ADH1C Genes Research Articles

Predicting Duodenal Cancer Risk in Patients with Familial Adenomatous Polyposis Using Machine Learning Model.

The aim of this study was to both classify data of familial adenomatous polyposis patients with and without duode- nal cancer and to identify important genes that may be related to duodenal cancer by XGboost model. The current study was performed using expression profile data from a series of duodenal samples from familial adenomatous polyposis patients to explore variations in the familial adenomatous polyposis duodenal adenoma-carcinoma sequence. The expression profiles obtained from cancerous, adenomatous, and normal tissues of 12 familial adenomatous polyposis patients with duodenal cancer and the tissues of 12 familial adenomatous polyposis patients without duodenal cancer were compared. The ElasticNet approach was utilized for the feature selection. Using 5-fold cross-validation, one of the machine learning approaches, XGboost, was utilized to classify duodenal cancer. Accuracy, balanced accuracy, sensitivity, specificity, positive predictive value, negative predictive value, and F1 score performance metrics were assessed for model performance. According to the variable importance obtained from the modeling, ADH1C, DEFA5, CPS1, SPP1, DMBT1, VCAN-AS1, APOB genes (cancer vs. adenoma); LOC399753, APOA4, MIR548X, and ADH1C genes (adenoma vs. adenoma); SNORD123, CEACAM6, SNORD78, ANXA10, SPINK1, and CPS1 (normal vs. adenoma) genes can be used as predictive biomarkers. The proposed model used in this study shows that the aforementioned genes can forecast the risk of duodenal cancer in patients with familial adenomatous polyposis. More comprehensive analyses should be performed in the future to assess the reliability of the genes determined.

Analysis of the role of glucose metabolism-related genes in dilated cardiomyopathy based on bioinformatics.

Dilated cardiomyopathy (DCM) is a prevalent condition with diverse etiologies, including viral infection, autoimmune response, and genetic factors. Despite the crucial role of energy metabolism in cardiac function, therapeutic targets for key genes in DCM's energy metabolism remain scarce. Our study employed the GSE79962 and GSE42955 datasets from the Gene Expression Omnibus (GEO) database for myocardial tissue sample collection and target gene identification via differential gene expression screening. Using various R packages, GSEA software, and the STRING database, we conducted data analysis, gene set enrichment, and protein-protein interaction predictions. The least absolute shrinkage and selection operator (LASSO) and Support Vector Machine (SVM) algorithms aided in feature gene selection, while the predictive model's efficiency was evaluated via the receiver operating characteristic (ROC) curve analysis. We used the non-negative matrix factorization (NMF) method for molecular typing and the cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) algorithm for predicting immune cell infiltration. The DLAT and LDHA genes may regulate the immune microenvironment of DCM by influencing activated dendritic cells, activated mast cells, and M0 macrophages, respectively. The BPGM, DLAT, PGM2, ADH1A, ADH1C, LDHA, and PFKM genes may regulate m6A methylation in DCM by affecting the ZC3H13, ALKBH5, RBMX, HNRNPC, METTL3, and YTHDC1 genes. Further regulatory mechanism analysis suggested that PFKM, DLAT, PKLR, PGM2, LDHA, BPGM, ADH1A, and ADH1C could be involved in the development of cardiomyopathy by regulating the Toll-like receptor signaling pathway. PFKM, DLAT, PKLR, PGM2, LDHA, BPGM, ADH1A, and ADH1C may serve as potential targets for guiding the diagnosis, treatment, and follow-up of DCM.

Association of ADH1B rs1229984, ADH1C rs698, and ALDH2 rs671 with Alcohol abuse and Alcoholic Cirrhosis in People Living in Northeast Vietnam.

