-54 pubmed
    ..The authors investigated the role of dietary selenium intake and its interplay with SNPs of the ALDH2 (glutamic acid [Glu] 487 lysine [Lys]) and the X-ray repair cross-complementing 1 (XRCC1) (arginine [Arg] 399 ..
  43. Linneberg A, Gonzalez Quintela A, Vidal C, Jørgensen T, Fenger M, Hansen T, et al. Genetic determinants of both ethanol and acetaldehyde metabolism influence alcohol hypersensitivity and drinking behaviour among Scandinavians. Clin Exp Allergy. 2010;40:123-30 pubmed publisher
    ..asthma and flushing have been shown to be because of a single nucleotide polymorphism (SNP), the acetaldehyde dehydrogenase 2 (ALDH2) 487lys, causing decreased acetaldehyde (the metabolite of ethanol) metabolism and high levels ..
  44. Wang Y, Zhang Y, Zhang J, Tang X, Qian Y, Gao P, et al. Association of a functional single-nucleotide polymorphism in the ALDH2 gene with essential hypertension depends on drinking behavior in a Chinese Han population. J Hum Hypertens. 2013;27:181-6 pubmed publisher
    ..Several epidemiological studies have investigated the association between hypertension and acetaldehyde dehydrogenase 2 (ALDH2) genotype, although the results are inconsistent...
  45. Matsuo K, Hamajima N, Hirai T, Kato T, Koike K, Inoue M, et al. Aldehyde dehydrogenase 2 (ALDH2) genotype affects rectal cancer susceptibility due to alcohol consumption. J Epidemiol. 2002;12:70-6 pubmed
    ..The alcohol related enzyme encoding gene ALDH2 has polymorphism Glu487Lys, and 487Lys allele is closely linked with phenotypic loss of enzyme activity...
  46. Yokoyama A, Kato H, Yokoyama T, Tsujinaka T, Muto M, Omori T, et al. Genetic polymorphisms of alcohol and aldehyde dehydrogenases and glutathione S-transferase M1 and drinking, smoking, and diet in Japanese men with esophageal squamous cell carcinoma. Carcinogenesis. 2002;23:1851-9 pubmed
    The genetic polymorphisms of aldehyde dehydrogenase-2 (ALDH2), alcohol dehydrogenase-2 (ADH2), ADH3, and glutathione S-transferase M1 (GSTM1) influence the metabolism of alcohol and other carcinogens...
  47. Nishimura F, Fukunaga T, Kajiura H, Umeno K, Takakura H, Ono T, et al. Effects of aldehyde dehydrogenase-2 genotype on cardiovascular and endocrine responses to alcohol in young Japanese subjects. Auton Neurosci. 2002;102:60-70 pubmed
    The present study was designed to investigate the effects of aldehyde dehydrogenase-2 (ALDH2) genotype on cardiovascular and endocrine responses to alcohol ingestion in young, healthy Japanese subjects...
  48. Lewis S, Smith G. Alcohol, ALDH2, and esophageal cancer: a meta-analysis which illustrates the potentials and limitations of a Mendelian randomization approach. Cancer Epidemiol Biomarkers Prev. 2005;14:1967-71 pubmed
    ..This can be illustrated by looking at the association between the ALDH2 polymorphism and esophageal cancer...
  49. Hui P, Nakayama T, Morita A, Sato N, Hishiki M, Saito K, et al. Common single nucleotide polymorphisms in Japanese patients with essential hypertension: aldehyde dehydrogenase 2 gene as a risk factor independent of alcohol consumption. Hypertens Res. 2007;30:585-92 pubmed
    ..including: obesity (adrenergic, beta-3-, receptor: ADRB3), alcohol consumption (aldehyde dehydrogenase 2: ALDH2), water-electrolyte metabolism (guanine nucleotide binding protein [G protein], beta polypeptide 3: GNB3), ..
  50. Peng G, Yin J, Wang M, Lee J, Hsu Y, Yin S. Alcohol sensitivity in Taiwanese men with different alcohol and aldehyde dehydrogenase genotypes. J Formos Med Assoc. 2002;101:769-74 pubmed
    ..that ADH2*2, encoding for high-maximal velocity (Vmax) beta2-alcohol dehydrogenase (ADH) activity, and mutant ALDH2*2, encoding for null aldehyde dehydrogenase (ALDH) 2 activity, independently influence susceptibility to ..
