Gene-environment Interaction Effects Research Articles

Gene‒environment interaction effect of hypothalamic‒pituitary‒adrenal axis gene polymorphisms and job stress on the risk of sleep disturbances.

Studies have shown that chronic exposure to job stress may increase the risk of sleep disturbances and that hypothalamic‒pituitary‒adrenal (HPA) axis gene polymorphisms may play an important role in the psychopathologic mechanisms of sleep disturbances. However, the interactions among job stress, gene polymorphisms and sleep disturbances have not been examined from the perspective of the HPA axis. This study aimed to know whether job stress is a risk factor for sleep disturbances and to further explore the effect of the HPA axis gene × job stress interaction on sleep disturbances among railway workers. In this cross-sectional study, 671 participants (363 males and 308 females) from the China Railway Fuzhou Branch were included. Sleep disturbances were evaluated with the Pittsburgh Sleep Quality Index (PSQI), and job stress was measured with the Effort-Reward Imbalance scale (ERI). Generalized multivariate dimensionality reduction (GMDR) models were used to assess gene‒environment interactions. We found a significant positive correlation between job stress and sleep disturbances (P < 0.01). The FKBP5 rs1360780-T and rs4713916-A alleles and the CRHR1 rs110402-G allele were associated with increased sleep disturbance risk, with adjusted ORs (95% CIs) of 1.75 [1.38-2.22], 1.68 [1.30-2.18] and 1.43 [1.09-1.87], respectively. However, the FKBP5 rs9470080-T allele was a protective factor against sleep disturbances, with an OR (95% CI) of 0.65 [0.51-0.83]. GMDR analysis indicated that under job stress, individuals with the FKBP5 rs1368780-CT, rs4713916-GG, and rs9470080-CT genotypes and the CRHR1 rs110402-AA genotype had the greatest risk of sleep disturbances. Individuals carrying risk alleles who experience job stress may be at increased risk of sleep disturbances. These findings may provide new insights into stress-related sleep disturbances in occupational populations.

Epistasis in neurotransmitter receptors linked to posttraumatic stress disorder and major depressive disorder comorbidity in traumatized Chinese.

Posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) comorbidity occurs through exposure to trauma with genetic susceptibility. Neuropeptide-Y (NPY) and dopamine are neurotransmitters associated with anxiety and stress-related psychiatry through receptors. We attempted to explore the genetic association between two neurotransmitter receptor systems and the PTSD-MDD comorbidity. Four groups were identified using latent profile analysis (LPA) to examine the patterns of PTSD and MDD comorbidity among survivors exposed to earthquake-related trauma: low symptoms, predominantly depression, predominantly PTSD, and PTSD-MDD comorbidity. NPY2R (rs4425326), NPY5R (rs11724320), DRD2 (rs1079597), and DRD3 (rs6280) were genotyped from 1,140 Chinese participants exposed to earthquake-related trauma. Main, gene-environment interaction (G × E), and gene-gene interaction (G × G) effects for low symptoms, predominantly depression, and predominantly PTSD were tested using a multinomial logistic model with PTSD-MDD comorbidity as a reference. The results demonstrated that compared to PTSD-MDD comorbidity, epistasis (G × G) NPY2R-DRD2 (rs4425326 × rs1079597) affects low symptoms (β = -0.66, OR = 0.52 [95% CI: 0.32-0.84], p = 0.008, pperm = 0.008) and predominantly PTSD (β = -0.56, OR = 0.57 [95% CI: 0.34-0.97], p = 0.037, pperm = 0.039), while NPY2R-DRD3 (rs4425326 × rs6280) impacts low symptoms (β = 0.82, OR = 2.27 [95% CI: 1.26-4.10], p = 0.006, pperm = 0.005) and predominantly depression (β = 1.08, R = 2.95 [95% CI: 1.55-5.62], p = 0.001, pperm = 0.001). The two G × G effects are independent. NPY and dopamine receptor genes are related to the genetic etiology of PTSD-MDD comorbidity, whose specific mechanisms can be studied at multiple levels.

