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May 6, 2013 - Running title: ADH and ALDH2 polymorphisms with CAD and MI risk. Hongguang ... meta-analysis provides strong evidence that ALDH2 rs671 ...
    Association of genetic polymorphisms in ADH and ALDH2 with risk of coronary artery disease and myocardial infarction: A meta-analysis Hongguang Han, Huishan Wang, Zongtao Yin, Hui Jiang, Minhua Fang, Jingsong Han PII: DOI: Reference:

S0378-1119(13)00607-0 doi: 10.1016/j.gene.2013.05.002 GENE 38609

To appear in:

Gene

Accepted date:

6 May 2013

Please cite this article as: Han, Hongguang, Wang, Huishan, Yin, Zongtao, Jiang, Hui, Fang, Minhua, Han, Jingsong, Association of genetic polymorphisms in ADH and ALDH2 with risk of coronary artery disease and myocardial infarction: A meta-analysis, Gene (2013), doi: 10.1016/j.gene.2013.05.002

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ACCEPTED MANUSCRIPT Association of genetic polymorphisms in ADH and ALDH2 with risk of coronary artery disease and myocardial infarction: a meta-analysis

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Running title: ADH and ALDH2 polymorphisms with CAD and MI risk Hongguang Han, Huishan Wang*, Zongtao Yin, Hui Jiang, Minhua Fang, Jingsong Han

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Department of Cardiovascular Surgery, General Hospital of Shenyang Military Region, Shenyang

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110840, China

*Correspondence to: Professor Huishan Wang, Department of Cardiovascular Surgery, General

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Hospital of Shenyang Military Region, Wenhua Road No.83, Shenhe District, Shenyang 110016,

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China.

Fax: +86-24-28897360

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Tel: +86-24-28897360

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E-mail address: [email protected] (H. Wang).

Abbreviations: ADH, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase; CAD, coronary artery disease; MI, myocardial infarction; RR, relative risk; 95%CI, 95% confidence interval; SNP, single nucleotide polymorphisms; HWE, Hardy-Weinberg equilibrium.

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ACCEPTED MANUSCRIPT Abstract Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are the major enzymes

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responsible for alcohol metabolism in humans. Emerging evidences have shown that functional polymorphisms in ADH and ALDH genes might play a critical role in increasing coronary artery

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disease (CAD) and myocardial infarction (MI) risks; however, individually published studies

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showed inconclusive results. The aim of this meta-analysis is to evaluate the associations between

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the genetic polymorphisms of ADH and ALDH genes with susceptibility to CAD and MI. A literature search was conducted on PubMed, Embase, Web of Science and Chinese BioMedical

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databases from inception through December 1st, 2012. Crude relative risks (RRs) with 95%

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confidence intervals (CIs) were calculated. Twelve case-control studies were included with a total

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of 9,616 subjects, including 2,053 CAD patients, 1,436 MI patients, and 6,127 healthy controls. Meta-analysis showed that mutant genotypes (GA+AA) of the rs671 polymorphism in the ALDH2

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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 = 1.32, 95%CI: 1.11-1.57, P = 0.002). However, there were no significant associations of ADH genetic polymorphisms to CAD and MI risks (CAD: RR = 0.92, 95%CI: 0.73-1.15, P = 0.445; MI: RR = 0.93, 95%CI: 0.84-1.03, P = 0.148). In conclusion, this meta-analysis provides strong evidence that ALDH2 rs671 polymorphism may be associated with increased risks of CAD and MI. However, further studies are still needed to accurately determine whether ADH genetic polymorphisms are associated with susceptibility to CAD and MI. Keywords: Aldehyde dehydrogenase; Alcohol dehydrogenase; Single nucleotide polymorphism; Myocardial infarction; Coronary artery disease; Meta-analysis

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ACCEPTED MANUSCRIPT 1. Introduction Coronary artery disease (CAD), including acute myocardial infarction (MI), is a leading cause

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of morbidity and mortality worldwide (Steptoe and Kivimaki, 2012). CAD is generally believed to be caused by a complex interplay of genetic and environmental factors (Guo et al., 2010). Alcohol

