Genetic-environmental Interactions Research Articles

Genetics of anomalies of the kidney and urinary tract with congenital heart disease: A review.

Congenital anomalies of the kidney and urinary tract (CAKUT) and congenital heart disease (CHD) are the most common congenital defects and constitute a major cause of morbidity in children. Anomalies of both systems may be isolated or associated with congenital anomalies of other organ systems. Various reports support the co-occurrence of CAKUT and CHD, although the prevalence can vary. Cardiovascular anomalies occur in 11.2% to 34% of patients with CAKUT, and CAKUT occur in 5.3% to 35.8% of those with CHD. The co-occurrence of genetic factors in both CAKUT and CHD would raise common etiologies including genetics, genetic-environmental interactions, or shared molecular mechanisms and pathways such as NODAL, NOTCH, BMP, WNT, and VEGF. Studies in animal models and humans have indicated a genetic etiology for CHD and CAKUT with hundreds of genes recognized and thousands of entries, found in a catalog of human genetic disorders. There are over 80 CAKUT genes and over 100 CHD genes available for clinical testing. For example, the HNFIB gene accounts for 5% to 31% of reported cases of CAKUT. In view of the association between CAKUT and CHD, a thorough cardiac examination should be performed in patients with CAKUT, and a similar evaluation for CAKUT in the presence of CHD. This will allow early diagnosis and therapeutic intervention to improve the long- term outcome of patients affected, and test for at-risk family members. We present here evidence for an association of anomalies involving the two organ systems, and discuss possible etiologies of targeted genes, their functions, biological processes and interactions on embryogenesis.

Investigating gene-environment interaction on attention in a double-hit model for Autism Spectrum Disorder.

Autism Spectrum Disorder (ASD) is a neurodevelopmental behavioral disorder characterized by social, communicative, and motor deficits. There is no single etiological cause for ASD, rather, there are various genetic and environmental factors that increase the risk for ASD. It is thought that some of these factors influence the same underlying neural mechanisms, and that an interplay of both genetic and environmental factors would better explain the pathogenesis of ASD. To better appreciate the influence of genetic-environment interaction on ASD-related behaviours, rats lacking a functional copy of the ASD-linked gene Cntnap2 were exposed to maternal immune activation (MIA) during pregnancy and assessed in adolescence and adulthood. We hypothesized that Cntnap2 deficiency interacts with poly I:C MIA to aggravate ASD-like symptoms in the offspring. In this double-hit model, we assessed attention, a core deficit in ASD due to prefrontal cortical dysfunction. We employed a well-established attentional paradigm known as the 5-choice serial reaction time task (5CSRTT). Cntnap2-/- rats exhibited greater perseverative responses which is indicative of repetitive behaviors. Additionally, rats exposed to poly I:C MIA exhibited premature responses, a marker of impulsivity. The rats exposed to both the genetic and environmental challenge displayed an increase in impulsive activity; however, this response was only elicited in the presence of an auditory distractor. This implies that exacerbated symptomatology in the double-hit model may situation-dependent and not generally expressed.

Identification of Epigenetic Biomarkers of Adolescent Idiopathic Scoliosis Progression: A Workflow to Assess Local Gene Expression.

Adolescent idiopathic scoliosis (AIS) is a three-dimensional structural deformity of the spine that affects 2-3% of adolescents under the age of 16. AIS etiopathogenesis is not completely understood; however, the disease phenotype is correlated to multiple genetic loci and results from genetic-environmental interactions. One of the primary, still unresolved issues is the implementation of reliable diagnostic and prognostic markers. For clinical management improvement, predictors of curve progression are particularly needed. Recently, an epigenetic contribution to AIS development and progression was proposed; nevertheless, validation of data obtained in peripheral tissues and identification of the specific mechanisms and genes under epigenetic control remain limited. In this study, we propose a methodological approach for the identification of epigenetic markers of AIS progression through an original workflow based on the preliminary characterization of local expression of candidate genes in tissues directly involved in the pathology. The feasibility of the proposed methodological protocol has been originally tested here in terms of identification of the putative epigenetic markers of AIS progression, collection of the different tissues, retrieval of an appropriate amount and quality of RNA and DNA, and identification of suitable reference genes.

Complicated incidental appendectomy in a patient with inflammatory bowel disease: Case report

Inflammatory bowel disease (IBD) is an immune-mediated disorder of the gastrointestinal tract, encompassing chronic conditions resulting in inflammation in the region. Its prototypical forms, Crohn's Disease (CD) and Ulcerative Retocolitis (UC), are influenced by genetic-environmental interactions, and their incidence has shown an increase due to the westernization of dietary patterns, registering around 7 million cases in 2017. Both CD and RU are characterized by chronic inflammation, and CD can affect any part of the gastrointestinal tract, from the mouth to the anus, with intermittent inflammation prone to complications such as stenosis and fistulas. RU, on the other hand, predominantly affects the colon and rectum, exhibiting continuous inflammation that can culminate in ulcers and bleeding.

