Interaction between the functional polymorphisms of the alcohol-metabolism genes in protection against alcoholism.

The genes that encode the major enzymes of alcohol metabolism, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), exhibit functional polymorphism. The variant alleles ADH2*2 and ADH3*1, which encode high-activity ADH isoforms, and the ALDH2*2 allele, which encodes the low-activity form of ALDH2, protect against alcoholism in East Asians. To investigate possible interactions among these protective genes, we genotyped 340 alcoholic and 545 control Han Chinese living in Taiwan at the ADH2, ADH3, and ALDH2 loci. After the influence of ALDH2*2 was controlled for, multiple logistic regression analysis indicated that allelic variation at ADH3 exerts no significant effect on the risk of alcoholism. This can be accounted for by linkage disequlibrium between ADH3*1 and ADH2*2 ALDH2*2 homozygosity, regardless of the ADH2 genotypes, was fully protective against alcoholism; no individual showing such homozygosity was found among the alcoholics. Logistic regression analyses of the remaining six combinatorial genotypes of the polymorphic ADH2 and ALDH2 loci indicated that individuals carrying one or two copies of ADH2*2 and a single copy of ALDH2*2 had the lowest risk (ORs 0.04-0.05) for alcoholism, as compared with the ADH2*1/*1 and ALDH2*1/*1 genotype. The disease risk associated with the ADH2*2/*2-ALDH2*1/*1 genotype appeared to be about half of that associated with the ADH2*1/*2-ALDH2*1/*1 genotype. The results suggest that protection afforded by the ADH2*2 allele may be independent of that afforded by ALDH2*2.     

Genotypes of alcohol-metabolizing enzymes in Japanese with alcohol liver diseases: a strong association of the usual Caucasian-type aldehyde dehydrogenase gene (ALDH1(2)) with the disease

Genetic polymorphisms of two major alcohol-metabolizing enzymes-i.e., one of the class I alcohol dehydrogenase isozymes (ADH2) and the mitochondrial aldehyde dehydrogenase (ALDH2)-exist in Japanese and other Orientals but not in Caucasians. Liver ADH activity of about 90% of Orientals is much higher than that of most Caucasians, while approximately 50% of Orientals lack the ALDH2 activity. The genetic differences have been implicated in the high incidence of alcohol sensitivity observed in Orientals. We determined, by means of hybridization of genomic DNA samples with allele-specific synthetic oligonucleotide probes, genotypes of the ADH2 and the ALDH2 loci of Japanese with alcoholic liver diseases and of control subjects. No significant difference between the patient and control groups was found in the ADH2 genotypes. A remarkable genetic difference between the two groups was found in the ALDH2 locus. The frequency of the typical (Caucasian-type) ALDH1(2) gene was found to be .65 and that of the atypical (Oriental type) ALDH2(2) gene was .35 in the controls, while these were .93 and .07, respectively, in the patients. Thus, most (20 of 23) of the Japanese patients were homozygous Caucasian type ALDH1(2)/ALDH1(2), only three were heterozygous ALDH1(2)/ALDH2(2), and none of the patients were homozygous Oriental type ALDH2(2)/ALDH2(2). The results indicate that Japanese with the atypical ALDH2(2) allele are at a much lower risk in developing the alcoholic liver diseases than are those with homozygous, usual (Caucasian-type) ALDH1(2)/ALDH1(2), presumably owing to their sensitivity to alcohol intoxication.     

Association analysis of gene polymorphism in alcohol metabolizing enzymes with risk for coronary atherosclerosis