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consumption has been demonstrated to be a major risk factor in the development of CAD

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(Hvidtfeldt et al., 2010). It is interesting to note that the correlation between alcohol consumption

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and CAD appears largely to be dependent on the consumption level; excessive alcohol consumption appears to be associated with increased CAD risk, whereas light-to-moderate alcohol consumption

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may actually lower the risk (Jo et al., 2007). However, the potential molecular mechanisms remain

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unclear. Some recent studies suggest that light to moderate alcohol consumption may have some

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beneficial effects on the body, such as rapid increases in alcohol metabolism, improvements in insulin sensitivity, increases in serum levels of high-density lipoprotein cholesterol (HDL-C), and

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improvements to the regularity of drinking habits (Bonnet et al., 2012; Fawehinmi et al., 2012). The primary enzymes involved in alcohol metabolism are alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) (Edenberg, 2007). The main pathway of alcohol metabolism involves the conversion of alcohol to acetaldehyde, a reaction mediated by ADH enzymes. In a second reaction catalyzed by ALDH enzymes, acetaldehyde is oxidized to acetate (Hines and Rimm, 2001). To date, seven ADH genes (ADH1-7) have been characterized. Among them, ADH2, ADH3 and ADH7 loci are polymorphic and relevant functional polymorphisms are found to be capable of affecting ethanol degradation rates and alcohol intake levels (Tolstrup et al., 2008). Although a large number of SNPs have been identified in the three genes above, rs1229984 (G>A) in the ADH2 gene, rs1693482 (G>A) in the ADH3 gene, and rs1154458 (G>C) in the ADH7 gene are the most common and extensively investigated polymorphisms (Wang et al., 2010; Frank et al., 3

ACCEPTED MANUSCRIPT 2012). Rs1229984 results from an arginine-to-histidine (R48H) substitution in exon 3 of the ADH2 gene; rs1693482 leads to a substitution of arginine-to-glutamine (Gln271Arg) in exon 3 of the

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ADH3 gene; while rs1154458 cause a C-to-G substitution in intron 5 of the ADH7 gene (Osier et al., 2002). In addition, eighteen genes have been identified in the ALDH superfamily; ALDH2 is one

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the most widely studied genes. ALDH2 is considered to be the principal enzyme involved in

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acetaldehyde oxidation (Li et al., 2006). More than 39 SNPs in human ALDH2 gene have been

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reported, but the rs671 (G>A) polymorphism is one of the most common variants (Macgregor et al., 2009). The common rs671 (G>A) polymorphism caused by a glycine-to-lysine amino acid

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substitution in exon 12, may decrease the enzyme activity, thus contributing to the development of

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cardiovascular diseases (Kimura et al., 2006). Genetic and epigenetic changes in ADH and ALDH

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genes may decrease the activity of enzymes involved in alcohol metabolism, which may also contribute to the development of CAD by affecting 4-hydroxy-2-nonenal (4-HNE) detoxification

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and asymmetric dimethylarginine (ADMA) accumulation in endothelial cells (Guo et al., 2010). Therefore, it was hypothesized that single nucleotide polymorphisms (SNPs) of ADH and ALDH genes could be functional and were associated with CAD and MI risks (Jo et al., 2007). Several studies have indicated that the genetic polymorphisms of ADH and ALDH2 genes might play a critical role in increasing CAD and MI risk (Hines et al., 2001; Jo et al., 2007; Guo et al., 2010). However, some other studies suggest that the ADH and ALDH2 polymorphisms are not associated with CAD and MI risks (Xue et al., 2007; Husemoen et al., 2010). In view of the conflicting results from the previous studies, we performed a meta-analysis of previously published data to evaluate the associations of ADH and ALDH2 genetic polymorphisms with susceptibility to CAD and MI.