Genetic Determinants of Thiazide-Induced Hyperuricemia, Hyperglycemia, and Urinary Electrolyte Disturbances - A Genome-Wide Evaluation of the UK Biobank.

Thiazide diuretics, widely used in hypertension, cause a variety of adverse reactions, including hyperglycemia, hyperuricemia, and electrolyte abnormalities. In this study, we aimed to identify genetic variants that interact with thiazide-use to increase the risk of these adverse reactions. Using UK Biobank data, we first performed genomewide variance quantitative trait locus (vQTL) analysis of ~ 6.2 million SNPs on 95,493 unrelated hypertensive White British participants (24,313 on self-reported bendroflumethiazide treatment at recruitment) for 2 blood (glucose and urate) and 2 urine (potassium and sodium) biomarkers. Second, we conducted direct gene-environment interaction (GEI) tests on the significant (P < 2.5 × 10-9 ) vQTLs, included a second UK Biobank cohort comprising 13,647 unrelated hypertensive White British participants (3,478 on thiazides other than bendroflumethiazide) and set significance at P = 0.05 divided by the number of vQTL SNPs tested for GEIs. The vQTL analysis identified eight statistically significant SNPs for blood glucose (5 SNPs) and serum urate (3 SNPs), with none being identified for the urinary biomarkers. Two of the SNPs (1 glucose SNP: CDKAL1 intron rs35612982, GEI P = 6.24 × 10-3 ; and 1 serum urate SNP: SLC2A9 intron rs938564, GEI P = 4.51 × 10-4 ) demonstrated significant GEI effects in the first, but not the second, cohort. Both genes are biologically plausible candidates, with the SLC2A9-mediated interaction having been previously reported. In conclusion, we used a two-stage approach to detect two biologically plausible genetic loci that can interact with thiazides to increase the risk of thiazide-associated biochemical abnormalities. Understanding how environmental exposures (including medications such as thiazides) and genetics interact, is an important step toward precision medicine and improved patient outcomes.

BDNF Val66Met polymorphism moderates negative symptom expression of bully victimization through resilience in Taiwanese youth

ABSTRACT Bully victimization is known to cause adverse psychological outcomes; however, resilience may mitigate the more adverse effects. Little is known regarding the role played by BDNF Val66Met polymorphism in youth resilience against psychological harm caused by bully victimization. In this cross-sectional study, a community sample of 598 participants (M age  = 20.1 ± 1.4 years, 48.8% males) completed the questionnaire on bully victimization, resilience, and psychological symptoms. Salivary genomic DNA was genotyped for the BDNF Val66Met polymorphism. A path analysis was used to test the mediating role of resilience in the association between bully victimization and psychological symptoms. Furthermore, the BDNF genotype was added to the model to explore its moderating effects on the mediating role of resilience in the path with 5000 bootstrapped samplings using SPSS PROCESS Macro. Results revealed a significant indirect effect via resilience that accounted for 17.2% of the association between bully victimization and psychological symptoms. While the Val66Met polymorphism interacted with bully victimization to predict resilience scores, bully victimization was more strongly associated with poor resilience (F = 4.59, p = 0.03) in subjects with the Met/Met genotype (β=-3.22, p < 0.001), as compared to participants with other genotypes (β=-1.33, p = 0.051). Findings suggest a gene-environment interaction effect on psychological resilience in bully-victimized youth.

Lack of Association between TP73 G4C14-A4T14 Polymorphism and Cervical Cancer Risk in Overall and Asian Women: A Meta-Analysis.