The allele and genotype distribution of two alcohol dehydrogenase genes ADH1B (exon 3 polymorphism A/G (47His)), ADH7 (intron 5 polymorphism G/C) and cytochrome P450 2E1 gene (CYP2E1; 5'-flanking region G/C and intron 6 T/A polymorphisms) were examined in Russian (Tomsk, n = 125) healthy population and in coronary atherosclerosis patients (CA, n = 92). The genotype frequencies followed the Hardy-Weinberg equilibrium and the alleles were in linkage equilibrium or gametic equilibrium in the control sample. Only two CYP2E1 gene polymorphisms were in linkage disequilibrium. The frequencies of the derived alleles at ADH1B (*G (+MslI) allele), CYP2E1 (**C2 (+PstI) allele) and CYP2E1 (*C (-Dra I)2 allele) were 8.48 +/- 1.86%; 1.20 +/- 0.69% and 10.00 +/- 1.90%, respectively. The 2ADH7 gene polymorphism showed a high level of heterozygosity; the frequency of the ADH7*C (-Sty I) allele was 44.58 +/- 3.21%. A significantly higher frequency of CYP2E1 (*C2 (+Pst I)) allele has been revealed in the CA group (P = 0.043; OR = 4.23; 95% CI 1.03-20.01). The tendency to significant effect of A1A2 genotype in ADH1B Msl 1 polymorphism was observed for systolic blood pressure in the control group (P = 0.068). The statistically significant two-way interaction effects of ADH7 StyI and CYP2E1 DraI on diastolic blood pressure (P = 0.029) and on the serum high density lipoprotein level (P = 0,042) were also revealed. Association of A1A2 genotype in ADHIB Msl I polymorphism with reduced amount in a serum of a very low density lipoprotein level (P = 0.045) have also been shown. This may result from multifunctional activity of alcohol metabolizing enzymes and their involvement in many metabolic and free radical reactions in the body.     

Metabolic control analysis and enzyme variation: nutritional manipulation of the flux from ethanol to lipids in Drosophila.

The effect that variation in activities of the enzymes alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) has on the flux from 14C-ethanol to lipids was examined in third-instar larvae of Drosophila melanogaster and D. simulans. The activities of ADH and ALDH were also nutritionally manipulated by the inhibitor, cyanamide. Feeding larvae cyanamide before the flux test eliminated greater than 98% of the ALDH activity but only 40% of the ADH activity. The mean +/- SD flux control coefficient for ADH activity was 0.86 +/- 0.12, and that for ALDH activity was 0.02 +/- 0.07. This suggests that ADH is the major rate-limiting enzyme for the ethanol-to-lipid pathway in Drosophila larvae under the current experimental conditions.     

Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese men.

The liver enzymes alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), which are responsible for the oxidative metabolism of ethanol, are polymorphic in humans. An allele encoding an inactive form of the mitochondrial ALDH2 is known to reduce the likelihood of alcoholism in Japanese. We hypothesized that the polymorphisms of both ALDH and ADH modify the predisposition to development of alcoholism. Therefore, we determined the genotypes of the ADH2, ADH3, and ALDH2 loci of alcoholic and nonalcoholic Chinese men living in Taiwan, using leukocyte DNA amplified by the PCR and allele-specific oligonucleotides. The alcoholics had significantly lower frequencies of the ADH2*2, ADH3*1, and ALDH2*2 alleles than did the nonalcoholics, suggesting that genetic variation in both ADH and ALDH, by modulating the rate of metabolism of ethanol and acetaldehyde, influences drinking behavior and the risk of developing alcoholism.     

Hardy weinberg expectations in canine breeds: implications for genetic studies

Hardy-Weinberg equilibrium (HWE) is a useful indicator of genotype frequencies within a population and whether they are based on a valid definition of alleles and a randomly mating sample. HWE assumes a stable population of adequate size without selective pressures and is used in human genetic studies as a guide to data quality by comparing observed genotype frequencies to those expected within a population. The calculation of genetic associations in case-control studies assume that the population is "in HWE." Canine breed populations deviate away from many of the criteria for HWE, and if genetic markers are not in HWE, conventional statistical analysis cannot be performed. To date, little attention has been paid as to whether genetic markers in dog breeds are distributed in compliance to HWE. In this study, 109 single-nucleotide polymorphisms (SNPs) were genotyped from 13 genes in a cohort of 894 dogs encompassing 33 breeds. Analysis of the entire cohort of dogs revealed a significant deviation away from HWE for all SNPs tested (P < 0.00001); analysis of the cohort stratified by breed and subbreed indicated that the majority of the markers complied with HWE expectation. This suggests that canine case-control association studies will be valid if performed within defined breeds.     

Robust indices of Hardy-Weinberg disequilibrium for QTL fine mapping

Hardy-Weinberg disequilibrium (HWD) measures have been proposed using dense markers to fine map a quantitative trait locus (QTL) to regions < approximately 1 cM. Earlier HWD measures may introduce bias in the fine mapping because they are dependent on marker allele frequencies across loci. Hence, HWD indices that do not depend on marker allele frequencies are desired for fine mapping. Based on our earlier work, here we present four new HWD indices that do not depend on marker allele frequencies. Two are for use when marker allele frequencies in a study population are known, and two are for use when marker allele frequencies in a study population are not known and are only known in the extreme samples. The new measures are a function of the genetic distance between the marker locus and a QTL. Through simulations, we investigated and compared the fine mapping performance of the new HWD measures with that of the earlier ones. Our results show that when marker allele frequencies vary across loci, the new measures presented here are more robust and powerful.     