2. Materials and methods 4

ACCEPTED MANUSCRIPT 2.1. Literature search Relevant papers published before December 1st, 2012 were identified through a search in

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PubMed, Embase, Web of Science and Chinese BioMedical databases using the following terms: ("genetic polymorphism" or "single nucleotide polymorphism" or "SNP" or "gene mutation" or

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"genetic variants") and ("myocardial ischemia" or "acute coronary syndrome" or "coronary disease"

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or "myocardial infarction" or "ischemic heart disease") and ("aldehyde dehydrogenase" or "alcohol

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dehydrogenase" or "ALDH" or "ADH"). The references used in the eligible articles or textbooks were also reviewed to find other potential studies. Disagreements were resolved through discussions

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between the authors.

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2.2. Inclusion and exclusion criteria

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Studies included in our meta-analysis had to meet the following criteria: (a) cohort studies, nested case-control studies, or case-control studies should be focused on the associations of between

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ADH or ALDH2 genetic polymorphisms and susceptibility to CAD or MI; (b) all patients should meet the diagnostic criteria for CAD or MI; (c) the minimum number of cases in included studies should be greater than 30; (d) published data on the allele and genotype frequencies of SNPs must be sufficient; (e) papers should be published in peer reviewed journals. Studies were excluded when they were: (a) not cohort studies, nested case-control studies, or case-control studies; (b) studies focused on the associations between ADH or ALDH2 genetic polymorphisms and drug responses in CAD or MI patients; (c) duplicate publications of data from the same study; (d) based on incomplete data; (e) meta-analyses, letters, reviews or editorial articles. If more than one study by the same author of the same case series were published, either the study with the largest sample size or the most recently published study was included. 2.3. Data extraction 5

ACCEPTED MANUSCRIPT Two reviewers independently extracted data using a standardized extraction form in order to avoid selection bias. For each study, the following characteristics and numbers were collected: the

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first author, year of publication, country, language, ethnicity of subjects, study design, number of subjects, source of cases and controls, clinical subtype, detecting sample, genotype method, allele

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and genotype frequencies, and evidence of Hardy-Weinberg equilibrium (HWE) in controls. In

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cases of conflicting evaluations and disagreements on inconsistent data from the eligible studies

2.4. Quality assessment of included studies

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were resolved through discussions and careful reexamination of the full text by the authors.

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Two authors independently assessed the quality of the included studies according to modified

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STROBE quality score systems (da Costa et al., 2011; Zhang et al., 2011). Forty assessment items

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relevant to quality appraisal were used in this meta-analysis with scores ranging from 0 to 40. Scores of 0-20, 20-30 and 30-40 were defined as low, moderate and high quality, respectively.

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Disagreements on STROBE scores of the included studies were resolved through a comprehensive reassessment by the authors. 2.5. Statistical analysis

Crude relative risks (RRs) with 95% confidence intervals (CI) were calculated for the strength of the associations between the genetic polymorphisms of ADH and ALDH2 genes with susceptibility to CAD and MI. The statistical significance of the pooled RR was examined through the Z test. Between-study variations and heterogeneities were estimated using Cochran’s Q-statistic with a P-value < 0.05 as cutoff for statistically significant heterogeneity (Higgins and Thompson, 2002). We also quantified the effect of heterogeneity using the I2 test (ranges from 0 to 100%), which represents the proportion of inter-study variability that can be contributed to heterogeneity rather than to chance (Zintzaras and Ioannidis, 2005). When a significant Q-test with P < 0.05 or 6

ACCEPTED MANUSCRIPT I2 > 50% indicated that heterogeneity among studies existed, the random effects model (DerSimonian Laird method) was conducted for the meta-analysis; otherwise, the fixed effects

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model (Mantel-Haenszel method) was used. To explore sources of heterogeneity, we also performed subgroup analyses by country, source of controls and genotype methods. We tested

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whether genotype frequencies of the controls were in HWE using the χ2 test. Sensitivity analysis

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was performed by omitting each study in turn to assess the quality and consistency of the results.

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Funnel plots were used to detect publication bias. We also used Duval and Tweedie's trim-and-fill method to detect publication bias (Munafò et al., 2004). Egger’s linear regression test was also used

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to evaluate publication bias (Peters et al., 2006). All the P values were two-sided. All analyses were

3. Results

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calculated using the STATA Version 12.0 software (Stata Corp, College Station, TX).