Alcohol abuse can cause developing cirrhosis, even liver cancer. Several single nucleotide polymorphisms (SNPs) of ADH1B, ADH1C, and ALDH2 genes have been reported to be associated with alcohol abuse and alcoholic cirrhosis (ALC). This study investigated the association between three SNPs of ADH1B rs1229984, ADH1C rs698, and ALDH2 rs671 with alcohol abuse and ALC in people living in the Northeast region of Vietnam. 306 male participants were recruited including 206 alcoholics (106 ALC, 100 without ALC) and 100 healthy non-alcoholics. Clinical characteristics were collected by clinicians. Genotypes were identified by Sanger sequencing. Chi-Square (χ2) and Fisher-exact tests were used to assess the differences in age and clinical characteristics, Child-Pugh score, frequencies of alleles and genotypes. Our data showed that the frequency of ALDH2*1 was significantly higher in alcoholics (88.59%) and ALC groups (93.40%) than that of healthy non-alcoholics (78.50%) with p=0.0009 and non-ALC group (83.50%) with p=0.002, respectively. We detected opposite results when examined ALDH2*2. Frequency of combined genotypes with high acetaldehyde accumulation were significantly lower in alcoholics and ALC group than those of control groups with p=0.005 and p=0.008, respectively. Meanwhile, the proportion of combined genotypes with non-acetaldehyde accumulation were significantly two times higher in the ALC group (19.98%) than those of the non-ALC group (8%) with p=0.035. These combined genotypes showed a decreasing trend in the Child-Pugh score from likely phenotype causing risk for non-acetaldehyde accumulation to high acetaldehyde accumulation. The ALDH2*1 allele was found as a risk factor for alcohol abuse and ALC, and combined genotypes of ADH1B rs1229984, ADH1C rs698, and ALDH2 rs671 with non-acetaldehyde accumulation increase ALC risk. In contrast, ALDH2*2 and the genotype combinations related to high acetaldehyde accumulation were protective factors against alcohol abuse and ALC.

Single Nucleotide Polymorphisms of ADH1B, ADH1C and ALDH2 Genes in 235 People Living in Thai Nguyen Province of Vietnam.

ADH1B, ADH1C and ALDH2 genes are mainly responsible for alcohol metabolism in the body. Several single nucleotide polymorphisms (SNPs) of these genes have been reported to be associated with alcohol dependence and are considered risk factors for various human diseases. This study aims to identify the prevalence of three SNPs of ADH1B (rs1229984), ADH1C (rs698) and ALDH2 (rs671) in 235 unrelated individuals living in Thai Nguyen province, the northeast region of Vietnam. The target genotypes were identified by using PCR direct sequencing, and their frequencies were compared to previous reports. Our data showed that allele frequencies of ADH1B*2, ADH1C*2 and ALDH2*2 were 68.8%, 8.3% and 20.4%, respectively. The ADH1B*2 and ADH1C*2 frequencies were similar to those of the Kinh ethnic individuals living in the south region of Vietnam, while the ALDH2*2 frequency was higher. Compared to data from other countries, ADH1B*2 frequency is similar to the Philippines (60.5%) and Mongolia (62.9%) but significantly different from the other populations. The ADH1C*2 frequency is not so different compared to Japanese (5.7%) and Chinese (7.1%) but is quite different in other populations. ALDH2*2 frequency was lower than Japanese (29.3%), Indonesian (30%) and higher than other countries. Regarding the risk of alcoholism, the percentage of Vietnamese people in this study with genotypes related to alcohol dependence is 8.1%. In contrast, the carrier has genotypes protecting against alcoholism with high frequency, 91.9%. Among them, the individuals can cause high acetaldehyde accumulation accounting for 33.2%. This study helps to understand the genetic polymorphisms of alcohol metabolism genes in the community living in Thai Nguyen province, northeast of Vietnam, and provides valuable scientific data relating to alcohol consumption behavior as well as public health protection.

Allelic variations in alcohol metabolism genes (ADH1B, ADH1C, CYP2E1) and alcohol use disorder (AUD) in northeastern Brazil

Alcohol use disorder (AUD) is a multifactorial disease caused by environmental and genetic factors. Genetic polymorphisms of the enzymes involved in alcohol metabolism influence the susceptibility to alcohol dependence. The distribution of the genetic variants varies depending on ethnicity. The aim of this study was to evaluate the effects of the polymorphisms of the three genes responsible for the degradation of ethanol, ADH1B, ADH1C, and CYP2E1 to examine the influence of these mutations on the risk for alcohol use disorder in a population from northeastern Brazil. In addition, the allelic distribution of the northeastern population will be compared with that obtained for other populations. The allelic and genotypic frequencies were determined in 163 alcoholic patients and 182 control subjects. Genotyping was performed by PCR-RFLP. The allele frequencies in the northeastern population were similar to those reported in studies in Mexico but differed significantly from those reported in studies of a Chinese population. The polymorphic variants of CYP2E1 were associated with a higher risk for alcohol use disorder [odds ratio (OR) = 2.80; 95% confidence interval (CI) = 1.35-5.83, p = 0.0072]. No significant result was obtained from the analyses of the ADH1C gene. A significant protective effect against alcohol dependence was observed in individuals carrying allelic and genotypic variations of the ADH1B gene, as determined through the combined analysis of homozygous and heterozygous variant forms of the gene in controls and alcoholics (P = 0.03). Furthermore, the combination of ADH1B*2 with ADH1C*1 and CYP2E1 (c1/c1) may confer protection against alcohol use disorder.

Allele-specific polymerase chain reaction for the discrimination of elite Korean cattle associated with high beef quality and quantity.