洛阳市汉族群体ADH2和ALDH2的基因多态性研究

为研究洛阳市汉族群体ADH2和ALDH2基因的多态性分布,应用聚合酶链反应-扩增片段长度多态性（PCR-APLP）分析法,对ADH2基因外显子3和ALDH2基因外显子12的特定片段同时进行特异性扩增,用非变性的聚丙烯酰胺垂直凝胶电泳和DNA银染方法判定基因型。ADH2*1和ADH2*2等位基因频率分别为42.86%和57.14%,ADH2*1/*1、*1/*2和*2/*2的基因型频率分别为22.86%、40.00%和37.14%;ALDH2*1和ALDH2*2的等位基因频率分别为85.24%和14.76%,ALDH2*1/*1、*1/*2和*2/*2的基因型频率分别为71.43%、27.62%和0.95%。洛阳市汉族群体ADH2和ALDH2的等位基因频率和基因型频率不同于台湾人和上海人,ALDH2*1/*1基因型频率明显高于上海人和台湾人的。因而,洛阳市居民对酒精的耐受性比上海人和台湾人强。 Studies of Genetic Polymorphisms of ADH2 and ALDH2 among the Han Population in Luoyang China ZHANG Zhu-mei1,LIU Cha-zhen1,BIAN Jian-chao1,TANG Bo-ming2,JIANG Feng1,WANG Qi-jun2,WANG Qi-min2,ZHU Xin2,SHEN Fu-min1 1.Department of Epidemiology,Public Health School of Fudan University,Shanghai 200032,China; 2.Section Office of Epidemiology,Luoyang Hygiene and Anti-epidemic Center,Luoyang 471000,China Abstract:In order to investigate genetic polymorphisms of ADH2 and ALDH2 among the Han population in Luoyang City,portions of exon 3 of ADH2 and exon 12 of ALDH gene were amplified by using polymerase chain reaction.The amplified products were electrophoresed on 10% undenatured vertical polyacrylamide gels and stained with argentine.Frequencies of ADH2*1 and ADH2*2 alleles are 42.86% and 57.14%.Frequencies of three genotypes of ADH2 are 22.86%、40.00% and 37.14%,respectively.Frequencies of ALDH2*1 and ALDH2*2 alleles are 85.24% and 14.76%.Genotype frequencies of ALDH2 loci are 71.43%、27.62% and 0.95%,respectively.Genetic polymorphisms of ADH2 and ALDH2 among the Han population in Luoyang City are different from those among Taiwanese and Shanghainese.Frequency of ALDH2*1/*1 in Luoyang people is higher than those in Shanghai and Taiwan.Therefore,there is a higher resistance to alcohol drinking in the Han population in Luoyang. Key words：polymerase chain reaction-amplified products length polymorphism; alcohol dehydrogenase 2; aldehyde dehydrogenase 2; genetic     

Polymorphisms of alcohol metabolizing enzyme and cytochrome P4502E1 genes in mongolian population

Although the genetic polymorphism of the alcohol-metabolizing enzymes was extensively studied at the molecular level by many investigators, the genetic polymorphism studies for ethanolmetabolizing enzymes in Mongolians are very rare. The present study was therefore performed to determine the genetic distribution of various forms of alcohol-metabolizing enzymes such as alcohol dehydrogenase 2 (ADH2, currently accepted nomenclature ADH1B), ADH3 (ADH1C), aldehyde dehydrogenase 2 (ALDH2) and cytochrome P4502E1 (CYP2E1) in 300 healthy Mongolian males. Genetic polymorphisms were determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) methods. The allele frequencies ofADH2 *1 andADH2 *2 were 0.24 and 0.76;ADH3 *1 andADH3 *2 were 0.92 and 0.08;ALDH2 *1 andALDH2 *2 were 0.96 and 0.04; andCYP2E1 *C andCYP2E1 *D were 0.15 and 0.85, respectively. Compared to the results reported by other investigators, the allele frequencies ofALDH2 *2 andCYP2E1 *C among Mongolian subjects were much lower than among East Asians (Korean, Japanese, and/or Han-Chinese), while those ofADH2 andADH3 were more similar. Interestingly, this study shows that the ineffectiveALDH2 gene (ALDH2*2 allele) among Mongolians is not as common as among East Asians.     