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3.1. Characteristics of included studies

In accordance with the inclusion criteria, 12 case-control studies (Hines et al., 2001; Takagi et al., 2002; Jo et al., 2007; Marusin et al., 2007; Xue et al., 2007; Bian et al., 2010; Cao and Chen, 2010; Guo et al., 2010; Tolstrup et al., 2010; Jiang et al., 2011; Xia et al., 2011; Xu et al., 2011) were included in this meta-analysis and 36 were excluded. The flow chart of the study selection process is shown in Fig. 1. A total of 9,616 subjects were involved in this meta-analysis, including 2,053 CAD patients, 1,436 MI patients, and 6,127 healthy controls. The publication years of the involved studies ranged from 2001 to 2011. All patients diagnosed with CAD or MI were confirmed by coronary angiography. Six studies used hospital-based controls, while the other six studies used population-based controls (community populations). Rs671 (G>A) in the ALDH2 gene, rs1229984 (G>A) in the ADH2 gene, rs1693482 (G>A) in the ADH3 gene, and rs1154458 (G>C) in 7

ACCEPTED MANUSCRIPT the ADH7 gene were the four well-characterized SNPs of the ADH superfamily. All included studies used blood samples for genotyping. The classical polymerase chain reaction-restriction

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fragment length polymorphism (PCR-RELP) method was performed in eight of the twelve studies. The other four studies used the Taqman assay. Overall, nine of these studies were conducted in

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Asian populations and three in Caucasian populations. The HWE test was conducted on the

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genotype distribution of the controls in all twelve studies. The controls were found to be in HWE in

included studies are summarized in Table 1.

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all the studies with respect to the selected polymorphisms (all P > 0.05). The characteristics of the

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3.2. Association of ALDH genetic polymorphisms with susceptibility to CAD and MI There were nine studies concerned with ALDH2 rs671 polymorphisms. The heterogeneity was

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significant (P < 0.05, I2 = 66.8%), which might be a result of differences in country, source of controls and genotype methods, so random effects model was used. The meta-analysis results

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revealed that mutant genotypes (GA+AA) of the ALDH2 rs671 polymorphism 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 = 1.32, 95%CI: 1.11-1.57, P = 0.002) (Fig. 2). To establish the effect of heterogeneity based on the results from the meta-analyses, we also performed subgroup analyses based on country, source of controls and genotype methods. A summary of the meta-analysis results on the associations between ALDH2 rs671 polymorphism and susceptibility to CAD and MI is provided in Table 2. Subgroup analysis by country showed significant associations between mutant genotypes (GA+AA) of ALDH2 rs671 polymorphism and increased risk of MI among Chinese and Korean populations (Chinese: RR = 1.42, 95%CI: 1.15-1.75, P = 0.001; Korean: RR = 1.40, 95%CI: 1.09-1.79, P = 0.009); but similar associations were not observed among Japanese populations. We also performed subgroup analyses based on source of controls and genotype methods. Results from 8

ACCEPTED MANUSCRIPT these two analyses indicated that mutant genotypes (GA+AA) of ALDH2 rs671 polymorphism were associated with increased risk of MI in hospital-based (RR = 1.42, 95%CI: 1.15-1.75, P = 0.001)

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and TaqMan assay (RR = 1.32, 95%CI: 1.07-1.63, P = 0.010) subgroups. However, there were no associations between mutant genotypes (GA+AA) of ALDH2 rs671 polymorphism and increased

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risk of MI in the population-based and PCR-RFLP subgroups. Although no significant association

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was found in Japanese populations, population-based and PCR-RFLP subgroups, these results

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might have lacked sufficient reliability due to the small sample size. Subgroup analyses by source of controls and genotype methods were also performed to

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evaluate the susceptibility of CAD. In contrast to MI risk, we found significant associations

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between mutant genotypes (GA+AA) of ALDH2 rs671 polymorphism and increased risk of CAD in