Techniques such as direct sequencing and PCR-RFLP (restriction fragment length polymorphism) are widely used to analyze the genotypes of livestock. However, these conventional methods have the disadvantage of taking a lot of time and incurring considerable cost. The allele-specific PCR method performs PCR using two primers, and a single nucleotide polymorphism (SNP) genotype can be identified through electrophoresis, saving time and cost. Highly accurate results can be obtained by designing specific primers according to the allele of the SNP under study, utilizing primer binding to a complementary matching sequence. In this study, we established a genotyping system with the AS-PCR technique, using SNPs related to the improvement of the meat quality and meat mass of Korean cattle. Using the PRIMER1 program, we designed specific primers for SNPs located at the 3 end, with one SNP marker in the HSPB1 gene related to meat quantity and two SNP markers in the ADH1C and FASN genes related to meat quality in cattle. AS-PCR was performed on 10 Korean cattle using the primers designed with this system, and the genotypes could be identified by the size of the PCR product amplified as a result of electrophoresis. In the case of the HSPB1 g.2352T C SNP, the T allele was amplified to 148 bp, and the C allele was amplified to 222 bp. The ADH1C c.-64T C SNP was amplified to 492 bp at the T allele and 330 bp at the C allele. The FASN g.17924G A SNP A allele was amplified to 377 bp and the G allele to 507 bp. The results for each SNP genotype were verified using direct sequencing, which showed that the genotypes identified by direct sequencing and the genotypes identified by the AS-PCR method matched exactly. The AS-PCR method therefore appears to be valuable for use in a genotyping system.

Genetic Variants of Alcohol Metabolizing Enzymes and Alcohol-Related Liver Cirrhosis Risk

Alcohol-related liver disease (ARLD) is a major public health issue caused by excessive alcohol consumption. ARLD encompasses a wide range of chronic liver lesions, alcohol-related liver cirrhosis being the most severe and harmful state. Variations in the genes encoding the enzymes, which play an active role in ethanol metabolism, might influence alcohol exposure and hence be considered as risk factors of developing cirrhosis. We conducted a case-control study in which 164 alcohol-related liver cirrhosis patients and 272 healthy controls were genotyped for the following functional single nucleotide variations (SNVs): ADH1B gene, rs1229984, rs1041969, rs6413413, and rs2066702; ADH1C gene, rs35385902, rs283413, rs34195308, rs1693482, and rs35719513; CYP2E1 gene, rs3813867. Furthermore, copy number variations (CNVs) for ADH1A, ADH1B, ADH1C, and CYP2E1 genes were analyzed. A significant protective association with the risk of developing alcohol-related liver cirrhosis was observed between the mutant alleles of SNVs ADH1B rs1229984 (Pc value = 0.037) and ADH1C rs283413 (Pc value = 0.037). We identified CNVs in all genes studied, ADH1A gene deletions being more common in alcohol-related liver cirrhosis patients than in control subjects, although the association lost statistical significance after multivariate analyses. Our findings support that susceptibility to alcohol-related liver cirrhosis is related to variations in alcohol metabolism genes.

Abstract 3255: The roles of ALDH2, ADH1B and ADH1C gene polymorphism in predicting upper digestive tract multiple primary malignancies in head and neck cancer patients

Abstract Head and neck cancer was closely related with habitual use of cigarette and alcohol. The genes involving in the metabolism of alcohol are reported to play roles in increasing risks of head and neck cancer. In this study, we investigated the single nucleotide polymorphisms (SNPs) of alcohol metabolizing enzymes (ALDH2, ADH1B and ADH1C) in their distributions among different tumor subsites and their risks of developing multiple primary cancers. We recruited 659 male head and neck cancer patients between Mar 1996 and Feb 2017. Four hundred and twenty-seven normal controls were also recruited. The SNPs in ALDH2 (rs671), ADH1B (rs1229984) and ADH1C (rs698) were analyzed by Taqman PCR primers and TaqMan probes synthesized by Applied Biosystems (Foster City, CA). Genotyping was performed using the Taqman-based allelic discrimination method on an Applied Biosystems 7500 Real-Time Polymerase Chain Reaction System (Applied Biosystems, Foster City, CA). The A allele carriers than G/G homozygotes in ALDH2 is significantly higher in oral cavity cancer (p = 0.016), oropharynx (p = 0.018) and hypopharynx cancer (p = 0.051) than normal population but not in tonsillar cancer (p = 0.099). In ADH1B, the G allele carriers is significantly higher than A/A homozygotes in oropharynx (p = 0.012), tonsillar cancer (p = 0.050) and hypopharynx cancer (p < 0.001) than normal population but not in oral cavity cancer (p = 0.406). We did not observe ADH1C (rs698) SNP significantly related with HNSCC tumor subsites (p > 0.05). For ALDH2 (A allele carriers vs G/G homozygotes) and ADH1B (G allele carriers vs A/A homozygotes), they significantly increased risks to develop multiple primary cancers in upper digestive tract (p < 0.001, OR [95% confidence interval, C.I.]: 5.358 [2.565-11.195]. and p < 0.001, OR [95% C.I.]: 2.907 [1.598 - 5.290]). Conclusion:ALDH2 (rs671) A allele carriers and ADH1B (rs1229984) G allele carriers had higher risks of developing multiple primary cancers in upper digestive tract. For those with high risk allele carriers, routine screening of upper digestive tract including laryngoscope and esophagoscope is suggested to detect new primaries early. Citation Format: Shiang-Fu Huang, Huei-Tzu Chien, Sou-De Cheng, Chun-Ta Liao, Hung-Ming Wang. The roles of ALDH2, ADH1B and ADH1C gene polymorphism in predicting upper digestive tract multiple primary malignancies in head and neck cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3255.