Growing studies revealed the association between polymorphisms in Tumor Protein TP73 (TP73) and susceptibility to cancer, especially with gynecological cancers. but, the results remained inconsistent. This meta-analysis was carried out to examine the relationship of the TP73 G4C14-to-A4T14 polymorphism (hereafter, G4C14-to-A4T14) with susceptibility to cervical cancer globally and by ethnicity. Eligible studies were collected by retrieving PubMed, Scopus, Web of Science, Embase, Wan Fang, and CNKI published before 25 October, 2023. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of such association. A total of 10 case-control studies with 1804 cervical cancer cases and 2433 healthy controls were included to this study. The pooled results showed that TP73 G4C14-to-A4T14 polymorphism was not associated with cervical cancer risk in overall. in terms of stratified analyses by ethnicity, this polymorphism was not associated with risk of cervical cancer among East-Asian women. however, there was a significant association based source of control among hospital-based studies. Inconsistent with previous meta-analyses, our pooled results revealed that TP73 G4C14-to-A4T14 polymorphism might not be a risk factor for development of cervical cancer globally and among East-Asian women. Moreover, further studies examining the effect of gene-gene and gene-environment interactions may eventually provide a better knowledge.

Enhanced polygenic risk score incorporating gene-environment interaction suggests the association of major depressive disorder with cardiac and lung function.

Depression has been linked to an increased risk of cardiovascular and respiratory diseases; however, its impact on cardiac and lung function remains unclear, especially when accounting for potential gene-environment interactions. We developed a novel polygenic and gene-environment interaction risk score (PGIRS) integrating the major genetic effect and gene-environment interaction effect of depression-associated loci. The single nucleotide polymorphisms (SNPs) demonstrating major genetic effect or environmental interaction effect were obtained from genome-wide SNP association and SNP-environment interaction analyses of depression. We then calculated the depression PGIRS for non-depressed individuals, using smoking and alcohol consumption as environmental factors. Using linear regression analysis, we assessed the associations of PGIRS and conventional polygenic risk score (PRS) with lung function (N = 42886) and cardiac function (N = 1791) in the subjects with or without exposing to smoking and alcohol drinking. We detected significant associations of depression PGIRS with cardiac and lung function, contrary to conventional depression PRS. Among smokers, forced vital capacity exhibited a negative association with PGIRS (β = -0.037, FDR = 1.00 × 10-8), contrasting with no significant association with PRS (β = -0.002, FDR = 0.943). In drinkers, we observed a positive association between cardiac index with PGIRS (β = 0.088, FDR = 0.010), whereas no such association was found with PRS (β = 0.040, FDR = 0.265). Notably, in individuals who both smoked and drank, forced expiratory volume in 1-second demonstrated a negative association with PGIRS (β = -0.042, FDR = 6.30 × 10-9), but not with PRS (β = -0.003, FDR = 0.857). Our findings underscore the profound impact of depression on cardiac and lung function, highlighting the enhanced efficacy of considering gene-environment interactions in PRS-based studies.

The interaction between polygenic risk and environmental influences: A direct test of the 3P model of insomnia in adolescents.

Stress is a universal phenomenon and one of the most common precipitants of insomnia. However, not everyone develops insomnia after experiencing a stressful life event. This study aims to test aspects of Spielman's '3P model of insomnia' (during adolescence) by exploring the extent to which: (a) insomnia symptoms are predicted by polygenic scores (PGS); (b) life events predict insomnia symptoms; (c) the interaction between PGS and life events contribute to the prediction of insomnia symptoms; (d) gene-environment interaction effects remain after controlling for sex. The sample comprised 4,629 twins aged 16 from the Twin Early Development Study who reported on their insomnia symptoms and life events. PGS for insomnia were calculated. In order to test the main hypothesis of this study (a significant interaction between PGS and negative life events), we fitted a series of mixed effect regressions. The best fit was provided by the model including sex, PGS for insomnia, negative life events, and their interactions (AIC = 26,158.7). Our results show that the association between insomnia symptoms and negative life events is stronger for those with a higher genetic risk for insomnia. This work sheds light on the complex relationship between genetic and environmental factors implicated for insomnia. This study has tested for the first time the interaction between genetic predisposition (PGS) for insomnia and environmental stressors (negative life events) in adolescents. This work represents a direct test of components of Spielman's 3P model for insomnia which is supported by our results.

Inducible and Conditional Activation of Adult Neurogenesis Rescues Cadmium-Induced Hippocampus-Dependent Memory Deficits in ApoE4-KI Mice.