Genetics of alcohol dehydrogenase and aldehyde dehydrogenase from Monodelphis domestica cornea: further evidence for identity of corneal aldehyde dehydrogenase with a major soluble protein

A didelphid marsupial, the gray short-tailed opossum (Monodelphis domestica), was used as a model species to study the biochemical genetics of alcohol dehydrogenases (ADHs) and aldehyde dehydrogenase (ALDH) in corneal tissue. Isoelectric point variants of corneal ALDH (designated ALDH3) and a major soluble protein in corneal extracts were observed among eight families of animals used in studying the genetics of these proteins. Both phenotypes exhibited identical patterns following PAGE-IEF and were inherited in a normal Mendelian fashion, with two alleles at a single locus (ALDH3) showing codominant expression. The data provided evidence for genetic identity of corneal ALDH with this major soluble protein, and supported biochemical evidence, recently reported for purified bovine corneal ALDH, that this enzyme constitutes a major portion of soluble corneal protein (Abedinia et al. 1990). Isoelectric point variants for corneal ADH were also observed, with patterns for the two major forms (ADH3 and ADH4) and one minor form (ADH5) being consistent with the presence of two ADH subunits (designated gamma and delta), and variant phenotypes existing for the gamma subunit. The genetics of this enzyme was studied in the eight families, and the results were consistent with codominant expression of two alleles at a single locus (designated ADH3). It is relevant that a major detoxification function has been proposed for corneal ADH and ALDH, in the oxidoreduction of peroxidic aldehydes induced by available oxygen and UV-B light (Holmes & VandeBerg, 1986a). In addition, a direct role for corneal ALDH as a UV-B photoreceptor in this anterior eye tissue has also been proposed (Abedinia et al. 1990).     

Population genetics of the yellow fever mosquito in Trinidad: comparisons of amplified fragment length polymorphism (AFLP) and restriction fragment length polymorphism (RFLP) markers

Recent development of DNA markers provides powerful tools for population genetic analyses. Amplified fragment length polymorphism (AFLP) markers result from a polymerase chain reaction (PCR)-based DNA fingerprinting technique that can detect multiple restriction fragments in a single polyacrylamide gel, and thus are potentially useful for population genetic studies. Because AFLP markers have to be analysed as dominant loci in order to estimate population genetic diversity and genetic structure parameters, one must assume that dominant (amplified) alleles are identical in state, recessive (unamplified) alleles are identical in state, AFLP fragments segregate according to Mendelian expectations and that the genotypes of an AFLP locus are in Hardy-Weinberg equilibrium (HWE). The HWE assumption is untestable for natural populations using dominant markers. Restriction fragment length polymorphism (RFLP) markers segregate as codominant alleles, and can therefore be used to test the HWE assumption that is critical for analysing AFLP data. This study examined whether the dominant AFLP markers could provide accurate estimates of genetic variability for the Aedes aegypti mosquito populations of Trinidad, West Indies, by comparing genetic structure parameters using AFLP and RFLP markers. For AFLP markers, we tested a total of five primer combinations and scored 137 putative loci. For RFLP, we examined a total of eight mapped markers that provide a broad coverage of mosquito genome. The estimated average heterozygosity with AFLP markers was similar among the populations (0.39), and the observed average heterozygosity with RFLP markers varied from 0.44 to 0.58. The average FST (standardized among-population genetic variance) estimates were 0.033 for AFLP and 0.063 for RFLP markers. The genotypes at several RFLP loci were not in HWE, suggesting that the assumption critical for analysing AFLP data was invalid for some loci of the mosquito populations in Trinidad. Therefore, the results suggest that, compared with dominant molecular markers, codominant DNA markers provide better estimates of population genetic variability, and offer more statistical power for detecting population genetic structure.     

