Gene-alcohol Interactions Research Articles

Gene-alcohol interactions in birth defects.

Most human birth defects are thought to result from complex interactions between combinations of genetic and environmental factors. This is true even for conditions that, at face value, may appear simple and straightforward, like fetal alcohol spectrum disorders (FASD). FASD describe the full range of structural and neurological disruptions that result from prenatal alcohol exposure. While FASD require alcohol exposure, evidence from human and animal model studies demonstrate that additional genetic and/or environmental factors can influence the embryo's susceptibility to alcohol. Only a limited number of alcohol interactions in birth defects have been identified, with many sensitizing genetic and environmental factors likely yet to be identified. Because of this, while unsatisfying, there is no definitively "safe" dose of alcohol for all pregnancies. Determining these other factors, as well as mechanistically characterizing known interactions, is critical for better understanding and preventing FASD and requires combined scrutiny of human and model organism studies.

Scale and Scope of Gene-Alcohol Interactions in Chronic Pancreatitis: A Systematic Review.

Background: Excessive alcohol consumption has long been known to be the primary cause of chronic pancreatitis (CP) but genetic risk factors have been increasingly identified over the past 25 years. The scale and scope of gene-alcohol interactions in CP nevertheless remain unclear. Methods: All studies that had obtained genetic variant data concurrently on alcoholic CP (ACP) patients, non-ACP (NACP) patients and normal controls were collated. Employing normal controls as a common baseline, paired ORACP and ORNACP (odds ratios associated with ACP and NACP, respectively) values were calculated and used to assess gene-alcohol interactions. Results: Thirteen variants involving PRSS1, SPINK1, CTRC, CLDN2, CPA1, CEL and CTRB1-CTRB2, and varying from very rare to common, were collated. Seven variants had an ORACP > ORNACP, which was regarded as an immediate indicator of gene-alcohol interactions in CP. Variants with an ORACP < ORNACP were also found to interact with alcohol consumption by virtue of their impact on age at first pancreatitis symptoms in ACP. Conclusions: This study revealed evidence for extensive gene-alcohol interactions in CP. Our findings lend support to the hypothesis that alcohol affects the expression of genetically determined CP and highlight a predominant role of weak-effect variants in the development of ACP.

Zebrafish Models of Craniofacial Malformations: Interactions of Environmental Factors.

The zebrafish is an appealing model organism for investigating the genetic (G) and environmental (E) factors, as well as their interactions (GxE), which contribute to craniofacial malformations. Here, we review zebrafish studies on environmental factors involved in the etiology of craniofacial malformations in humans including maternal smoking, alcohol consumption, nutrition and drug use. As an example, we focus on the (cleft) palate, for which the zebrafish ethmoid plate is a good model. This review highlights the importance of investigating ExE interactions and discusses the variable effects of exposure to environmental factors on craniofacial development depending on dosage, exposure time and developmental stage. Zebrafish also promise to be a good tool to study novel craniofacial teratogens and toxin mixtures. Lastly, we discuss the handful of studies on gene–alcohol interactions using mutant sensitivity screens and reverse genetic techniques. We expect that studies addressing complex interactions (ExE and GxE) in craniofacial malformations will increase in the coming years. These are likely to uncover currently unknown mechanisms with implications for the prevention of craniofacial malformations. The zebrafish appears to be an excellent complementary model with high translational value to study these complex interactions.

Role of Rare and Low-Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels.