The apolipoprotein E (ApoE) gene is a genetic risk factor for late-onset Alzheimer's disease, in which ε4 allele carriers have increased risk compared to the common ε3 carriers. Cadmium (Cd) is a toxic heavy metal and a potential neurotoxicant. We previously reported a gene-environment interaction (GxE) effect between ApoE4 and Cd that accelerates or increases the severity of the cognitive decline in ApoE4-knockin (ApoE4-KI) mice exposed to 0.6 mg/L CdCl2 through drinking water compared to control ApoE3-KI mice. However, the mechanisms underlying this GxE effect are not yet defined. Because Cd impairs adult neurogenesis, we investigated whether genetic and conditional stimulation of adult neurogenesis can functionally rescue Cd-induced cognitive impairment in ApoE4-KI mice. We crossed either ApoE4-KI or ApoE3-KI to an inducible Cre mouse strain, Nestin-CreERTM:caMEK5-eGFPloxP/loxP (designated as caMEK5), to generate ApoE4-KI:caMEK5 and ApoE3-KI:caMEK5. Tamoxifen administration in these mice genetically and conditionally induces the expression of caMEK5 in adult neural stem/progenitor cells, enabling the stimulation of adult neurogenesis in the brain. Male ApoE4-KI:caMEK5 and ApoE3-KI:caMEK5 mice were exposed to 0.6 mg/L CdCl2 throughout the experiment, and tamoxifen was administered once Cd-induced impairment in spatial working memory was consistently observed. Cd exposure impaired spatial working memory earlier in ApoE4-KI:caMEK5 than in ApoE3-KI:caMEK5 mice. In both strains, these deficits were rescued after tamoxifen treatment. Consistent with these behavioral findings, tamoxifen treatment enhanced adult neurogenesis by increasing the morphological complexity of adult-born immature neurons. These results provide evidence for a direct link between impaired spatial memory and adult neurogenesis in this GxE model.

Gene-Environment Interaction and Risk of Schizophrenia

Schizophrenia is a chronic mental disease that affects less than 1% of the population in the United States. In the introduction, the article provides a general overview of schizophrenia disorder, incorporating potential causal factors of schizophrenia in biological and environmental areas. It also demonstrated the individual and social impacts with present symptoms. Later in the mainbody sections, the article presents the general effects of gene-environment interaction on the risk of schizophrenia and the moderating role of environmental factors in schizophrenia by looking at the influences of childhood adversity in siblings with and without schizhophrenia, the role of family history and epigenetics, the effect of socioeconomic status (SES), and the relationship between stress and neurotransmitter activity in schizophrenia. On of the limitations of previous studies is that they were mainly conducted in adults who were diagnosed with schizophrenia already. Future studies should identify at-risk children and families to conduct longitudianl studies on this topic. This review can provide some guidance to the desgin of prevention and intervention programs at schools and communities for at-risk families.

A Varying Coefficient Model to Jointly Test Genetic and Gene-Environment Interaction Effects.

Most human traits are influenced by the interplay between genetic and environmental factors. Many statistical methods have been proposed to screen for gene-environment interaction (GxE) in the post genome-wide association study era. However, most of the existing methods assume a linear interaction between genetic and environmental factors toward phenotypic variations, which diminishes statistical power in the case of nonlinear GxE. In this paper, we present a flexible statistical procedure to detect GxE regardless of whether the underlying relationship is linear or not. By modeling the joint genetic and GxE effects as a varying-coefficient function of the environmental factor, the proposed model is able to capture dynamic trajectories of GxE. We employ a likelihood ratio test with a fast Monte Carlo algorithm for hypothesis testing. Simulations were conducted to evaluate validity and power of the proposed model in various settings. Real data analysis was performed to illustrate its power, in particular, in the case of nonlinear GxE.

Gene-environment interactions in the pathogenesis of common craniofacial anomalies.