Distinct Prognostic Values of Alcohol Dehydrogenase Family Members for Non-Small Cell Lung Cancer.

BackgroundNon-small cell lung cancer (NSCLC) is a leading cause of cancer-related death worldwide. The relationships of alcohol dehydrogenase (ADH) enzymes, encoded by the genes ADH1 (1A), ADH1B (ADH2), ADH1C (ADH3), ADH4, ADH5, ADH6, and ADH7, with NSCLC have not been studied. The aim of this study was to explore the associations between NSCLC prognosis and the expression patterns of ADH family members.Material/MethodsThe online resource Metabolic gEne RApid Visualizer was used to assess the expression patterns of ADH family members in normal and primary lung tumor tissues. The GeneMANIA plugin of Cytoscape software and STRING website were used to evaluate the relationships of the 7 ADH family members at the gene and protein levels. Gene ontology enrichment analysis and KEGG pathway analysis were performed using DAVID. The online website Kaplan-Meier Plotter was used to construct survival curves between NSCLC and ADH isoforms.ResultsThe prognosis of patients with high expression levels of the ADH1B, ADH1C, ADH4, and ADH5 genes was better than those with low expression in adenocarcinoma and all (containing adenocarcinoma and squamous cell cancer) histological types (all P<0.05). Low expression of ADH7 was associated with a better prognosis in patients with both the adenocarcinoma and squamous cell cancer histological types (P=9e-05). Moreover, expression of ADH family members was associated with smoking status, clinical stage, and chemotherapy status.ConclusionsADH1B, ADH1C, ADH4, ADH5, and ADH7 appear to be useful biomarkers for the prognosis of NSCLC patients.

Polymorphisms in alcohol dehydrogenase (ADH1) and cytochrome p450 2E1 (CYP2E1) genes in patients with cirrhosis and/or hepatocellular carcinoma

Introduction: One of the most important risk factors for hepatocellular carcinoma (HCC) is alcohol consumption: Studies in different populations suggest that the risk of liver disease could be associated with genetic variants of the enzymes involved in alcohol metabolism, such as alcohol dehydrogenase (ADH) and cytochrome P450 CYP2E1. Objective: To identify and characterize the allelic variants of ADH1B, ADH1C and CYP2E1 genes in Colombian patients with cirrhosis and/or HCC. Materials and methods: We included samples from patients attending the hepatology unit between 2005-2007 and 2014-2016 of a hospital in Medellin. Samples were genotyped using PCR-RFLP. We compared the results with two control groups and the 1000 Genomes Project database. Results: We collected 97 samples from patients with a diagnosis of cirrhosis and/or HCC. The two main risk factors were chronic alcohol consumption (18.6%) and cholangiopathies (17.5%). The most frequent genotypes in the study population were ADH1B*1/1 (82%), ADH1C*1/1 (59%), and CYP2E1*C/C (84%). Conclusions: This first study of polymorphisms in Colombian patients diagnosed with cirrhosis and/or HCC showed genotypes ADH1B*1/1, ADH1C*1/1 and CYP2E1*C/C as the most frequent. We found no significant differences in the genotype frequency between cases and controls. Further studies are necessary to explore the association between polymorphisms and the risk of end-stage liver disease from alcohol consumption.

Analysis of the Association of Nonsynonymous Polymorphisms in ADH Genes with Hazardous Drinking in HIV-1-Positive Individuals.

