1241Alcohol and hypertensive disorders of pregnancy: a negative control analysis

Background Alcohol increases blood pressure, yet estimates of its association with pre-eclampsia range from positive to negative. Here we estimated the association of maternal drinking during pregnancy with preeclampsia and gestational hypertension, separately and jointly as hypertensive disorders of pregnancy (HDP). We also used partner’s alcohol intake as a negative control exposure to strengthen causal inference. Methods We used data on self-reported alcohol intake in the Avon Longitudinal Study of Parents And Children (ALSPAC, N∼9,000). HDP was ascertained from obstetric notes. Multivariable multinomial regression models were adjusted for confounders and mutually-adjusted for partner’s or maternal alcohol. Sensitivity analyses assessed the robustness of results to assumptions of no selection bias, no reporting bias, and no residual confounding (e.g. comparing estimates for beer and wine separately, which have different socioeconomic patterning). Results In mutually-adjusted analyses, maternal and partner’s drinking were associated with decreased HDP odds (OR(95% CI): 0.86(0.77–0.96) and 0.82(0.70-0.97)) respectively. In contrast, the negative control design confirmed the expected associations for maternal but not partner’s smoking (figure), demonstrating the validity of this approach. Multiple sensitivity analyses did not alter results. Estimates were more extreme for increasing levels of wine compared to increasing levels of beer drinking. Conclusions Our extensive negative control and sensitivity analyses point at confounding mechanisms shared between mothers and partners as the most plausible explanation for the alcohol-HDP association. Key messages It is unlikely that alcohol intake in pregnancy reduces the risk of HDP.

Acetaldehyde Enhances Alcohol Sensitivity and Protects against Alcoholism: Evidence from Alcohol Metabolism in Subjects with Variant ALDH2*2 Gene Allele

Alcoholism is a complex behavior trait influenced by multiple genes as well as by sociocultural factors. Alcohol metabolism is one of the biological determinants that can significantly influence drinking behaviors. Alcohol sensitivity is thought to be a behavioral trait marker for susceptibility to develop alcoholism. The subjective perceptions would be an indicator for the alcohol preference. To investigate alcohol sensitivity for the variants ADH1B*2 and ALDH2*2, sixty healthy young males with different combinatory ADH1B and ALDH2 genotypes, ADH1B*2/*2–ALDH2*1/*1 (n = 23), ADH1B*2/*2–ALDH2*1/*2 (n = 27), and ADH1B*1/*1–ALDH2*1/*1 (n = 10), participated in the study. The subjective perceptions were assessed by a structured scale, and blood ethanol and acetaldehyde were determined by GC and HPLC after an alcohol challenge in two dose sessions (0.3 g/kg or 0.5 g/kg ethanol). The principal findings are (1) dose-dependent increase of blood ethanol concentration, unaffected by ADH1B or ALDH2; (2) significant build-up of blood acetaldehyde, strikingly influenced by the ALDH2*2 gene allele and correlated with the dose of ingested alcohol; (3) the increased heart rate and subjective sensations caused by acetaldehyde accumulation in the ALDH2*2 heterozygotes; (4) no significant effect of ADH1B polymorphism in alcohol metabolism or producing the psychological responses. The study findings provide the evidence of acetaldehyde potentiating the alcohol sensitivity and feedback to self-control the drinking amount. The results indicate that ALDH2*2 plays a major role for acetaldehyde-related physiological negative responses and prove the genetic protection against development of alcoholism in East Asians.

An exploratory assessment of the applicability of direct-to-consumer genetic testing to translational research in Japan

Objective In order to assess the applicability of a direct-to-consumer (DTC) genetic testing to translational research for obtaining new knowledge on relationships between drug target genes and diseases, we examined possibility of these data by associating SNPs and disease related phenotype information collected from healthy individuals. Results A total of 12,598 saliva samples were collected from the customers of commercial service for SNPs analysis and web survey were conducted to collect phenotype information. The collected dataset revealed similarity to the Japanese data but distinguished differences to other populations of all dataset of the 1000 Genomes Project. After confirmation of a well-known relationship between ALDH2 and alcohol-sensitivity, Phenome-Wide Association Study (PheWAS) was performed to find association between pre-selected drug target genes and all the phenotypes. Association was found between GRIN2B and multiple phenotypes related to depression, which is considered reliable based on previous reports on the biological function of GRIN2B protein and its relationship with depression. These results suggest possibility of using SNPs and phenotype information collected from healthy individuals as a translational research tool for drug discovery to find relationship between a gene and a disease if it is possible to extract individuals in pre-disease states by properly designed questionnaire.