Craniofacial anomalies often exhibit phenotype variability and non-mendelian inheritance due to their multifactorial origin, involving both genetic and environmental factors. A combination of epidemiologic studies, genome-wide association, and analysis of animal models have provided insight into the effects of gene-environment interactions on craniofacial and brain development and the pathogenesis of congenital disorders. In this chapter, we briefly summarize the etiology and pathogenesis of common craniofacial anomalies, focusing on orofacial clefts, hemifacial microsomia, and microcephaly. We then discuss how environmental risk factors interact with genes to modulate the incidence and phenotype severity of craniofacial anomalies. Identifying environmental risk factors and dissecting their interaction with different genes and modifiers is central to improved strategies for preventing craniofacial anomalies.

Genome-Wide Association Study Identifies ROBO2 as a Novel Susceptibility Gene for Anthracycline-Related Cardiomyopathy in Childhood Cancer Survivors.

Interindividual variability in the dose-dependent association between anthracyclines and cardiomyopathy suggests a modifying role of genetic susceptibility. Few previous studies have examined gene-anthracycline interactions. We addressed this gap using the Childhood Cancer Survivor Study (discovery) and the Children's Oncology Group (COG) study COG-ALTE03N1 (replication). A genome-wide association study (Illumina HumanOmni5Exome Array) in 1,866 anthracycline-exposed Childhood Cancer Survivor Study participants (126 with heart failure) was used to identify single-nucleotide polymorphisms (SNPs) with either main or gene-environment interaction effect on anthracycline-related cardiomyopathy that surpassed a prespecified genome-wide threshold for statistical significance. We attempted replication in a matched case-control set of anthracycline-exposed childhood cancer survivors with (n = 105) and without (n = 160) cardiomyopathy from COG-ALTE03N1. Two SNPs (rs17736312 [ROBO2]) and rs113230990 (near a CCCTC-binding factor insulator [< 750 base pair]) passed the significance cutoff for gene-anthracycline dose interaction in discovery. SNP rs17736312 was successfully replicated. Compared with the GG/AG genotypes on rs17736312 and anthracyclines ≤ 250 mg/m2, the AA genotype and anthracyclines > 250 mg/m2 conferred a 2.2-fold (95% CI, 1.2 to 4.0) higher risk of heart failure in discovery and an 8.2-fold (95% CI, 2.0 to 34.4) higher risk in replication. ROBO2 encodes transmembrane Robo receptors that bind Slit ligands (SLIT). Slit-Robo signaling pathway promotes cardiac fibrosis by interfering with the transforming growth factor-β1/small mothers against decapentaplegic (Smad) pathway, resulting in disordered remodeling of the extracellular matrix and potentiating heart failure. We found significant gene-level associations with heart failure: main effect (TGF-β1, P = .007); gene*anthracycline interaction (ROBO2*anthracycline, P = .0003); and gene*gene*anthracycline interaction (SLIT2*TGF-β1*anthracycline, P = .009). These findings suggest that high-dose anthracyclines combined with genetic variants involved in the profibrotic Slit-Robo signaling pathway promote cardiac fibrosis via the transforming growth factor-β1/Smad pathway, providing credence to the biologic plausibility of the association between SNP rs17736312 (ROBO2) and anthracycline-related cardiomyopathy.

The main effect and gene-environment interaction effect of the ADCYAP1R1 polymorphism rs2267735 on the course of posttraumatic stress disorder symptoms-A longitudinal analysis.

Many studies have been performed to investigate the association between the ADCYAP1R1 polymorphism rs2267735 and posttraumatic stress disorder (PTSD), but the results have been inconsistent, and the way in which this gene affects the course of PTSD has not been widely investigated. Thus, a longitudinal study of the course (development trajectory) of PTSD is needed. In this study, we performed a longitudinal analysis of rs2267735 in 1017 young, trauma-exposed Chinese people (549 females and 468 males, ranging from 7 to 11 years old). At four time points after trauma exposure (2.5, 3.5, 4.5, and 5.5 years), we measured PTSD symptoms with the University of California, Los Angeles PTSD Reaction Index (PTSD-RI) for DSM-IV (Child Version). We employed a latent growth model (LGM) for the longitudinal data to test the association between rs2267735 (main and gene-environment interaction effects) and the course of PTSD symptoms. The results of LGM showed that the gene-environment interaction (rs2267735 × trauma exposure) effects were associated with PTSD symptoms in girls at 2.5 years (β = -0.291 and P = 0.013 for LGM intercept). The gene-environment interaction (rs2267735 × trauma exposure) effect was also correlated with PTSD symptoms in girls at 3.5 and 4.5 years (β = -0.264 and P = 0.005; β = -0.217 and P = 0.013). Our study revealed that the gene-environment interaction of the ADCYAP1R1 polymorphism rs2267735 is associated with PTSD symptoms in girls at 2.5 years and that the effects may be stable over time and not related to the PTSD symptom recovery rate. This is the first study to detect the how the ADCYAP1R1 gene affects the course of PTSD after trauma exposure in a longitudinal view.