Alcohol dehydrogenases ADH1B and ADH7 gene polymorphism in Russian population from the Siberian region

The Allele and genotype didtributions of the two alcohol dehydrogenase genes ADH1B (polymorphism A/G in exon 3, detected with restrictase MslI) and ADH7 (polymorphism G/C in intron 5, detected with restrictase StyI) was studied in three Russian populations from the Siberian region. The absence of interpopulation and intersexual differences in the allele frequency was determined. The allele ADH1B*G (+MslI, A2) was found in low frequency (3.6-7.5%), the mutant allele ADH7 (-StyI, B2) frequency in total population (n = 339) was 46.02%. The genotype distributions of the ADH1B and ADH7 in these populations were agreed with the Hardy-Weinberg equilibrium and linkage equilibrium. Increased frequency of ADH7 B2 allele was revealed in elder group (after 40 years) in the total sample and in the Tomsk city inhabitants (n = 113) on 11% (P = 0.001) and 9% (P = 0.017) accordingly. ADH7 and ADH1B genes polymorpisms did not show association with antioxidant activity, which was determined from the blood plasma ability to reduce the yield of products interacting with thiobarbituric acid in the lecitin-Fe2+ ions model system. The statistically significant decrease of serum very low density lipoproteins (LPVLD) level (on 9.95%, P = 0.045) and close to statistically significant decrease systolic pressure (on 6.80%, P = 0.068) and serum triglycerides level (on 6.16 of %, P = 0.058) were revealed among the A2 allele ADH1B gene carriers in Tomsk population.     

An estimate of polymorphism of ADH1B,ALDH2, and CYP2E1 alcohol biotransformation genes in Siberian indigenous and immigrant populations

In the present article, the polymorphism of ADH1B, ALDH2, and CYP2E1 genes is studied in populations of Shors, Russians of Siberia, and progenies of mixed Russian-Shor marriages. Reliable differences between groups according to the frequency of ADH1B, ALDH2, and CYP2E1 genotypes and alleles are revealed. The article shows the high heterozygosis levels of the ADH1B and ALDH2 genes. Gene distances prove that mongrels and Shors are very close to each other (d = 0.005) and Russians of Siberia are not similar to the Russians of the Central Russia (d = 0.046).     

Further clarification of the contribution of the ADH1C gene to vulnerability of alcoholism and selected liver diseases

The alcohol dehydrogenase 1C (ADH1C) subunit is an important member of the alcohol dehydrogenase family, a set of genes that plays a major role in the catabolism of ethanol. Numerous association studies have provided compelling evidence that ADH1C gene variation (formerly ADH3) is associated with altered genetic susceptibility to alcoholism and alcohol-related liver disease, cirrhosis, or pancreatitis. However, the results have been inconsistent, partially, because each study involved a limited number of subjects, and some were underpowered. Using cumulative data over the past two decades, this meta-analysis (6,796 cases and 6,938 controls) considered samples of Asian, European, African, and Native American origins to examine whether the aggregate genotype provide statistically significant evidence of association. The results showed strong evidence of association between ADH1C Ile350Val (rs698, formerly ADH1C *1/*2) and alcohol dependence (AD) and abuse in the combined studies. The overall allelic (Val vs. Ile or *2 vs. *1) P value was 1 × 10(-8) and odds ratio (OR) was 1.51 (1.31, 1.73). The Asian populations produced stronger evidence of association with an allelic P value of 4 × 10(-33) [OR 2.14 (1.89, 2.43)] with no evidence of heterogeneity, and the dominant and recessive models revealed even stronger effect sizes. The strong evidence remained when stricter criteria and sub-group analyses were applied, while Asians always showed stronger associations than other populations. Our findings support that ADH1C Ile may lower the risk of AD and alcohol abuse as well as alcohol-related cirrhosis in pooled populations, with the strongest and most consistent effects in Asians.     

Extended genetic effects of ADH cluster genes on the risk of alcohol dependence: from GWAS to replication

Alcohol dependence (AD) is a multifactorial and polygenic disorder involving complex gene-to-gene and gene-to-environment interactions. Several genome-wide association studies have reported numerous risk factors for AD, but replication results following these studies have been controversial. To identify new candidate genes, the present study used GWAS and replication studies in a Korean cohort with AD. Genome-wide association analysis revealed that two chromosome regions on Chr. 4q22-q23 (ADH gene cluster, including ADH5, ADH4, ADH6, ADH1A, ADH1B, and ADH7) and Chr. 12q24 (ALDH2) showed multiple association signals for the risk of AD. To investigate detailed genetic effects of these ADH genes on AD, a follow-up study of the ADH gene cluster on 4q22-q23 was performed. A total of 90 SNPs, including ADH1B rs1229984 (H47R), were genotyped in an additional 975 Korean subjects. In case–control analysis, ADH1B rs1229984 (H47R) showed the most significant association with the risk of AD (p = 2.63 × 10^?21, OR = 2.35). Moreover, subsequent conditional analyses revealed that all positive associations of other ADH genes in the cluster disappeared, which suggested that ADH1B rs1229984 (H47R) might be the sole functional genetic marker across the ADH gene cluster. Our findings could provide additional information on the ADH gene cluster regarding the risk of AD, as well as a new and important insight into the genetic factors associated with AD.     