Alcohol intake influences plasma lipid levels, and such effects may be moderated by genetic variants. We aimed to characterize the role of aggregated rare and low-frequency protein-coding variants in gene by alcohol consumption interactions associated with fasting plasma lipid levels. In the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, fasting plasma triglycerides and high- and low-density lipoprotein cholesterol were measured in 34 153 individuals with European ancestry from 5 discovery studies and 32 277 individuals from 6 replication studies. Rare and low-frequency functional protein-coding variants (minor allele frequency, ≤5%) measured by an exome array were aggregated by genes and evaluated by a gene-environment interaction test and a joint test of genetic main and gene-environment interaction effects. Two dichotomous self-reported alcohol consumption variables, current drinker, defined as any recurrent drinking behavior, and regular drinker, defined as the subset of current drinkers who consume at least 2 drinks per week, were considered. We discovered and replicated 21 gene-lipid associations at 13 known lipid loci through the joint test. Eight loci (PCSK9, LPA, LPL, LIPG, ANGPTL4, APOB, APOC3, and CD300LG) remained significant after conditioning on the common index single-nucleotide polymorphism identified by previous genome-wide association studies, suggesting an independent role for rare and low-frequency variants at these loci. One significant gene-alcohol interaction on triglycerides in a novel locus was significantly discovered (P=6.65×10-6 for the interaction test) and replicated at nominal significance level (P=0.013) in SMC5. In conclusion, this study applied new gene-based statistical approaches and suggested that rare and low-frequency genetic variants interacted with alcohol consumption on lipid levels.

Animal models of gene-alcohol interactions.

Most birth defects arise from complex interactions between multiple genetic and environmental factors. However, our current understanding of how these interactions and their contributions affect birth defects remains incomplete. Human studies are limited in their ability to identify the fundamental causes of birth defects due to ethical and practical limitations. Animal models provide a great number of resources not available to human studies and they have been critical in advancing our understanding of birth defects and the complex interactions that underlie them. In this review, we discuss the use of animal models in the context of gene-environment interactions that underlie birth defects. We focus on alcohol which is the most common environmental factor associated with birth defects. Prenatal alcohol exposure leads to a wide range of cognitive impairments and structural deficits broadly termed fetal alcohol spectrum disorders (FASD). We discuss the broad impact of prenatal alcohol exposure on the developing embryo and elaborate on the current state of gene-alcohol interactions. Additionally, we discuss how animal models have informed our understanding of the genetics of FASD. Ultimately, these topics will provide insight into the use of animal models in understanding gene-environment interactions and their subsequent impact on birth defects.

Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions.

A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.

Alcohol Intake Interacts with Functional Genetic Polymorphisms of Aldehyde Dehydrogenase (ALDH2) and Alcohol Dehydrogenase (ADH) to Increase Esophageal Squamous Cell Cancer Risk

IntroductionStudies have reported alcohol consumption and genetic variants as major contributing factors for esophageal squamous cell carcinoma (ESCC). However, the complicated interactions between alcohol and genetic factors involved in alcohol metabolism have not been well elucidated with respect to augmented risk of ESCC. MethodsWe performed a large population-based case-control study in a Chinese city with a high ESCC incidence by enrolling 1190 case patients and 1883 controls. We integrated candidate single-nucleotide polymorphism data, detailed alcohol consumption records, gene-alcohol interactions, and single-nucleotide polymorphism functional information to untangle the complicated relationship between alcohol, variants of genes encoding alcohol metabolism enzymes, and ESCC risk. The gene-alcohol interaction was tested by including their product term in a multivariable logistic regression model. Synergy index and ratio of ORs were calculated to assess interaction on additive and multiplicative scale, respectively. ResultsWe confirmed two ESCC susceptibility loci, rs671 in aldehyde dehydrogenase 2 family member gene (ALDH2) and rs1042026 in alcohol dehydrogenase 1B (class I), beta polypeptide gene (ADH1B), that significantly altered alcohol consumption behavior and subsequently modified the association between alcohol consumption and ESCC risk. The rs671(A) allele was associated with ESCC risk in alcohol drinkers (adjusted odds ratio =1.98, 95% confidence interval [CI]: 1.51–2.60) but not in nondrinkers. Healthy individuals who carry different ALDH2 and ADH1B genotypes exhibit diversified drinking behavior, with the proportion of drinkers varying between 23.7% and 54.3%. Among individuals with a fast ethanol oxidization rate, we observed a strong interaction between heavy alcohol consumption and ethanal oxidization rate on both the additive scale (synergy index 4.80 [95% CI: 1.82–12.68]) and the multiplicative scale (ratio of ORs 2.93, 95% CI: 1.39–6.35). ConclusionsOur observation highlights the need for preventing excessive use of alcohol, especially in individuals harboring active alcohol dehyrogenase and inactive ALDH2 variants.