Transcriptional profiles in the mouse amygdala after a cognitive judgment bias test largely depend on the genotype.

Background: The amygdala is crucial for emotional cognitive processing. Affective or emotional states can bias cognitive processes, including attention, memory, and decision-making. This can result in optimistic or pessimistic behaviors that are partially driven by the activation of the amygdala. The resulting emotional cognitive bias is a common feature of anxiety and mood disorders, both of which are interactively influenced by genetic and environmental factors. It is also known that emotional cognitive biases can be influenced by environmental factors. However, little is known about the effects of genetics and/or gene-environment interactions on emotional cognitive biases. We investigated the effects of the genetic background and environmental enrichment on the transcriptional profiles of the mouse amygdala following a well-established cognitive bias test. Methods: Twenty-four female C57BL/6J and B6D2F1N mice were housed either in standard (control) conditions or in an enriched environment. After appropriate training, the cognitive bias test was performed on 19 mice that satisfactorily completed the training scheme to assess their responses to ambiguous cues. This allowed us to calculate an "optimism score" for each mouse. Subsequently, we dissected the anterior and posterior portions of the amygdala to perform RNA-sequencing for differential expression and other statistical analyses. Results: In general, we found only minor changes in the amygdala's transcriptome associated with the levels of optimism in our mice. In contrast, we observed wide molecular effects of the genetic background in both housing environments. The C57BL/6J animals showed more transcriptional changes in response to enriched environments than the B6D2F1N mice. We also generally found more dysregulated genes in the posterior than in the anterior portion of the amygdala. Gene set overrepresentation analyses consistently implicated cellular metabolic responses and immune processes in the differences observed between mouse strains, while processes favoring neurogenesis and neurotransmission were implicated in the responses to environmental enrichment. In a correlation analysis, lipid metabolism in the anterior amygdala was suggested to influence the levels of optimism. Conclusions: Our observations underscore the importance of selecting appropriate animal models when performing molecular studies of affective conditions or emotional states, and suggest an important role of immune and stress responses in the genetic component of emotion regulation.

Do methylenetetrahydrofolate dehydrogenase, cyclohydrolase, and formyltetrahydrofolate synthetase 1 polymorphisms modify changes in intelligence of school-age children in areas of endemic fluorosis?

Background:Excessive exposure to fluoride can reduce intelligence. Methylenetetrahydrofolate dehydrogenase, cyclohydrolase, and formyltetrahydrofolate synthetase 1 (MTHFD1) polymorphisms have important roles in neurodevelopment. However, the association of MTHFD1 polymorphisms with children's intelligence changes in endemic fluorosis areas has been rarely explored.Methods:A cross-sectional study was conducted in four randomly selected primary schools in Tongxu County, Henan Province, from April to May in 2017. A total of 694 children aged 8 to 12 years were included in the study with the recruitment by the cluster sampling method. Urinary fluoride (UF) and urinary creatinine were separately determined using the fluoride ion-selective electrode and creatinine assay kit. Children were classified as the high fluoride group and control group according to the median of urinary creatinine-adjusted urinary fluoride (UFCr) level. Four loci of MTHFD1 were genotyped, and the Combined Raven's Test was used to evaluate children's intelligence quotient (IQ). Generalized linear model and multinomial logistic regression model were performed to analyze the associations between children's UFCr level, MTHFD1 polymorphisms, and intelligence. The general linear model was used to explore the effects of gene-environment and gene-gene interaction on intelligence.Results:In the high fluoride group, children's IQ scores decreased by 2.502 when the UFCr level increased by 1.0 mg/L (β = −2.502, 95% confidence interval [CI]:−4.411, −0.593), and the possibility for having “excellent” intelligence decreased by 46.3% (odds ratio = 0.537, 95% CI: 0.290, 0.994). Children with the GG genotype showed increased IQ scores than those with the AA genotype of rs11627387 locus in the high fluoride group (P < 0.05). Interactions between fluoride exposure and MTHFD1 polymorphisms on intelligence were observed (Pinteraction < 0.05).Conclusion:Our findings suggest that excessive fluoride exposure may have adverse effects on children's intelligence, and changes in children's intelligence may be associated with the interaction between fluoride and MTHFD1 polymorphisms.