  51. Jo S, Kim E, Park M, Han C, Park H, Jang Y, et al. A Glu487Lys polymorphism in the gene for mitochondrial aldehyde dehydrogenase 2 is associated with myocardial infarction in elderly Korean men. Clin Chim Acta. 2007;382:43-7 pubmed
    A homozygous mutant (ALDH2*2/*2) of the gene for mitochondrial aldehyde dehydrogenase 2 (ALDH2) at codon 487 was reported to be associated with myocardial infarction (MI) among Japanese men...
  52. McKay J, Truong T, Gaborieau V, Chabrier A, Chuang S, Byrnes G, et al. A genome-wide association study of upper aerodigestive tract cancers conducted within the INHANCE consortium. PLoS Genet. 2011;7:e1001333 pubmed publisher
    ..in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene...
  53. Hirose M, Kono S, Tabata S, Ogawa S, Yamaguchi K, Mineshita M, et al. Genetic polymorphisms of methylenetetrahydrofolate reductase and aldehyde dehydrogenase 2, alcohol use and risk of colorectal adenomas: Self-Defense Forces Health Study. Cancer Sci. 2005;96:513-8 pubmed
    ..This study investigated the relationship of functional MTHFR C677T and ALDH2 polymorphisms to colorectal adenomas with reference to alcohol consumption in a case-control study of male ..
  54. Kawase T, Matsuo K, Hiraki A, Suzuki T, Watanabe M, Iwata H, et al. Interaction of the effects of alcohol drinking and polymorphisms in alcohol-metabolizing enzymes on the risk of female breast cancer in Japan. J Epidemiol. 2009;19:244-50 pubmed
    ..have investigated genetic polymorphisms of alcohol dehydrogenase-1B (ADH1B) His48Arg and aldehyde dehydrogenase-2 (ALDH2) Glu504Lys, because of the strong impact these polymorphisms have on exposure to and accumulation of acetaldehyde...
  55. Assanangkornchai S, Noi pha K, Saunders J, Ratanachaiyavong S. Aldehyde dehydrogenase 2 genotypes, alcohol flushing symptoms and drinking patterns in Thai men. Psychiatry Res. 2003;118:9-17 pubmed
    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...
  56. Munaka M, Kohshi K, Kawamoto T, Takasawa S, Nagata N, Itoh H, et al. Genetic polymorphisms of tobacco- and alcohol-related metabolizing enzymes and the risk of hepatocellular carcinoma. J Cancer Res Clin Oncol. 2003;129:355-60 pubmed
    ..S-transferase ( GST) M1, GSTT1, GSTP1-1( GSTP1), cytochrome P450 2E1 ( CYP2E1) and aldehyde dehydrogenase 2 ( ALDH2) on the risk of hepatocellular carcinoma (HCC) was observed in 78 Japanese patients with HCC and 138 non-cancer ..
  57. Li Y, Zhang D, Jin W, Shao C, Yan P, Xu C, et al. Mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys polymorphism contributes to the variation in efficacy of sublingual nitroglycerin. J Clin Invest. 2006;116:506-11 pubmed
    ..Recently, it was shown that mitochondrial aldehyde dehydrogenase-2 (ALDH2) is responsible for formation of NO, the metabolite needed for GTN efficacy...
  58. Ji Y, Tae K, Ahn T, Lee S, Kim K, Park C, et al. ADH1B and ALDH2 polymorphisms and their associations with increased risk of squamous cell carcinoma of the head and neck in the Korean population. Oral Oncol. 2011;47:583-7 pubmed publisher
    ..We genotyped ADH1B +3170A>G (rs1229984) and ALDH2 +1951G>A (rs671) SNPs in 225 Korean SCCHN patients and 301 healthy controls by single base extension and TaqMan ..
  59. Yokoyama A, Watanabe H, Fukuda H, Haneda T, Kato H, Yokoyama T, et al. Multiple cancers associated with esophageal and oropharyngolaryngeal squamous cell carcinoma and the aldehyde dehydrogenase-2 genotype in male Japanese drinkers. Cancer Epidemiol Biomarkers Prev. 2002;11:895-900 pubmed
    Aldehyde dehydrogenase-2 (ALDH2) is a key enzyme for the elimination of acetaldehyde, an established animal carcinogen generated by alcohol metabolism...