Multi-omics characterization of type 2 diabetes mellitus-induced gastroenteropathy in the db/db mouse model.

Gastrointestinal dysfunction are often associated with type 2 diabetes mellitus (T2DM), a complicated metabolic illness. Contributing factors have been proposed, including genetic predisposition, gene environmental, and lifestyle interactions, but the pathophysiology remains unknown. We aim to explore the possible causes behind gastrointestinal dysfunction caused by type 2 diabetes in this study. A comprehensive analysis of the gastric sinus metabolome, transcriptome, and proteome in db/db mice with gastrointestinal dysfunction was conducted. The model group of mice had considerably lower small intestine propulsion and gastric emptying rates, higher blood glucose levels, and were significantly obese compared to the control group. We identified 297 genes, 350 proteins, and 1,001 metabolites exhibiting significant differences between db/db and control mice (p < 0.05). Moreover, multi-omics analysis revealed that the genes, proteins, and metabolites in the T2DM-induced gastroenteropathy mice group were involved in arachidonic acid metabolism, glycerophospholipid metabolism and vitamin digestion and absorption. Specifically, Cbr3, Etnppl, and Apob were the major mRNAs associated with T2DM-induced gastrointestinal dysfunction, while Cyp2b10, Cyp2b19, Pgs1, Gpat3, Apoa4, and Tcn2 were the major proteins associated with T2DM-induced gastrointestinal injury, and 16(R)-HET, 5-HETE, LysoPC (22:0), and Pantothenic acid were the major metabolites associated with T2DM-induced gastrointestinal disorders. The mechanism of action of diabetic gastroenteropathy may be related to vitamin digestion and absorption, glycerophospholipid metabolism, and arachidonic acid metabolism.

Local adaptation and broad performance are synergistic to productivity in modern barley

AbstractCrop populations have enormous impacts on agricultural productivity, yet decelerating gains from breeding suggest that selection strategies need to be reconsidered to better align priorities of breeders and growers. Breeders benefit from releasing broadly adapted varieties that perform acceptably well across their target region; growers benefit from selecting a variety that specializes in their specific location. We tested whether these interests are compatible using 182 entries in a mega‐population of malting barley (spring, two‐row, multi‐environment trial [S2MET] population; Hordeum vulgare L.), which was grown across the northern United States. We assessed the strength of genetic–environment interactions (G×E), quantified local adaptation benefits, and tested whether local adaptation and genetic yield potential were correlated. Breeding programs favored broad adaptation (p &lt; 0.001). Still, 63% of entries (114) were among the top 10%, best performing at some locations, and among the worst 10% at others. Some of the best overall entries were specialists, performing especially well in their home locations, and in general, genetic potential and local specialization were positively correlated (p &lt; 0.001). These results suggest that breeding for local performance and broad performance are mutually supporting goals. Releasing broadly excellent, locally exceptional varieties may accelerate genetic gain to meet projected global agricultural demand.

A rat model established by simulating genetic–environmental interactions recapitulates human Alzheimer's disease pathology

BackgroundIn humans, Alzheimer’s disease (AD) is typically sporadic in nature, and its pathology is usually influenced by extensive factors. The study established a rat model based on the genetic–environmental interaction. MethodsA rat model was established by transduction of an adeno-associated virus combined with acrolein treatment. Rats were assigned to the normal control (NC), acrolein group, AAV (-) group, AAV-APP group, and AAV-APP/acrolein group. The success of model construction was verified in multiple ways, including by assessing cognitive function, examining microstructural changes in the brain in vivo, and performing immunohistochemistry. The contribution of genetic (APP mutation) and environmental (acrolein) factors to AD-like phenotypes in the model was explored by factorial analysis. Results1) The AAV-APP/acrolein group showed a decline in cognitive function, as indicated by a reduced gray matter volume in key cognition-related brain areas, lower FA values in the hippocampus and internal olfactory cortex, and Aβ deposition in the cortex and hippocampus. 2) The AAV-APP group also showed a decline in cognitive function, although the group exhibited atypical brain atrophy in the gray matter and insignificant Aβ deposition. 3) The acrolein group did not show any significant changes in Aβ levels, gray matter volume, or cognitive function. 4) The genetic factor (APP mutation) explained 39.74% of the AD-like phenotypes in the model factors, and the environmental factor (acrolein exposure) explained 33.3%. ConclusionsThe genetic–environmental interaction rat model exhibited a phenotype that resembled the features of human AD and will be useful for research on AD.