Developmental modeling of hepatogenesis using obese iPSCs-hepatocyte differentiation uncovers pathological features

Obesity is a multigene disorder. However, in addition to genetic factors, environmental determinants also participate in developing obesity and related pathologies. Thus, obesity could be best described as a combination of genetic and environmental perturbations often having its origin during the early developmental period. Environmental factors such as energy-dense food and sedentary lifestyle are known to be associated with obesogenicity. However, the combinatorial effects of gene-environment interactions are not well understood. Understanding the role of multiple genetic variations leading to subtle gene expression changes is not practically possible in monogenic or high-fat-fed animal models of obesity. In contrast, human induced pluripotent stem cells (hiPSCs) from individuals with familial obesity or an obesogenic genotype could serve as a good model system. Herein, we have used hiPSCs generated from normal and genetically obese subjects and differentiated them into hepatocytes in cell culture. We show that hepatocytes from obese iPSCs store more lipids and show increased cell death than normal iPSCs. Whole transcriptome analyses in both normal and obese iPSCs treated with palmitate compared to control revealed LXR-RXR and hepatic fibrosis pathways were enriched among other pathways in obese iPSCs compared to normal iPSCs. Among other genes, increased CD36 and CAV1 expression and decreased expression of CES1 in obese iPSCs could have been responsible for excess lipid accumulation, resulting in differential expression of genes associated with hepatic fibrosis, a key feature of non-alcoholic fatty liver disease (NAFLD). Our results demonstrate that iPSCs derived from genetically obese subjects could serve as an excellent model to understand the effects of this multigene disorder on organ development and may uncover pathologies of NAFLD, which is highly associated with obesity.

843 Gene-environment interaction effects of AKR1C3 and particulate matter exposure in atopic eczema

The etiology of atopic eczema (AE) is complex and involves genetic as well as environmental factors. Chronic exposure to airborne particulate matter (PM) contributes to the development and worsening of AE. Biological effects of PM are mainly initiated by surface-bound polycyclic aromatic hydrocarbons (PAH). Previous data of our laboratory indicate that by stimulating cutaneous aryl hydrocarbon receptor activity and downstream expression of aldo-keto reductase (AKR) 1C3, PAH may enforce the 11-ketoreduction of mast cell-derived prostaglandin (PG) D2, a metabolically unstable stimulator of Th2 cells, to 9α,11β-PGF2, a stable inducer of proatopic Th2 responses.

The relationship between P16INK4A and TP53 promoter methylation and the risk and prognosis in patients with oesophageal cancer in Thailand

DNA methylation can regulate the expression of tumour suppressor genes P16 and TP53, environmental factors, which are both important factors related to an increased risk and prognosis of oesophageal cancer (EC). However, the association between these two genes methylation status, as well as the effects of gene-environment interactions, EC risk remains unclear. A Hospital-based case–control study data were collected from 105 new EC cases and 108 controls. Promoter methylation status was investigated for P16 and TP53 genes using methylation-specific polymerase (MSP) chain reaction methods with SYBR green. Logistic and Cox regression models were used to analyse the association of P16 and TP53 promotor methylation status with EC risk and prognosis, respectively. Our results suggest P16, TP53 methylation significantly increased the risk of EC (OR = 5.24, 95% CI: 2.57–10.66, P < 0.001; OR = 3.38, 95% CI: 1.17–6.67, P < 0.001, respectively). In addition, P16 and TP53 promoter methylation status and the combined effects between environmental factors and its methylations in tissue were correlated with the EC risk and prognosis of EC patients. As a new biomarker, the methylation of P16 and TP53 can serve as a potential predictive biomarker of EC.