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the population-based (RR = 1.35, 95%CI: 1.15-1.59, P < 0.001) and PCR-RFLP (RR = 1.25, 95%CI: 1.05-1.48, P = 0.011) subgroups. However, no significant associations were found in

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hospital-based and TaqMan assay subgroups (all P > 0.05), which may be due to the small sample

3.3. Association of ADH genetic polymorphisms with susceptibility to CAD and MI Only three studies referred to the three ADH genetic polymorphisms. Since significant heterogeneity existed (P = 0.027, I2 = 67.3%), the random effects model was used. There was no evidence that mutant genotypes of ADH genetic polymorphisms were associated with susceptibility to CAD and MI (CAD: RR = 0.92, 95%CI: 0.73-1.15, P = 0.445; MI: RR = 0.93, 95%CI: 0.84-1.03, P = 0.148) (Fig. 3). Due to insufficient numbers of eligible studies, further subgroup analyses could not be performed. 3.4. Sensitivity analysis and publication bias Sensitivity analysis was performed to assess the influence of each individual study on the 9

ACCEPTED MANUSCRIPT pooled RR by omitting of individual studies. The analysis results suggested that no individual studies significantly affected the pooled RR (Fig. 4), indicating a statistically robust result.

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Funnel plot and Egger's linear regression test were performed to assess the publication bias of the included studies. The shapes of the funnel plots did not reveal any evidence of obvious

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asymmetry (Fig. 5). Egger's test also showed that there was no strong statistical evidence of

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publication bias (ALDH: t = 1.09, P = 0.301; ADH: t = -2.36, P = 0.142). A pooled RR corrected

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for possible publication bias was also calculated using Duval and Tweedie’s trim-and-fill method, which is an extension of the funnel plot method. The estimated number of missing studies is 2 for

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ALDH and 1 for ADH. Meta-analysis with and without trim-and-fill method did not draw different

4. Discussion

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conclusions, indicating that our results were statistically robust (Fig. 6).

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ADH and ALDH are the major enzymes in alcohol metabolism of the oxidative and non-oxidative metabolic pathways in the human liver (Hurley and Edenberg, 2012). After ADH enzymes convert alcohol to acetaldehyde, ALDH enzymes catalyze acetaldehyde to acetic acid (Tsuchihashi-Makaya et al., 2009). There are seven ADH genes (ADH1-7) identified in humans, all found in a cluster of approximately 380 kb located on chromosome 4 (4q21-23) (Buscemi et al., 2011). The ADH2, ADH3 and ADH7 genes are the most polymorphic loci. The ALDH superfamily encodes a group of enzymes that metabolize a wide variety of endogenous and exogenous aldehydes (Sophos et al., 2003). The ALDH superfamily consists of at least 20 families, among which ALDH2 is the most widely investigated. Many previous genetic studies have suggested that ADH and ALDH2 genetic polymorphisms may play an important role in the development of CAD and MI (Hines et al., 2001; Jo et al., 2007; Guo et al., 2010), while other studies found no 10

ACCEPTED MANUSCRIPT convincing evidence of these polymorphisms in increasing CAD and MI risks (Xue et al., 2007; Husemoen et al., 2010). This discrepancy could be caused by several factors, including differences

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in study designs, sample size, ethnicity, statistical methods, etc. This meta-analysis aims to provide a more comprehensive and reliable analysis of the associations between functional polymorphisms

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in the ADH and ALDH2 genes and susceptibility to CAD and MI.