Abstract MP62: Role of Rare and Low-Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels

Introduction: Alcohol intake modifies plasma lipid levels and such effects may be modulated by genetic variants. We use emerging statistical methods that extend well-established common variant approaches to characterize the role of aggregated rare and low-frequency variants in gene by alcohol consumption interactions associated with fasting plasma lipid levels. Methods: Up to 247,870 exonic variants on the Illumina HumanExome BeadChip and fasting plasma triglycerides (TG), and high- and low-density lipoprotein cholesterol (HDL-c and LDL-c) were measured in 46,443 European Americans from 4 studies (the Atherosclerosis Risk in Communities (ARIC) study, the Framingham Heart Study, the Netherlands Epidemiology of Obesity Study and the Women’s Genome Health Study) of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Using the gene-based rareGE method, we conducted exome-wide gene-environment (GxE) tests with genetic main effects estimated as fixed and random effects, and a joint analysis of genetic main and GxE interaction effects. Rare and low-frequency (minor allele frequency ≤ 5%) functional variants, (i.e. frameshift, nonsynonymous, stop/gain, stop/loss, and splicing) were aggregated by genes. Two dichotomous self-reported alcohol consumption variables, current drinker (at least 1 drink per week, yes/no) and regular drinker (at least 2 drinks per week, yes/no) were considered. A sample size weighted Z-test (weighted Stouffer’s method) was used to meta-analyze study-specific p -values. Exome-wide significance level was set at p &lt; 3.7*10 -6 (0.05/13368 genes), using a Bonferroni procedure to correct for multiple testing. Results: We identified 24 gene-lipid associations at 13 known lipid loci (within 500kb) harboring rare and low-frequency variants through the joint analysis. In ARIC, numerous genes ( PCSK9, LPL, LIPG, ANGPTL4, APOB, APOC3-A5 ) remained significant after conditioning on common index single nucleotide polymorphisms (SNPs), suggesting an independent role for rare variants at loci highlighted by previous genome-wide association studies. However, no significant gene-alcohol interactions were observed with rare and low-frequency variants on TG, HDL-c or LDL-c. Conclusion: This study applied new statistical approaches to investigate the role of rare and low-frequency variants in gene-alcohol consumption interactions on lipid levels. Results show promise for other larger scale studies analyzing rare variant GxE interactions.

Abstract P185: Novel Loci for Blood Pressure Using Gene-alcohol Interactions and 1000g Imputed Data