Hazardous drinking (HD) is a serious health problem in people infected with human immunodeficiency virus type 1 (HIV-1). Single nucleotide polymorphisms (SNPs) in alcohol dehydrogenase (ADH) genes have been associated with HD in different populations, but there were no data about this in HIV-1-positive individuals. This study investigated the association of 4 nonsynonymous SNPs in ADH genes (Arg48His and Arg370Cys in ADH1B gene; Arg272Gln and Ile350Val in ADH1C gene) with HD in people living with HIV-1. This case-control study included 365 HIV-1-positive individuals (121 with HD and 244 without HD). Sociodemographic variables were collected with a standardized individual questionnaire. HD (score ≥8) and binge drinking (BD) (drinks on the same occasion ≥5) were detected with the Alcohol Use Disorders Identification Test. The 4 SNPs were genotyped by the polymerase chain reaction-restriction fragment length polymorphism method. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated using logistic regression analysis. The Bonferroni correction was used (considering the 4 SNPs studied). There were no significant differences in the frequencies of Arg370Cys, Arg272Gln, and Ile350Val polymorphisms between HD cases and controls. Otherwise, Arg/His genotype (rs1229984) in ADH1B gene showed a protective effect against HD (aOR=0.36; 95% CI: 0.14 to 0.90) and BD (aOR=0.49; 95% CI: 0.21 to 0.95). Nevertheless, these differences were no longer significant after Bonferroni correction. The results of this study suggest a possible effect of the Arg48His genotype on the protection against HD in HIV-1-positive individuals.

Effect of single-nucleotide polymorphisms in ADH1B, ADH4, ADH1C, OPRM1, DRD2, BDNF, and ALDH2 genes on alcohol dependence in a Caucasian population.

Alcohol is a frequently used addictive substance worldwide. Aim of this study is to determine the frequency distribution of SNPs within ADH1B,ADH4,ADH1C,ALDH2, BDNF,OPRM1, and DRD2 genes in a southeastern European Caucasian population from Greece. For this purpose samples of 1276 volunteers were analyzed after deidentification and anonymization. The allele distribution of the examined polymorphisms in the present Greek population cohort was as follows: rs1229984 (ADH1B): GG(wt) = 64.14%, GA = 29.86%, AA = 4.00%; rs1693482 (ADH1C): CC(wt) = 57.45%, CT = 36.76%, TT = 5.80%; rs1799971 (OPRM1): AA(wt) = 72.43%, AG = 28.72%, GG = 1.89%; rs1800497 (DRD2): CC(wt) = 70.84%, CT = 27.18%, TT = 1.98%; rs1800759 (ADH4): CC(wt) = 34.25%, CA = 48.12%, AA = 17.63%; rs6265 (BDNF): GG(wt) = 65.99%, GA = 31.02%, AA = 2.99%; and rs671 (ALDH2): GG(wt) = 99.84% GA = 0.16%, AA = 0.00%. Mutant rs1229984 allele A was ~6.5× more frequent in the Greek than in the European population. Mutant rs1693482 allele T was ~1.7× more frequent in the European than in the Greek population. Mutant alleles for polymorphisms rs1800759 and rs1799971 show similar frequencies in both northern and southern Europeans. One rs671 mutant A allele was detected in the Greek population (0.08%). The mutant rs1800497 allele T was ~1.2× more frequent in the European than in the Greek population and the mutant rs6265 allele A was ~1.1× more frequent in the European than in the Greek population. An alcohol addiction‐specific algorithm was generated (TGS) that may predict alcohol addiction prevalence in a population. According to our findings, the analyzed Southeastern population may differ genetically from north Europeans due to influences from neighboring Asian and African populations and a calculated TGS score >50 indicates individuals with low susceptibility to develop alcohol addiction.

Alcohol metabolism and oesophageal cancer: a systematic review of the evidence.

Alcohol is a major risk factor for oesophageal squamous cell carcinoma (OSCC), the most prevalent histological subtype of oesophageal cancer (OC) worldwide. The metabolism of alcohol is regulated by specific enzymes whose activity and expression is influenced by genetic polymorphisms. We conducted a systematic review of current epidemiological evidence of the relationship between alcohol intake and OC risk, including the role of tobacco smoking and functional polymorphisms of alcohol dehydrogenases (ADHs) and aldehyde dehydrogenases (ALDHs). Potential biological mechanisms underlying oesophageal carcinogenesis are also discussed. Frequency and intensity of alcohol intake have been consistently associated with an increased risk of OSCC in regions with low and high incidence of the disease. The highest risk was reported among tobacco smokers, whereas the association between alcohol and OSCC risk was weak in the absence of tobacco use. The ADH1B, ADH1C and ALDH2 gene polymorphisms influence the risk of OSCC through modulation of acetaldehyde metabolism and propensity to alcohol intake. These functional variants may be suitable proxies of alcohol exposure for use in Mendelian randomization studies if complemented by reported alcohol intake data. Recent epidemiological and experimental studies investigating the role of alcohol consumption in OC development have implicated the microbiome as a new promising avenue for research, which entail novel potential mechanisms of alcohol-related oesophageal carcinogenesis. Microbial communities associated with alcohol consumption might be used as biomarkers to raise the potential of intervening among susceptible individuals.