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In this meta-analysis, 12 independent case-control studies were included with a total of 9,616

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subjects, including 2,053 CAD patients, 1,436 MI patients, and 6,127 healthy controls. When all the eligible studies were pooled into the meta-analysis, the results showed that mutant genotypes of

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ALDH2 rs671 polymorphism were associated with increased risks in both CAD and MI. The

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overall pooled RR estimates were 1.20 (95%CI = 1.03-1.40) for CAD risk and 1.32 (95%CI =

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1.11-1.57), suggesting that carriers of the A allele of rs671 conferred about 1.20-fold increased risk for CAD and 1.32-fold increased risk for MI. Although the geographic variations in the prevalence

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of cardiovascular disease including CAD and MI are well known, the molecular basis is not fully understood. Large differences in common SNPs that influence the risks of cardiovascular disease were found in the worldwide populations and are mostly due to genetic drift (Ding et al., 2011). Subgroup analysis by country displayed significant associations between ALDH2 rs671 polymorphism and an increased risk of MI among Chinese and Korean populations. Although similar associations were not observed among Japanese populations, this result from a single study was also unreliable. Another possible explanation for this difference could be that inherited mutations in ALDH2 are associated with changes in alcohol metabolism and thereby affecting inter-individual differences in incidences of MI (Hurley and Edenberg, 2012). Further subgroup analyses indicated that ALDH2 rs671 polymorphism was associated with an increased risk of MI in the hospital-based and TaqMan assay subgroups; while ALDH2 rs671 polymorphism showed 11

ACCEPTED MANUSCRIPT significant associations with an increased risk of CAD in the population-based and PCR-RFLP subgroups. The possible reasons for the diverse results might include differences in genetic

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backgrounds and environments, different matching criteria and selection biases. In some respects, these findings are consistent with the previous hypothesis that certain mutations in the ALDH genes

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may increase the risks of CAD and MI, suggesting that they may be useful as biomarkers in

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predicting an individual’s susceptibility to CAD and MI (Jo et al., 2007). Nevertheless, due to the

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small sample size, no statistically significant associations were found between ADH genetic polymorphisms and CAD and MI risks.

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Similar to other meta-analyses, our study also bears some limitations and shortages. First, the

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sample size is still relatively small and may not provide sufficient statistical power to estimate the

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correlation between polymorphisms in the ADH and ALDH2 genes and susceptibility to CAD and MI. Therefore, more studies with larger sample size are still needed to accurately provide a more

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representative statistical analysis. Second, as a type of a retrospective study, a meta-analysis may encounter recall or selection bias and may possibly influence the reliability of our study results (Chen et al., 2012). Finally, although all cases and controls of each study were well defined with similar inclusion criteria, there may be other potential factors that were not taken into account that could have influenced our results. In spite of these limitations, however, this is the first meta-analysis of the relationship of ADH and ALDH2 polymorphisms with CAD and MI risks. In summary, our meta-analysis suggests that the ALDH2 rs671 polymorphism may be associated with CAD and MI risks. However, further studies are needed to determine whether ADH genetic polymorphisms are associated with susceptibility to CAD and MI. These relationships have the potential to provide a more detailed profiling of ADH and ALDH2 genes involved in alcohol metabolism and can help us better understand the biological processes associated with the 12

ACCEPTED MANUSCRIPT development and progression of CAD and MI.

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Acknowledgments We would like to acknowledge the helpful comments on this paper received from the reviewers.

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We would also like to thank all our colleagues working in the Department of Cardiovascular

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Surgery, General Hospital of Shenyang Military Region, Shenyang, China.

Conflicts of interest

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All authors read and approved the final manuscript. None of the authors had any conflicts of

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interest.

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28, 123-137.

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ACCEPTED MANUSCRIPT Figure legends Fig. 1. Flow chart of literature search and study selection.

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Fig. 2. Forest plot of RR with a random-effects model for the association between ALDH2 rs671 polymorphism and susceptibility to CAD and MI.

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polymorphisms and susceptibility to CAD and MI.

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Fig. 3. Forest plot of RR with a random-effects model for associations between ADH genetic

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Fig. 4. Sensitivity analysis of pooled RR coefficients on the association between ALDH2 rs671 polymorphism and susceptibility to CAD and MI. Results were computed by omitting each study in

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turn. Meta-analysis random-effects estimates (exponential form) were used. The two ends of the

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dotted lines represent the 95% CI.