Alcohol consumption has a complex relationship with blood pressure (BP). Whereas heavy alcohol consumption is associated with high BP, moderate alcohol consumption is associated with unchanged or modestly lower BP. We performed genome-wide meta-analysis of single SNP x alcohol drinking status interaction on systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP) blood pressure using 1000G imputed data. Our preliminary results comprise 23 European ancestry studies, including 87,098 individuals with known drinking status. Interaction associations were preformed using linear regression with main and interaction effects and accounting for family structure as needed. Meta-analyses were performed with METAL, for a 2 degrees of freedom joint test, after applying study- and meta-based genomic control adjustments. Results were further filtered if the meta-analysis N &lt; 5,000 individuals or if the number of cohorts contributing to meta-analysis were &lt; 3 for each SNP. For DBP, six novel loci (TRAF3IP1, ANKRD36, NLGN1, UBE3D, OFCC1 and C1orf167) were identified (p &lt; 5E-08). Known BP loci were found to be significant using the same interaction model, including MTHFR, CLCN6, NPPB, MECOM, NOS3, CACNB2, SH2B3, ATXN2, ALDH2, ATP2B1, CSK, FURIN and ZNF831. The significant DBP genes are enriched for hypertension (p-FDR=8.5E-08) and cardiac arrhythmias (p-FDR=5.3E-07) disease loci. MAP analyses identified similar loci as for DBP, while for SBP, ANKRD36 SNPs yielded the most significant associations. For PP, MYPN variants were most significant. In general for the joint test, known BP gene variants showed non-significant levels of meta-heterogeneity and common allele frequency (≥5%), whereas the novel loci often presented meta-heterogeneity and low allele frequency (≈1-5%). TRAF3IP1 interacts among others with TRAF3, reported in mice involved in a new pathway TRAF3-TBK1-AKT for cardiac hypertrophy and heart failure. ANKRD36 interacts with PHLPP2, involved in rats in FKBP51-PHLPP2-AKT signaling during cerebral ischemia/reperfusion injury. NLGN1 has been reported to associate with BP in ASCOT study (N=3,802), while in our meta-analysis out of 6 contributing studies, the joint test significance originates only from the GS_SFHS (N=6,504). Another significant result was C1orf167- rs12561919, a missense SNP considered cis-eQTL for neighboring BP known genes CLCN6 and MTHFR. Employing SNP x drinking status interaction for BP traits, we identified both novel and previously known BP genes. Our findings may provide insights into mechanisms underlying BP and inform lifestyle and therapeutic BP interventions.

Gene-alcohol interactions identify several novel blood pressure loci including a promising locus near SLC16A9.

Alcohol consumption is a known risk factor for hypertension, with recent candidate studies implicating gene-alcohol interactions in blood pressure (BP) regulation. We used 6882 (predominantly) Caucasian participants aged 20–80 years from the Framingham SNP Health Association Resource (SHARe) to perform a genome-wide analysis of SNP-alcohol interactions on BP traits. We used a two-step approach in the ABEL suite to examine genetic interactions with three alcohol measures (ounces of alcohol consumed per week, drinks consumed per week, and the number of days drinking alcohol per week) on four BP traits [systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP) pressure]. In the first step, we fit a linear mixed model of each BP trait onto age, sex, BMI, and antihypertensive medication while accounting for the phenotypic correlation among relatives. In the second step, we conducted 1 degree-of-freedom (df) score tests of the SNP main effect, alcohol main effect, and SNP-alcohol interaction using the maximum likelihood estimates (MLE) of the parameters from the first step. We then calculated the joint 2 df score test of the SNP main effect and SNP-alcohol interaction using MixABEL. The effect of SNP rs10826334 (near SLC16A9) on SBP was significantly modulated by both the number of alcoholic drinks and the ounces of alcohol consumed per week (p-values of 1.27E-08 and 3.92E-08, respectively). Each copy of the G-allele decreased SBP by 3.79 mmHg in those consuming 14 drinks per week vs. a 0.461 mmHg decrease in non-drinkers. Index SNPs in 20 other loci exhibited suggestive (p-value ≤ 1E-06) associations with BP traits by the 1 df interaction test or joint 2 df test, including 3 rare variants, one low-frequency variant, and SNPs near/in genes ESRRG, FAM179A, CRIPT-SOCS5, KAT2B, ADCY2, GLI3, ZNF716, SLIT1, PDE3A, KERA-LUM, RNF219-AS1, CLEC3A, FBXO15, and IGSF5. SNP-alcohol interactions may enhance discovery of novel variants with large effects that can be targeted with lifestyle modifications.