  60. Ohta S, Ohsawa I, Kamino K, Ando F, Shimokata H. Mitochondrial ALDH2 deficiency as an oxidative stress. Ann N Y Acad Sci. 2004;1011:36-44 pubmed
    Mitochondrial aldehyde dehydrogenase 2 (ALDH2) plays a major role in ethanol metabolism. It is involved in acetaldehyde detoxification. A polymorphism of the ALDH2 gene is specific to North-East Asians...
  61. Lee C, Lee J, Wu D, Goan Y, Chou S, Wu I, et al. Carcinogenetic impact of ADH1B and ALDH2 genes on squamous cell carcinoma risk of the esophagus with regard to the consumption of alcohol, tobacco and betel quid. Int J Cancer. 2008;122:1347-56 pubmed
    ..The genotoxic effect of the ADH1B and ALDH2 genes modulating an individual's alcohol-metabolizing capacity on ESCC may be linked to drinking behavior, intake ..
  62. Macgregor S, Lind P, Bucholz K, Hansell N, Madden P, Richter M, et al. Associations of ADH and ALDH2 gene variation with self report alcohol reactions, consumption and dependence: an integrated analysis. Hum Mol Genet. 2009;18:580-93 pubmed publisher
    ..The role of two genetic variants in ALDH2 and ADH1B in AD risk has been extensively investigated...
  63. Ferrari P, McKay J, Jenab M, Brennan P, Canzian F, Vogel U, et al. Alcohol dehydrogenase and aldehyde dehydrogenase gene polymorphisms, alcohol intake and the risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition study. Eur J Clin Nutr. 2012;66:1303-8 pubmed publisher
    ..into Cancer and Nutrition (EPIC) to evaluate the impact of rs1229984 (ADH1B), rs1573496 (ADH7) and rs441 (ALDH2) polymorphisms on CRC risk...
  64. Kuo P, Kalsi G, Prescott C, Hodgkinson C, Goldman D, van den Oord E, et al. Association of ADH and ALDH genes with alcohol dependence in the Irish Affected Sib Pair Study of alcohol dependence (IASPSAD) sample. Alcohol Clin Exp Res. 2008;32:785-95 pubmed publisher
    ..A total of 77 single nucleotide polymorphisms (SNPs) in the seven ADH (ADH1-7) and two ALDH genes (ALDH1A1 and ALDH2) were genotyped using the Illumina GoldenGate protocols...
  65. Iwai N, Tago N, Yasui N, Kokubo Y, Inamoto N, Tomoike H, et al. Genetic analysis of 22 candidate genes for hypertension in the Japanese population. J Hypertens. 2004;22:1119-26 pubmed
    ..NPHS2, SGK, SLC12A1, PTGES), and others related to cardiovascular physiology (GJA4, NOS1, NTRK3, P2RX4, SPP1, ALDH2)...
  66. Wu C, Wu D, Hsu H, Kao E, Lee J, Lin C, et al. Relationship between genetic polymorphisms of alcohol and aldehyde dehydrogenases and esophageal squamous cell carcinoma risk in males. World J Gastroenterol. 2005;11:5103-8 pubmed
    To investigate the association between the genetic polymorphisms of ADH2 and ALDH2, lifetime alcohol consumption and esophageal cancer risk in the Taiwanese men...
  67. Otani T, Iwasaki M, Hanaoka T, Kobayashi M, Ishihara J, Natsukawa S, et al. Folate, vitamin B6, vitamin B12, and vitamin B2 intake, genetic polymorphisms of related enzymes, and risk of colorectal cancer in a hospital-based case-control study in Japan. Nutr Cancer. 2005;53:42-50 pubmed
    ..Four genetic polymorphisms-MTHFR C677T and A1298C, MTRR A66G, and ALDH2 Glu487Lys-were determined using blood samples...
  68. Yamada Y, Imai T, Ishizaki M, Honda R. ALDH2 and CYP2E1 genotypes, urinary acetaldehyde excretion and the health consequences in moderate alcohol consumers. J Hum Genet. 2006;51:104-11 pubmed
    Deficiencies in mitochondrial low-Km aldehyde dehydrogenase (ALDH2) activity, and consequently high blood acetaldehyde levels, have been suggested to relate to various diseases in Japanese, including esophageal cancer...