Progress In Psychiatric Genetics In China

Overall Abstract The purpose of this symposium is to highlight recent progress in psychiatric genetics in Chinese samples, complementing findings largely from Caucasian samples. We will stress commonalities and differences between existing studies and Chinese studies. Weihua Yue from Peking University reports on a multi-site GWAS of schizophrenia with >10,000 samples. 13 SNPs were selected for replication in another 10,000 samples. 4 SNPs in 3 regions out of 13 survived after confirmation in the replication sample, 9/13 SNPs were in the same direction, and 7/13 SNPs were both p Yin Yao from NIMH integrated functional magnetic resonance imaging (fMRI) and brain-gene ResNet (BGR) data to identify functional pathways associated with SCZ phenotypes. Automated Anatomical Labeling based brain connectivity analysis on fMRI data and Gene Set and Subnetwork Enrichment Analyses identified 4 SCZ candidate brain regions (P Gang Chen from Nanjing University of Chinese Medicine will report on a GWAS of alcohol dependence symptom count (ADSC) in sample of 3838 European and African Americans from the “Study of Addiction: Genetics and Environment”. Using a mixed linear approach, 20 SNPs showed significant (permutation testing) association with ADSC after accounting for ethnicity, co-morbidities, and including additive as well as dominance and epistasis in the model. Association with the previously known ADH1C gene was confirmed, as well as several other known and new genes. The detected SNPs explain ~20% of the variance, half of which is accounted for by dominance and epistatic interactions, suggesting such networks are important in the genetic architecture of alcoholism. Margit Burmeister will report on implementing in China Srijan Sen’s “medical intern health study”. Medical graduates are recruited after matching in now 55 hospitals in the US. Baseline surveys include personality, stress level, other psychological tests and the PHQ9 depression score. Depression increases from ~4% of incoming Medical graduates to ~ 26% during internship. Perceived stress, work hour and medical errors are associated with increased PHQ9 scores. Most residents do not seek care for their depression symptoms, out of fear of reprisal. In China, a formal residency program has recently been introduced in several cities. Interviews with residents documented similar concerns as in the US. Our pilot data (N=75, ~75% participation) in 2015 in Peking Union Medical College demonstrate a similar increase of depression scores from ~4% to ~ 22%, suggesting that work-stress induced depression may be modeled similarly in China as in the US, where a GWAS of the first ~7500 interns will soon become available.

Research Article Alcohol metabolizing gene polymorphisms and their relationship with oral cancer risk and clinicopathological features

Oral cancer incidence is higher in individuals between the fifth and seventh decades of life, but some studies indicate a decreasing age trend. From the epidemiological point of view, alcohol consumption is associated with the emergence of oral cancer by interfering with mechanisms of DNA synthesis and repair. From a genetic standpoint, variant alleles in genes encoding the enzymes of alcohol (CYP2E1 and ADH) and acetaldehyde (ALDH2) metabolism may play an important role in the genesis of oral cancer. This study aimed to assess the relation of polymorphisms ADH1B (rs1229984 and rs2066702), ADH1C (rs698), ALDH2 (rs671) and CYP2E1 96bp insertion and the risk of squamous cell carcinoma of the mouth floor, as well as its clinicopathological and prognostic characteristics in relation to alcohol consumption. Our sample group was made of 301 patients, with 159 controls without a previous history of cancer and 142 patients with oral cancer. Genomic DNA was extracted from peripheral blood samples and genotypes were determined by PCR-RFLP. Our results suggest that the presence of ALDH2 Lys504 allele and 96bp insertion CYP2E1 were significantly associated with oral cancer risk. ADH1C gene Ile350 allele was associated with the presence of positive lymph nodes, and lymphatic invasion was related to the presence of polymorphic alleles ADH1B*1, ADH1C Ile350 and ALDH2 Lys504. In conclusion, these results reveal potential markers of oral cancer risk and behavior

Causal Role of Alcohol Consumption in an Improved Lipid Profile: The Atherosclerosis Risk in Communities (ARIC) Study