Saturated fat intake and alcohol consumption modulate the association between the APOE polymorphism and risk of future coronary heart disease: a nested case-control study in the Spanish EPIC cohort

The association is still not clear between the common APOE polymorphism and coronary heart disease (CHD) risk, nor its modulation by diet. Thus, our aim was to study the association between the APOE genotypes and incident CHD and how dietary fat and alcohol consumption modify these effects. We performed a nested case-control study in the Spanish European Prospective Investigation into Cancer and Nutrition cohort. Healthy men and women (41 440, 30–69 years) were followed up over a 10-year period, with the incident CHD cases being identified. We analyzed 534 incident CHD cases and 1123 controls. APOE, dietary intake and plasma lipids were determined at baseline. The APOE polymorphism was significantly associated with low-density lipoprotein cholesterol (LDL-C), and gene–alcohol interactions in determining LDL-C were detected. In the whole population, the E2 allele was significantly associated with a lower CHD risk than E3/E3 subjects [odds ratio (OR), 0.58; 95% confidence interval (CI), 0.38–0.89]. The E4 allele did not reach statistical significance vs. E3/E3 (OR, 1.17; 95% CI, 0.88–1.58). However, saturated fat intake modified the effect of the APOE polymorphism in determining CHD risk. When saturated fat intake was low (<10% of energy), no statistically significant association between the APOE polymorphism and CHD risk was observed ( P=.682). However, with higher intake (≥10%), the polymorphism was significant ( P=.005), and the differences between E2 and E4 carriers were magnified (OR for E4 vs. E2, 3.33; 95% CI, 1.61–6.90). Alcohol consumption also modified the effect of the APOE on CHD risk. In conclusion, in this Mediterranean population, the E2 allele is associated with lower CHD risk, and this association is modulated by saturated fat and alcohol consumption.

Influence of alcohol consumption and gene polymorphisms ofADH2andALDH2on hepatocellular carcinoma in a Japanese population

Although alcohol intake as well as hepatitis viruses has been associated with hepatocellular carcinoma (HCC), gene-alcohol interactions on HCC risk remain to be elucidated. We conducted a case-control study to examine whether polymorphisms of alcohol dehydrogenase 2 (ADH2) and aldehyde dehydrogenase 2 (ALDH2) modified the HCC risk depending on the amount of alcohol intake. ADH2 and ALDH2 genotyping was performed by a duplex polymerase chain reaction with confronting two-pair primers in 209 newly diagnosed HCC cases and 2 different controls [275 hospital controls and 381 patients with chronic liver disease (CLD)]. Multiple logistic regression analyses revealed that heavy drinkers consuming >or=3 "go"s/day of sake (69 g of ethanol/day) showed an increased risk of HCC based on comparison of HCC cases with hospital controls [adjusted odds ratio (OR) = 13.5; 95% confidence interval (CI) 3.3-54.3] or CLD patients (adjusted OR = 7.0; 95% CI 2.5-19.2), whereas the overall risk was not elevated among light to moderate drinkers consuming <3 "go"s/day. Interestingly, light to moderate drinking was associated with an increased risk among those with ALDH2*1/*2 (adjusted OR = 4.5 or 2.0), but not among those with ALDH2*1/*1 (adjusted OR = 0.8 or 1.0; p interaction = 0.03 or 0.13). However, this gene-alcohol interaction was not observed for heavy drinking. Among light to moderate drinkers, people with the combination of ALDH2*1/*2 and ADH2*2/*2 revealed the highest risk of HCC. These findings indicate that the ALDH2 polymorphism may modify HCC risk among light to moderate drinkers.

Alcohol and gene interactions

Alcohol use produces both desirable and undesirable effects, ranging from short-term euphoria and reduction in cardiovascular risk, to violence, accidents, dependence and liver disease. Outcomes are affected by the amount of alcohol used (which is itself affected by genetic variation) and also by the drinker's genes. Genetic effects have been most clearly demonstrated for alcohol dependence, and several of the genes for which variation leads to increased dependence risk have been identified. These include genes for enzymes involved in alcohol metabolism (alcohol dehydrogenase and aldehyde dehydrogenase), and genes for receptors affected by alcohol (particularly gamma-aminobutyric acid receptors). Many other gene/dependence associations have been reported but not fully substantiated. Genetic effects on phenotypes other than alcohol dependence are less well understood, and need to be clarified before a full picture of gene-alcohol interactions can be achieved.