  69. Yokoyama A, Omori T, Tanaka Y, Yokoyama T, Sugiura H, Mizukami T, et al. p53 Protein accumulation, cancer multiplicity, and aldehyde dehydrogenase-2 genotype in Japanese alcoholic men with early esophageal squamous cell carcinoma. Cancer Lett. 2007;247:243-52 pubmed
    ..with esophageal SCC, and more frequently found in those with inactive heterozygous aldehyde dehydrogenase-2 (ALDH2). p53 alterations have been suspected as key molecular events in such multifocal esophageal carcinogenesis...
  70. Nagasawa H, Wada M, Arawaka S, Kawanami T, Kurita K, Daimon M, et al. A polymorphism of the aldehyde dehydrogenase 2 gene is a risk factor for multiple lacunar infarcts in Japanese men: the Takahata Study. Eur J Neurol. 2007;14:428-34 pubmed
    ..of the present study was to examine the association between a polymorphism of the aldehyde dehydrogenase 2 (ALDH2) gene and lacunar infarcts of the brain...
  71. Chen L, Smith G, Harbord R, Lewis S. Alcohol intake and blood pressure: a systematic review implementing a Mendelian randomization approach. PLoS Med. 2008;5:e52 pubmed publisher
    ..robust evidence on the nature of this association by use of a common polymorphism in aldehyde dehydrogenase 2 (ALDH2) as a surrogate for measuring alcohol consumption. ALDH2 encodes a major enzyme involved in alcohol metabolism...
  72. Guo Y, Wang Q, Liu Y, Chen H, Qi Z, Guo Q. Genetic polymorphisms in cytochrome P4502E1, alcohol and aldehyde dehydrogenases and the risk of esophageal squamous cell carcinoma in Gansu Chinese males. World J Gastroenterol. 2008;14:1444-9 pubmed
    To evaluate the association between genetic polymorphisms in CYP2E1, ALDH2 and ADH1B and the risk of esophageal squamous cell carcinoma (ESCC) in a high risk area of Gansu Province, in Chinese males...
  73. Husemoen L, Fenger M, Friedrich N, Tolstrup J, Beenfeldt Fredriksen S, Linneberg A. The association of ADH and ALDH gene variants with alcohol drinking habits and cardiovascular disease risk factors. Alcohol Clin Exp Res. 2008;32:1984-91 pubmed publisher
    ..The ALDH1b ala69val variant was associated with nondrinking and total alcohol intake. The ALDH2 promoter variant was associated with binge-drinking, and the ALDH1b1 ala69val polymorphism was associated with ..
  74. Zhang G, Mai R, Huang B. Meta-analysis of ADH1B and ALDH2 polymorphisms and esophageal cancer risk in China. World J Gastroenterol. 2010;16:6020-5 pubmed
    To evaluate whether alcohol dehydrogenase-1B (ADH1B) His47Arg and aldehyde dehydrogenase-2 (ALDH2) Glu487Lys polymorphism is involved in the esophageal squamous cell carcinoma (ESCC) risk in Chinese Han population...
  75. Duell E, Sala N, Travier N, Munoz X, Boutron Ruault M, Clavel Chapelon F, et al. Genetic variation in alcohol dehydrogenase (ADH1A, ADH1B, ADH1C, ADH7) and aldehyde dehydrogenase (ALDH2), alcohol consumption and gastric cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Carcinogenesis. 2012;33:361-7 pubmed publisher
    ..loci (alcohol dehydrogenase, ADH1 gene cluster: ADH1A, ADH1B and ADH1C; ADH7 and aldehyde dehydrogenase, ALDH2), alcohol intake and GC risk...
  76. Wang H, Zhou P, Liu P, Zhang Y. ALDH2 and ADH1 genetic polymorphisms may contribute to the risk of gastric cancer: a meta-analysis. PLoS ONE. 2014;9:e88779 pubmed publisher
    We conducted a meta-analysis of case-control studies to determine whether ALDH2, ADH1 and ADH2 genetic polymorphisms contribute to the pathogenesis of gastric cancer...