Aldehyde dehydrogenase gene superfamily: the 2000 update

Aldehyde dehydrogenase (ALDH) superfamily represents a group of NAD(P)(+)-dependent enzymes that catalyze the oxidation of a wide spectrum of endogenous and exogenous aldehydes. With the advent of megabase genome sequencing, the ALDH superfamily is expanding rapidly on many fronts. As expected, ALDH genes are found in virtually all genomes analyzed to date, indicating the importance of these enzymes in biological functions. Complete genome sequences of various species have revealed additional ALDH genes. As of July 2000, the ALDH superfamily consists of 331 distinct genes, of which eight are found in archaea, 165 in eubacteria, and 158 in eukaryota. The number of ALDH genes in some species with their genomes completely sequenced and annotated, Escherichia coli and Caenorhabditis elegans, ranges from 10 to 17. In the human genome, 17 functional genes and three pseudogenes have been identified to date. Divergent evolution, based on multiple alignment analysis of 86 eukaryotic ALDH amino-acid sequences, was the basis of the standardized ALDH gene nomenclature system (Pharmacogenetics 9: 421-434, 1999). Thus far, the eukaryotic ALDHs comprise 20 gene families. A complete list of all ALDH sequences known to date is presented here along with the evolution analysis of the eukaryotic ALDHs.     

Liver alcohol dehydrogenase and aldehyde dehydrogenase in the Japanese: isozyme variation and its possible role in alcohol intoxication.

Forty autopsy livers from Japanese individuals were studied concerning alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) isozymes using electrophoretic and enzyme assay methods. A remarkably high frequency (85%) was found for the atypical ADH phenotype. The gene frequencies of ADH22 and ADH32 were .625 and .05, respectively. The usual ALDH phenotype showed two major isozyme bands, a faster migrating (low Km for acetaldehyde) and a slower migrating isozyme (high Km for acetaldehyde). Fifty-two percent of the specimens had an unusual phenotype of ALDH, which showed only the slower migrating isozyme. The usual phenotype was inhibited about 20%--30% by disulfiram and the unusual type up to 90%. Such a high incidence in the Japanese of the unusual phenotype, which lacks in the low Km isozyme, suggests that the initial intoxicating symptoms after alcohol drinking in these subjects might be due to delayed oxidation of acetaldehyde rather than its higher-than-normal production by typical or atypical ADH.     

Synergistic Association between Two Alcohol Metabolism Relevant Genes and Coronary Artery Disease among Chinese Hypertensive Patients

Objective

Coronary artery disease (CAD) is a multifactorial and polygenic disease. The aim of this study was to examine the association between six polymorphisms of four alcohol metabolism relevant genes (ADH1B, ADH1C, ALDH1b1, ALDH2) and the risk of CAD in Han Chinese.

Methods and Results

This was a hospital-based case-control study involving 1365 hypertensive patients. All study subjects were angiographically confirmed. Genotypes were determined with ligase detection reaction method. There was no observable deviation from the Hardy-Weinberg equilibrium for six examined polymorphisms in controls. The genotype and allele distributions of ALDH1b1 rs2073478 and ALDH2 rs671 polymorphisms differed significantly between the two groups (P≤0.005), even after the Bonferroni correction. The most common allele combination was A-C-C-G-C-G (alleles in order of rs1229984, rs1693482, rs2228093, rs2073478, rs886205, rs671) and its frequency was slightly higher in controls than in CAD patients (P = 0.067). After assigning the most common allele combination as a reference, allele combination A-C-C-T-C-A, which simultaneously possessed the risk alleles of rs2073478 and rs671 polymorphisms, was associated with a 1.80-fold greater risk of CAD. Further, a two-locus model including rs2073478 and rs671 that had a maximal testing accuracy of 0.598 and a cross-validation consistency of 10 (P = 0.008) was deemed as the overall best MDR model, which was further validated by classical Logistic regression model.

Conclusion

Our findings provide clear evidence for both individual and interactive associations of ALDH1b1 and ALDH2 genes with the development of CAD in Han Chinese.