Airway inflammation in adolescents and elderly women: Chronic air pollution exposure and polygenic susceptibility

Background and aimThe fractional exhaled nitric oxide (FeNO) concentration in the exhaled breath is a biomarker for eosinophilic airway inflammation. We explored the interplay between chronic air pollution exposure and polygenic susceptibility to airway inflammation at different critical age stages. MethodsAdolescents (15 yr) enrolled in the GINIplus/LISA birth cohorts (n = 2434) and 220 elderly women (75 yr on average) enrolled in the SALIA cohort with FeNO measurements available were investigated. Environmental main effects of the mean of ESCAPE land-use regression air pollutant concentrations within a time window of 15 years and main effects of the polygenic risk scores (PRS) using internal weights from elastic net regression of genome-wide derived single nucleotide polymorphisms were investigated. Furthermore, we examined gene-environment interaction (GxE) effects on natural log-transformed FeNO levels by adjusted linear regression models. ResultsWhile we observed no significant environmental and polygenic main effects on airway inflammation in either age group, we found robust harmful effects of chronic nitrogen dioxide (NO2) exposure in the GxE models for elderly women (16.2 % increase in FeNO, p-value = 0.027). Stratified analyses found GxE effects between the PRS and chronic NO2 exposure in never-smoker elderly women and in adolescents without any inflammatory respiratory conditions. ConclusionsFeNO measurement is a useful biomarker to detect higher risk of NO2-induced eosinophilic airway inflammation in the elderly. There was limited evidence for GxE effects on airway inflammation in adolescents or the elderly. Further GxE studies in subpopulations should be conducted to investigate the assumption that susceptibility to airway inflammation differs between age stages.

Emotional self-regulation, impulsivity, 5-HTTLPR and tobacco use behavior among psychiatric inpatients

BackgroundWhile the serotonin transporter (SLC6A4) gene, 5-HTTLPR, interacts with the social environment to influence both emotional self-regulation and smoking behavior, less is known about interactions between emotional self-regulation and 5-HTTLPR or their joint influence on tobacco use. Here, we examined such interactions among psychiatric inpatients, the population with the highest rates of smoking. MethodsParticipants (506 adults) were psychiatric inpatients at The Menninger Clinic in Houston TX between 2012 and 16. Most were white (89%), male (55%), with a mean age of 32.3 years. Participants completed the Difficulties in Emotional Regulation Scale (DERS) at admission. We examined interactions with smoking among three DERS subscales and 5-HTTLPR, controlling for sex, race and age. ResultsSmoking rates were higher among those with the 5-HTTPLR L'L' genotype compared to peers carrying an S′ allele (47.9% vs. 37.4%, respectively). Among S′ allele carrying participants, impulse control difficulties (OR = 1.09; 95%CI: 1.03–1.14) and lack of emotion clarity (OR = 1.06; 95%CI: 1.00–1.11) increased risk for ever using tobacco, while accessing more ways to regulate emotion (OR = 0.95; 95%CI: 0.92–0.99) offered a protective effect against ever using tobacco. Neither demographic nor DERS covariates were associated with using tobacco among the L′L′ group. LimitationsThis ethnically homogenous sample limits generalizability and using a binary outcome can over-estimate a gene environment interaction effect. ConclusionsEmotional self-regulation exerts a stronger influence on using tobacco among carriers of an S′ allele of 5-HTTLPR than peers with the L′L′ genotype. Promoting emotional self-regulatory skills may have benefits for preventing tobacco use.