IntroductionHealth benefits of low-to-moderate alcohol consumption may operate through an improved lipid profile. A Mendelian randomization (MR) approach was used to examine whether alcohol consumption causally affects lipid levels.MethodsThis analysis involved 10,893 European Americans (EA) from the Atherosclerosis Risk in Communities (ARIC) study. Common and rare variants in alcohol dehydrogenase and acetaldehyde dehydrogenase genes were evaluated for MR assumptions. Five variants, residing in the ADH1B, ADH1C, and ADH4 genes, were selected as genetic instruments and were combined into an unweighted genetic score. Triglycerides (TG), total cholesterol, high-density lipoprotein cholesterol (HDL-c) and its subfractions (HDL2-c and HDL3-c), low-density lipoprotein cholesterol (LDL-c), small dense LDL-c (sdLDL-c), apolipoprotein B (apoB), and lipoprotein (a) (Lp(a)) levels were analyzed.ResultsAlcohol consumption significantly increased HDL2-c and reduced TG, total cholesterol, LDL-c, sdLDL-c, and apoB levels. For each of these lipids a non-linear trend was observed. Compared to the first quartile of alcohol consumption, the third quartile had a 12.3% lower level of TG (p < 0.001), a 7.71 mg/dL lower level of total cholesterol (p = 0.007), a 10.3% higher level of HDL2-c (p = 0.007), a 6.87 mg/dL lower level of LDL-c (p = 0.012), a 7.4% lower level of sdLDL-c (p = 0.037), and a 3.5% lower level of apoB (p = 0.058, poverall = 0.022).ConclusionsThis study supports the causal role of regular low-to-moderate alcohol consumption in increasing HDL2-c, reducing TG, total cholesterol, and LDL-c, and provides evidence for the novel finding that low-to-moderate consumption of alcohol reduces apoB and sdLDL-c levels among EA. However, given the nonlinearity of the effect of alcohol consumption, even within the range of low-to-moderate drinking, increased consumption does not always result in a larger benefit.

Abstract 4585: Folate-mediated one-carbon metabolism polymorphisms associated with risk and survival of colorectal cancer

Abstract Introduction Folate-mediated one-carbon metabolism (FOCM) is a key pathway necessary for nucleotide synthesis, DNA methylation, replication and repair. Genetic variants in FOCM genes, especially the MTHFR-C677T polymorphism, have been associated with colorectal neoplasia. Moreover, FOCM is an important target for chemotherapeutic drugs for the treatment of colorectal cancer (CRC), such as 5-fluorouracil (5-FU). We performed a comprehensive assessment of FOCM-related genetic variation in relation to CRC risk and survival in an unfortified population. Methods Associations of 457 tagging and candidate SNPs in 47 FOCM-related genes with CRC risk and survival were investigated within a German population-based case-control study (the DACHS- study). Using multivariate adjusted logistic (n = 1754 incident cases and 1781 matched controls) and Cox regression (5 years follow-up of CRC cases only; 585 deceased), we evaluated co-dominant, dominant, and log-additive modes of inheritance. SNPs were genotyped using the Illumina GoldenGate Assay. Correction for multiple testing was performed using false discovery rates (FDR). Results Individuals having both variant alleles of a candidate SNP in the ADH1C gene (rs1693482) had a significantly decreased risk of developing CRC (ORhet = 0.94 [95% CI = 0.81-1.10]; ORhzv = 0.74 [95% CI = 0.59-0.92]; p-trend = 0.013). Before correction for multiple testing, 19 nominally significant genetic main effects on CRC risk were observed. None of the studied tagging SNPs was significantly associated with risk after multiple test correction. One polymorphism in the PON1 gene (rs3917538) was significantly associated with overall survival (HRhet = 1.22 [95% CI = 1.03-1.45]; HRhzv = 2.00 [95% CI = 1.48-2.71]; p-trend = 0.01), after correction for multiple testing. Effect modification by 5-FU chemotherapy was observed between two polymorphisms (MTHFR-rs4846047 [Int-pFDR = 0.02] and TK1-rs1811086 [Int-pFDR = 0.02]) for the endpoint overall survival. Cases with variant alleles of these SNPs had a reduced effect of 5-FU on overall survival. Conclusion Genetic variation in FOCM appears to be associated with CRC risk and survival. Furthermore, 5-FU might interact with FOCM polymorphisms. Further large investigations are required to replicate our findings. Citation Format: Akke Botma, Katharina Buck, Yesilda Balavarca, Dominique Scherer, Nina Habermann, Reka Toth, Lina Jansen, Michael Hoffmeister, Hermann Brenner, Elisabeth J. Kap, Petra Seibold, Axel Benner, Alexis Ulrich, Barbara Burwinkel, Jenny Chang-Claude, Cornelia M. Ulrich. Folate-mediated one-carbon metabolism polymorphisms associated with risk and survival of colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4585. doi:10.1158/1538-7445.AM2015-4585

Genetic polymorphisms of ADH1B, ADH1C and ALDH2 in Turkish alcoholics: lack of association with alcoholism and alcoholic cirrhosis.