  77. Sun F, Tsuritani I, Yamada Y. Contribution of genetic polymorphisms in ethanol-metabolizing enzymes to problem drinking behavior in middle-aged Japanese men. Behav Genet. 2002;32:229-36 pubmed
    Among ethanol-metabolizing enzymes, the ALDH2*2 allele, ADH2*2 allele, and c2 allele of the cytochrome P450-2E1 (CYP2E1) gene are unique to Orientals...
  78. Choi J, Abel J, Neuhaus T, Ko Y, Harth V, Hamajima N, et al. Role of alcohol and genetic polymorphisms of CYP2E1 and ALDH2 in breast cancer development. Pharmacogenetics. 2003;13:67-72 pubmed
    ..association between alcohol consumption and genetic polymorphisms in the alcohol metabolizing enzymes, CYP2E1 and ALDH2, in individual susceptibility to breast cancer in a Korean study population...
  79. Asakage T, Yokoyama A, Haneda T, Yamazaki M, Muto M, Yokoyama T, et al. Genetic polymorphisms of alcohol and aldehyde dehydrogenases, and drinking, smoking and diet in Japanese men with oral and pharyngeal squamous cell carcinoma. Carcinogenesis. 2007;28:865-74 pubmed
    The genetic polymorphisms of aldehyde dehydrogenase-2 (ALDH2), alcohol dehydrogenase-1B (ADH1B, previously called ADH2), and ADH1C (previously called ADH3) affect the metabolism of alcohol...
  80. Zhou S, Huriletemuer -, Wang J, Zhang C, Zhao S, Wang D, et al. Absence of association on aldehyde dehydrogenase 2 (ALDH2) polymorphism with Mongolian Alzheimer patients. Neurosci Lett. 2010;468:312-5 pubmed publisher
    ..Furthermore, another gene mitochondrial aldehyde dehydrogenase (ALDH2) has also been proposed to be potentially associated with AD, based on its possible relations toward acetaldehyde ..
  81. Yokoyama A, Mizukami T, Matsui T, Yokoyama T, Kimura M, Matsushita S, et al. Genetic polymorphisms of alcohol dehydrogenase-1B and aldehyde dehydrogenase-2 and liver cirrhosis, chronic calcific pancreatitis, diabetes mellitus, and hypertension among Japanese alcoholic men. Alcohol Clin Exp Res. 2013;37:1391-401 pubmed publisher
    ..2 allele) and active form of aldehyde dehydrogenase-2 (ALDH2) encoded by ALDH2*1/*1 (vs. *2 allele) increases the risk of alcoholism in East Asians...
  82. Yokoyama A, Tsutsumi E, Imazeki H, Suwa Y, Nakamura C, Mizukami T, et al. Salivary acetaldehyde concentration according to alcoholic beverage consumed and aldehyde dehydrogenase-2 genotype. Alcohol Clin Exp Res. 2008;32:1607-14 pubmed publisher
    ..Inactive heterozygous aldehyde dehydrogenase-2 (ALDH2) increases the risk of UADT cancer in drinkers...
  83. Shin C, Kim N, Cho S, Kim J, Jung H, Song I. Association between alcohol intake and risk for gastric cancer with regard to ALDH2 genotype in the Korean population. Int J Epidemiol. 2011;40:1047-55 pubmed publisher
    ..between alcohol consumption and the risk for gastric cancer was investigated in the Korean population with the ALDH2 genotype...
  84. Brennan P, Lewis S, Hashibe M, Bell D, Boffetta P, Bouchardy C, et al. Pooled analysis of alcohol dehydrogenase genotypes and head and neck cancer: a HuGE review. Am J Epidemiol. 2004;159:1-16 pubmed
    ..for alcohol dehydrogenase (ADH), ADH1B*2 and ADH1C*1, and the null allele for aldehyde dehydrogenase (ALDH), ALDH2*2, results in increased acetylaldehyde levels and is hypothesized to increase the risk of head and neck cancer...