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Fig. 5. Funnel plot of the association between ALDH2 rs671 polymorphism and susceptibility to CAD and MI. Each point represents a separate study for the indicated association. Log[RR], natural

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logarithm of RR. Horizontal line, mean magnitude of the effect. Fig. 6. Funnel plot using the trim and fill method for the association between ALDH2 rs671 polymorphism and susceptibility to CAD and MI. Each point represents a separate study for the indicated association. Log[RR], natural logarithm of RR. Horizontal line, mean magnitude of the effect.

Table legends Table 1. Characteristics of the included studies in this meta-analysis. Table 2. Meta-analysis of the association between ALDH2 rs671 polymorphism and susceptibility to CAD and MI. 17

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Fig. 1

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ACCEPTED MANUSCRIPT Study ID

RR (95% CI)

Weight %

Xue et al (2007)

0.86 (0.55, 1.34)

4.27

Xu et al (2011)

1.47 (1.26, 1.71)

10.96

Xia et al (2011)

1.09 (0.94, 1.25)

11.34

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CAD

Jiang et al (2011) Guo et al (2010)

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Subtotal (I2 = 64.3%, P = 0.016)

MI Xue et al (2007)

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Xu et al (2011) Xia et al (2011) Jiang et al (2011) Jo et al (2007) Takagi et al (2002) Subtotal (I2 = 71.5%, P = 0.002)

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NOTE: Weights are from random effects analysis

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Bian et al (2010)

1

1.35 (1.15, 1.59)

10.67 7

1.19 (0.91, 1.54)

7.79

1.20 (1.03, 1.40)

47.27

1.30 (0.83, 2.03)

4.19

1.48 (1.14, 1.91)

7.89

1.12 (0.94, 1.33)

10.32

2.38 (1.31, 4.32)

2.72

1.58 (1.19, 2.08)

7.32

1.40 (1.09, 1.79)

8.08

1.02 (0.92, 1.14)

12.21

1.32 (1.11, 1.57)

52.73

4.32

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0.232

Fig. 2

2.23

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Cao et al (2010)

0.77 (0.39, 1.51)

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RR (95% CI)

Weight %

Marusin et al (2007)

0.38 (0.19, 0.76)

2.98

Marusin et al (2007)

0.97 (0.82, 1.16)

23.89

1.02 (0.94, 1.10)

38.26

0.92 (0.73, 1.15)

65.13

0.93 (0.84, 1.03)

34.87

0.93 (0.84, 1.03)

34.87

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CAD

Tolstrup et al (2010)

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Subtotal (I2 = 74.3%, P = 0.021)

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NOTE: Weights are from random effects analysis 1

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0.192

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Hines et al (2001)

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Fig. 3

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5.21

ACCEPTED MANUSCRIPT CAD Lower CI Limit

Estimate

Upper CI Limit

Xue et al (2007)

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Xu et al (2011)

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Xia et al (2011)

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Jiang et al (2011)

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Bian et al (2010)

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Jo et al (2007)

Takagi et al (2002) 1.07 1.11

1.32

1.57

1.74

Upper CI Limit

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Xue et al (2007)

Estimate

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Lower CI Limit

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MI

Xu et al (2011)

Xia et al (2011)

Jiang et al (2011)

Guo et al (2010)

Cao et al (2010) 0.94

1.03

1.20

Fig. 4

21

1.40

1.48

ACCEPTED MANUSCRIPT ALDH gene 1

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Log[RR]

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0.5

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0

−0.5

0.2 SE(Log[RR])

0.4

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0

ADH gene

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1

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Log[RR]

0.5

0

−0.5

−1 0

0.2 SE(Log[RR])

Fig. 5

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0.4

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Fig. 6

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ACCEPTED MANUSCRIPT

Number First author

Year Country

Ethnicity

Source

Clinical subtype

Genotype method

Jiang et al 2011

China

Asian

Asian

P value (HWE test)

rs671 (G>A)

0.840

PCR-RFLP

ALDH2

rs671 (G>A)

0.611

PCR-RFLP

ALDH2

rs671 (G>A)

0.697

HB

PCR-RFLP

ALDH2

rs671 (G>A)