Transcriptomic analyses of gastrulation-stage C57BL/6J and C57BL/6NHsd mouse embryos with differential susceptibility to alcohol

Fetal Alcohol Spectrum Disorders (FASD) are a serious public health concern, affecting approximately 5% of live births in the US. The more severe craniofacial and central nervous system malformations characteristic of FASD are caused by alcohol exposure during gastrulation (embryonic day 7 in mice; 3rd week of human pregnancy). Genetics are a known contributor to differences in alcohol sensitivity in humans and in animal models of FASD. Our study profiled gene expression in gastrulation-stage embryos from two commonly used, genetically similar mouse substrains, C57BL/6J and C57BL/6NHsd, that differ in alcohol sensitivity. First, we established normal gene expression patterns at three finely resolved timepoints during gastrulation and developed a web-based interactive tool. Baseline transcriptional differences across strains were associated with immune signaling, indicative of their molecular divergence. Second, we examined the gene networks impacted by alcohol in each strain. Alcohol was associated with a more pronounced transcriptional effect in the 6J's vs. 6N's, matching the 6J's increased susceptibility. The 6J strain exhibited down-regulation of cell proliferation and morphogenic signaling pathways and up-regulation of pathways related to cell death and craniofacial defects, while 6N's show enrichment of hypoxia (up) and cellular metabolism (down) pathways. Collectively, these datasets 1) provide insight into the changing transcriptional landscape across gastrulation in two commonly used mouse strains, 2) establish a valuable resource that enables the discovery of candidate genes that may modify susceptibility to prenatal alcohol exposure that can be validated in humans, and 3) identify novel pathogenic mechanisms potentially involved in alcohol's impact on development.

Sex Differences in Acute Alcohol Sensitivity of Naïve and Alcohol Dependent Central Amygdala GABA Synapses

Aims Alcohol use disorder (AUD) is linked to hyperactivity of brain stress systems, leading to withdrawal states which drive relapse. AUD differs among the sexes, as men are more likely to have AUD than women, but women progress from casual use to binge and heavy alcohol use more quickly and are more likely to relapse into repetitive episodes of heavy drinking. In alcohol dependence animal models of AUD, the central amygdala (CeA) functions as a hub of stress and anxiety processing and gamma-Aminobutyric acid (GABA)ergic signaling within the CeA is involved in dependence-induced increases in alcohol consumption. We have shown dysregulation of CeA GABAergic synaptic signaling in alcohol dependence animal models, but previous studies have exclusively used males. Methods Here, we used whole-cell patch clamp electrophysiology to examine basal CeA GABAergic spontaneous inhibitory postsynaptic currents (sIPSC) and the effects of acute alcohol in both naïve and alcohol dependent rats of both sexes. Results We found that sIPSC kinetics differ between females and males, as well as between naïve and alcohol-dependent animals, with naïve females having the fastest current kinetics. Additionally, we find differences in baseline current kinetics across estrous cycle stages. In contrast to the increase in sIPSC frequency routinely found in males, acute alcohol (11–88 mM) had no effect on sIPSCs in naïve females, however the highest concentration of alcohol increased sIPSC frequency in dependent females. Conclusion These results provide important insight into sex differences in CeA neuronal function and dysregulation with alcohol dependence and highlight the need for sex-specific considerations in the development of effective AUD treatment.

Sleep modulates alcohol toxicity in Drosophila

Study ObjectivesAlcohol abuse is a significant public health problem, particularly in populations in which sleep deprivation is common as such as shift workers and aged individuals. Although research demonstrates the effect of alcohol on sleep, little is known about the role of sleep in alcohol sensitivity and toxicity. We investigated sleep as a factor modulating alcohol toxicity using Drosophila melanogaster, a model system ideal for studies of sleep, alcohol and aging.MethodsFollowing 24 hours of sleep deprivation using mechanical stimulation, Drosophila were exposed to binge-like alcohol exposures. Behavioral sensitivity, tolerance, and mortality were assessed. The effects of chronic sleep deprivation on alcohol toxicity were investigated using a short sleep mutant insomniac. Pharmacological induction of sleep for prior to alcohol exposure was accomplished using a GABAA-receptor agonist, 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP) to determine if increased sleep mitigated the effects of alcohol toxicity on middle-aged flies and flies with environmentally disrupted circadian clocks mimicking groups more vulnerable to the effects of alcohol.ResultsAcute sleep deprivation increased alcohol-induced mortality following alcohol exposure. However, sleep deprivation had no effect on alcohol absorbance or clearance. Sleep deprivation also abolished functional tolerance measured 24 hours after the initial alcohol exposure, although tolerance at 4 h was observed. Pharmacologically increasing sleep prior to alcohol exposure decreased alcohol-induced mortality.ConclusionsSleep quantity prior to alcohol exposure affects alcohol toxicity with decreased sleep increasing alcohol toxicity and dampened 24-hour alcohol tolerance. In contrast, increased sleep mitigated alcohol-induced mortality even in vulnerable groups such as aging flies and those with circadian dysfunction.Statement of significanceWith the growing incidence of sleep deprivation and sleep disorders across adolescents and adults, it is important to understand the role of sleep in alcohol toxicity to develop future therapies for prevention and treatment of alcohol-induced pathologies. Using Drosophila melanogaster, an established model for both sleep and alcohol research, we found that acute and chronic sleep deprivation increased alcohol toxicity and eliminated long-term functional alcohol tolerance. In contrast, increased sleep prior to binge-like alcohol exposure mitigated alcohol-induced mortality even in vulnerable groups with higher susceptibility to alcohol toxicity.