Interleukin-6 promoter polymorphism modulates the effects of heavy alcohol consumption on early carotid artery atherosclerosis: the Carotid Atherosclerosis Progression Study (CAPS).

A J-shaped relationship has been demonstrated between alcohol and both clinical cardiovascular events and carotid atherosclerosis. A similar J-shaped relationship has been found between alcohol intake and inflammatory markers. If inflammation were on the intermediate causal pathway between alcohol intake and atherosclerosis, then genetic determinants of enhanced inflammation would be expected to modify this relationship. In a large community population (n=1000; age, 50 to 65 years), we studied the effects of the interleukin-6 (IL-6)-174 polymorphism and gene-alcohol interactions on common carotid artery intima-media thickness (CCA-IMT) and carotid plaque. The CC genotype was associated with significantly higher IL-6 levels; the odds ratio (OR) for IL-6 in the top quartile was 2.07 (95% CI, 1.16 to 3.72; P=0.014). Interactions were seen between genotype and alcohol consumption for both IL-6 levels and CCA-IMT. In individuals who drank >30 g/d of alcohol, the CC genotype was associated with higher IL-6 levels, elevated CCA-IMT (P=0.001), and increased risk of carotid plaque (OR, 3.64; 95% CI, 1.15 to 11.54; P=0.028). The J-shaped relationship between alcohol intake and IMT was seen only for the CC genotype. These data suggest that the IL-6-174 promotor polymorphism may modulate the effects of alcohol on carotid atherosclerosis. These data support the hypothesis that inflammation forms part of the intermediate causal pathway between alcohol intake and atherosclerosis.

Role of alcohol dehydrogenase 3 and cytochrome P-4502E1 genotypes in susceptibility to cancers of the upper aerodigestive tract

Alcohol is a recognized risk factor for upper aerodigestive tract (UAT) cancers, but the mechanism by which alcohol causes cancer remains obscure. Ethanol is oxidized to acetaldehyde (the suspected carcinogenic agent in alcohol) by alcohol dehydrogenases (ADHs) and cytochrome P-4502E1 (CYP2E1), both of which exhibit great inter-individual variability in activity. The hypothesis that these polymorphisms influence susceptibility to alcohol-related cancers remains poorly documented. We investigated whether ADH(3) and CYP2E1 DraI and RsaI genotypes modified the risk of UAT cancers among 121 oral cavity/pharyngeal cancer patients, 129 laryngeal cancer patients, and 172 controls, all French Caucasians. Cancer risks and gene-alcohol interactions were analyzed by unconditional logistic regression, accounting for potential confounders. ADH(3) genotype was not associated with UAT cancer. In contrast, a 2-fold risk of oral cavity/pharyngeal (OR = 2.0, 95% CI 1.0-3.9) and laryngeal (OR = 1.8, 95% CI 1.0-3.5) cancers was observed for carriers of the CYP2E1 DraI C variant allele compared with other individuals. The risk associated with the CYP2E1 RsaI c2 variant allele also increased for oral cavity/pharyngeal cancer (OR = 2.6, 95% CI 1.0-6. 6). The effects of ADH(3) or CYP2E1 genotype and alcohol or tobacco were independent. The highest risk of oral cavity/pharyngeal cancer was observed among the heaviest drinkers (>80 g/day) with the CYP2E1 DraI C allele (OR = 5.8, 95% CI 1.9-18.2) or the CYP2E1 RsaI c2 allele (OR = 7.2, 95% CI 1.4-38.2) compared with lighter drinkers with other genotypes. Our study suggests that CYP2E1 genotype modifies the risk of UAT cancers, but due to the low frequency of CYP2E1 variant alleles, large-scale studies are needed to confirm our findings.