  85. Kollau A, Hofer A, Russwurm M, Koesling D, Keung W, Schmidt K, et al. Contribution of aldehyde dehydrogenase to mitochondrial bioactivation of nitroglycerin: evidence for the activation of purified soluble guanylate cyclase through direct formation of nitric oxide. Biochem J. 2005;385:769-77 pubmed
    ..Conversion of GTN into 1,2-GDN (1,2-glycerol dinitrate) and nitrite by mitochondrial ALDH2 (aldehyde dehydrogenase 2) may be an essential pathway of GTN bioactivation in blood vessels...
  86. Luo X, Kranzler H, Zuo L, Wang S, Schork N, Gelernter J. Diplotype trend regression analysis of the ADH gene cluster and the ALDH2 gene: multiple significant associations with alcohol dependence. Am J Hum Genet. 2006;78:973-87 pubmed
    ..within the ADH gene cluster (including the ADH1A, ADH1B, ADH1C, ADH5, ADH6, and ADH7 genes), 4 markers within the ALDH2 gene, and 38 unlinked ancestry-informative markers in a case-control sample of 801 individuals...
  87. Zhang F, Hou L, Terry M, Lissowska J, Morabia A, Chen J, et al. Genetic polymorphisms in alcohol metabolism, alcohol intake and the risk of stomach cancer in Warsaw, Poland. Int J Cancer. 2007;121:2060-4 pubmed
    ..ADH1B (Ex9+5C>T, Ex3+23A>G, Ex3+58A>T and Ex9+77A>G), ADH1C (Ex8-56A>G and Ex6-14G>A) and ALDH2 (Ex1+82A>G), on levels of alcohol drinking and susceptibility of stomach cancer...
  88. Yang H, Zhou Y, Zhou Z, Liu J, Yuan X, Matsuo K, et al. A novel polymorphism rs1329149 of CYP2E1 and a known polymorphism rs671 of ALDH2 of alcohol metabolizing enzymes are associated with colorectal cancer in a southwestern Chinese population. Cancer Epidemiol Biomarkers Prev. 2009;18:2522-7 pubmed publisher
    To screen for tagging single nucleotide polymorphisms (tagSNP) in the major alcohol metabolizing enzymes: ADH1B, ALDH2, and CYP2E1, and to evaluate the association between these tagSNPs and colorectal cancer (CRC) in a southwestern ..
  89. Husemoen L, Jørgensen T, Borch Johnsen K, Hansen T, Pedersen O, Linneberg A. The association of alcohol and alcohol metabolizing gene variants with diabetes and coronary heart disease risk factors in a white population. PLoS ONE. 2010;5:e11735 pubmed publisher
    ..interactions were observed between alcohol and ADH1b (rs1229984) with respect to LDL and between alcohol and ALDH2 (rs886205) with respect to IGT/diabetes...
  90. Wu M, Chang S, Kampman E, Yang J, Wang X, Gu X, et al. Single nucleotide polymorphisms of ADH1B, ADH1C and ALDH2 genes and esophageal cancer: a population-based case-control study in China. Int J Cancer. 2013;132:1868-77 pubmed publisher
    ..China, we aimed to provide further information on the association of ADH1B (rs1229984), ADH1C (rs698) and ALDH2 (rs671) polymorphisms with EC in a Chinese population...
  91. Nakagawa T, Kajiwara A, Saruwatari J, Hamamoto A, Kaku W, Oniki K, et al. The combination of mitochondrial low enzyme-activity aldehyde dehydrogenase 2 allele and superoxide dismutase 2 genotypes increases the risk of hypertension in relation to alcohol consumption. Pharmacogenet Genomics. 2013;23:34-7 pubmed publisher
    A cooperative role of mitochondrial aldehyde dehydrogenase 2 (ALDH2) and superoxide dismutase 2 (SOD2) to maintain the vascular function has recently been demonstrated in nitrate tolerance...
  92. Kuriki K, Hamajima N, Chiba H, Kanemitsu Y, Hirai T, Kato T, et al. Relation of the CD36 gene A52C polymorphism to the risk of colorectal cancer among Japanese, with reference to with the aldehyde dehydrogenase 2 gene Glu487Lys polymorphism and drinking habit. Asian Pac J Cancer Prev. 2005;6:62-8 pubmed
    ..and oxidized low-density lipoprotein (LDL) scavenger, while alcohol is metabolized by aldehyde dehydrogenase 2 (ALDH2) and decreases transiently metabolism of dietary fat and serum lipids...