No data exists regarding the alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) gene polymorphisms in Turkish alcoholic cirrhotics. We studied the polymorphisms of ADH1B, ADH1C and ALDH2 genes in alcoholic cirrhotics and compared the results with non-cirrhotic alcoholics and healthy volunteers. Overall, 237 subjects were included for the study: 156 alcoholic patients (78 cirrhotics, 78 non-cirrhotic alcoholics) and 81 healthy volunteers. Three different single-nucleotide-polymorphism genotyping methods were used. ADH1C genotyping was performed using a polymerase chain reaction-restriction fragment length polymorphism method. The identified ADH1C genotypes were named according to the presence or absence of the enzyme restriction sites. ADH1B (Arg47Hys) genotyping was performed using the allele specific primer extension method, and ALDH2 (Glu487Lys) genotyping was performed by a multiplex polymerase chain reaction using two allele-specific primer pairs. For ADH1B, the frequency of allele *1 in the cirrhotics, non-cirrhotic alcoholics and healthy volunteers was 97.4%, 94.9% and 99.4%, respectively. For ADH1C, the frequency of allele *1 in the cirrhotics, non-cirrhotic alcoholics and healthy volunteers was 47%, 36.3% and 45%, respectively. There was no statistical difference between the groups for ADH1B and ADH1C (p&gt;0.05). All alcoholic and non-alcoholic subjects (100%) had the allele *1 for ALDH2. The obtained results for ADH1B, ADH1C, and ALDH gene polymorphisms in the present study are similar to the results of Caucasian studies. ADH1B and ADH1C genetic variations are not related to the development of alcoholism or susceptibility to alcoholic cirrhosis. ALDH2 gene has no genetic variation in the Turkish population.

A genetic view of addiction

The genetic analyses of addictions recently converted to genome-wide association studies (GWAS) and thanks to national and international consortia, allowed to recruit large cohorts of patients. This approach allowed the identification of the first susceptibility gene in addiction (tobacco), with genes CHRNA5, CHRNA3 and CHRNB4 encoding the α5, α3 and b4 subunits involved in the formation of nicotinic receptors, explaining 14% of the attributable risk for tobacco dependence. Variants of ADH1B and ADH1C genes encoding alcohol dehydrogenases enzymes have also been consistently associated, this time with alcohol dependence (AD). Finally, DRD2 and ANKK1 genes, involved in the dopaminergic pathway, and which were initially associated with AD, are now considered to be involved in a broader phenotype (addiction to psychoactive substances) including opiates. Future directions in molecular study of addiction are genex environment interactions though the epigenetic approach. Numerous studies already investigated the methylome in addiction, including histone and microRNA modifications.

Meta-analysis of six genes (BDNF, DRD1, DRD3, DRD4, GRIN2B and MAOA) involved in neuroplasticity and the risk for alcohol dependence

BackgroundAlcohol-related problems have a large impact on human health, accounting for around 4% of deaths and 4.5% of disability-adjusted life-years around the world. Genetic factors could explain a significant fraction of the risk for alcohol dependence (AD). Recent meta-analyses have found significant pooled odds ratios (ORs) for variants in the ADH1B, ADH1C, DRD2 and HTR2A genes. MethodsIn the present study, we carried out a meta-analysis of common variants in 6 candidate genes involved in neurotransmission and neuroplasticity: BDNF, DRD1, DRD3, DRD4, GRIN2B and MAOA. We carried out a systematic search for published association studies that analyzed the genes of interest. Relevant articles were retrieved and demographic and genetic data were extracted. Pooled ORs were calculated using a random-effects model using the Meta-Analyst program. Dominant, recessive and allelic models were tested and analyses were also stratified by ethnicity. ResultsForty two published studies were included in the current meta-analysis: BDNF-rs6265 (nine studies), DRD1-rs4532 (four studies), DRD3-rs6280 (eleven studies), DRD4-VNTR (seven studies), GRIN2B-rs1806201 (three studies) and MAOA-uVNTR (eight studies). We did not find significant pooled ORs for any of the six genes, under different models and stratifying for ethnicity. ConclusionsIn terms of the number of candidate genes included, this is one of the most comprehensive meta-analyses for genetics of AD. Pooled ORs did not support consistent associations with any of the six candidate genes tested. Future studies of novel genes of functional relevance and meta-analyses of quantitative endophenotypes could identify further susceptibility molecular factors for AD.