0.112

HB

TaqMan assay

ALDH2

rs671 (G>A)

0.108

30

HB

HB

MI

89

30

HB

HB

CAD

546

546

HB

HB

MI

122

244

HB

CAD

490

433

HB

MI

205

433

CAD

108

34

MI

54

SC

ALDH2

231

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China

Asian

SNP ID

PCR-RFLP

CAD

MA

Xia et al 2011

China

Asian

HB

HB

TaqMan assay

ALDH2

rs671 (G>A)

0.108

HB

HB

PCR-RFLP

ALDH2

rs671 (G>A)

0.809

34

HB

HB

PCR-RFLP

ALDH2

rs671 (G>A)

0.209

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Xu et al 2011

China

Gene

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Case Control Case Control Xue et al 2007

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Table 1 Characteristics of included studies in this meta-analysis. STROBE score 23/40

28/40

26/40

29/40

China

Asian

CAD

417

448

HB

PB

PCR-RFLP

ALDH2

rs671 (G>A)

0.223

27/40

Cao et al 2010

China

Asian

CAD

169

151

HB

HB

PCR-RFLP

ALDH2

rs671 (G>A)

0.150

21/40

Bian et al 2010

China

Asian

MI

106

212

HB

HB

TaqMan assay

ALDH2

rs671 (G>A)

0.188

25/40

Jo et al 2007

Korea

Asian

MI

122

439

HB

PB

TaqMan assay

ALDH2

rs671 (G>A)

0.962

30/40

Takagi et al 2002

Japan

Asian

MI

342

1820

HB

PB

PCR-RFLP

ALDH2

rs671 (G>A)

0.350

24/40

Marusin et al 2007

Russia

Caucasian

CAD

92

125

HB

PB

PCR-RFLP

ADH2

rs1229984(G>A)

0.327

CAD

92

125

HB

PB

PCR-RFLP

ADH7

rs1154458 G>C)

0.155

MI

396

770

HB

PB

PCR-RFLP

ADH3

rs1693482 (G>A)

0.470

26/40

CAD

770

875

HB

PB

TaqMan assay

ADH2

rs1229984(G>A)

0.580

31/40

USA

Caucasian

Tolstrup et al 2010 Denmark Caucasian

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Hines et al 2001

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Guo et al 2010

HB: hospital-based; PB: population-based; CAD: coronary artery disease; MI: myocardial infarction; PCR-RELP: polymerase chain reaction-restriction fragment length polymorphism; ALDH: aldehyde dehydrogenase; ADH: alcohol dehydrogenase; SNP: single nucleotide polymorphism.

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Table 2 Meta-analysis of the association between ALDH2 rs671 polymorphism and susceptibility to CAD and MI. MI CAD Subgroups RR 95%CI P RR 95%CI P Country Chinese 1.42 1.15-1.75 0.001 1.2 1.03-1.40 0.021 1.40 1.09-1.79 0.009 Korean Japanese 1.02 0.92-1.14 0.658 Source of controls Hospital-based 1.42 1.15-1.75 0.001 1.14 0.94-1.39 0.182 Population-based 1.17 0.87-1.58 0.302 1.35 1.15-1.59 < 0.001 Genotype methods PCR-RFLP 1.36 0.99-1.87 0.052 1.25 1.05-1.48 0.011 TaqMan assay 1.32 1.07-1.63 0.010 1.09 0.94-1.25 0.25 Overall 1.32 1.11-1.57 0.002 1.2 1.03-1.40 0.021

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MI: myocardial infarction; CAD: coronary artery disease; RR: relative risk; 95%CI: 95% confidence interval;

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PCR-RFLP: polymerase chain reaction-restriction fragment length polymorphism.

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ACCEPTED MANUSCRIPT Research Highlights (1) The first meta-analysis of ADH and ALDH2 genes with CAD and MI risks.

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(2) Role of ADH and ALDH2 genes in CAD and MI risks has been explained. (3) ALDH2 rs671polymorphism may increase the risks of CAD and MI.

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(4) This meta-analysis will be helpful in clarifying current controversies.

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