Modelling α-synuclein processing in primary patient cells for pharmacological intervention

Aim: Parkinson’s disease (PD) is a complex, chronic neurodegenerative disorder with predominately sporadic etiology. Intricate genetic-environmental interactions lead to the hallmarks of the disease: degeneration of dopaminergic neurons and the deposition of α-synuclein aggregates. The aim of this study was to establish a novel primary patient cell model as an in vitro screen to study α-synuclein processing for drug screening. Methods: Primary patient olfactory neuroepithelial-derived cells (ONS) were exposed to α-synuclein and examined for cytotoxicity, processing, and solubility over 48 h. Epigallocatechin gallate (EGCG), which is known to destabilise α-synuclein fibrils, was used to investigate the solubilisation of α-synuclein in the model system. Results: Exposure to 0.1 μmol/L α-synuclein preformed fibrils was not toxic to ONS over 48 h. ONS processing of α-synuclein was observed to be different in PD cells by their increased accumulation in the cytoplasm. Processing deficits in the PD ONS were confirmed by immunoblotting with an increase in sodium dodecyl sulfate (SDS)-insoluble α-synuclein after 48 h. Conclusions: The data has illustrated the utility of primary patient ONS as a model system to understand the processing of α-synuclein. Considerable differences in α-synuclein processing were identified in PD ONS. Furthermore, the data suggests that primary patient ONS are a viable in vitro drug screening platform for α-synuclein pathology in PD.

Genetic stability observed in third-generation progeny trial of Acacia mangium: the importance of genotype by environment interaction assessment in advance generation breeding strategy

The breeding program for Acacia mangium has entered advanced-generation breeding cycles through adopting a recurrent selection system and a sub-lining breeding population. Genetic variation changes along the successive generations could affect its genetic stability on wide ranges of sites. The aim of this study is to observe genetic stability in third-generation progeny trials of A. mangium established at three different sites in Indonesia. Analysis was conducted, including single-site and multi-sites analyses for height, diameter, and stem forking that were grouped into two sets of analysis based on the genetic background of the trial: SET01 for the single sub-line and SET02 for the composite sub-lines. Index selection for multiple-traits was then used to identify the family changing ranks for multiple-traits and genetic gain prediction. The results showed that the recurrent selection system adopted in the breeding strategy for single-site analysis could maintain sufficient genetic variance of A. mangium in the third-generation progeny trial. Family heritability was moderate to high for almost all traits. However, a strong genetic-environment interaction (G × E) exists in multi-sites analysis for the single sub-line population (SET01), indicating a less sufficient genetic variation and a low Type B genetic correlation in anticipating a wider range of environment. On the contrary, compositing selected family from several sub-lines (SET02) could diminish the strength of G × E and increase Type B correlation. Selection and genetic gain prediction could be more effective in multi-sites analysis for SET02, but it was less effective for SET01. The results imply that adopting a recurrent selection system in advanced-generation breeding of A. mangium should consider structuring the breeding population. It could be practiced by compositing selected superior families from several sub-lines into one breeding population to maintain high genetic stability, while increasing genetic diversity and productivity.

Effects of genotype and environment on forage yield, nutritive value and morphology of lablab (Lablab purpureus (L.) sweet)

The goal of the study is to determine the effect of genotype and environment on forage yield, forage nutritive value and to determine the relation between morphology and forage yield and nutritive value of lablab. Thirteen genotypes (one local and 12 improved) were replicated 3 times in a randomized complete block trial across three locations in Ethiopian lowlands namely, Bechi, Kite and Tepi. All forage samples were analyzed for dry matter (DM), crude protein (CP), and in vitro dry matter digestibility (IVDMD) using a combination of conventional nutritional analyses and near infrared reflectance spectroscopy. There was a significant (P < 0.001) effect of genotype, location and genotype*location on forage yield of DM, forage yield of CP, forage yield of IVDMD, CP, and IVDMD. The difference between means of minimum and maximum genotypes was 12.9 t/ha of DM, 3.12 t/ha CP, 8.22 t/ha IVDMD, 57 g/kg of CP and 56 g/kg of IVDMD. The correlation between plant morphology and forage yield and nutritive value was weak (r ≤ 0.41) in all locations and the combined data. Both genotype and location should be considered by the farmers when they decide to grow lablab for forage production. Morphological traits of lablab are not suitable to evaluate forage yield and nutritive value. Enhancing the awareness of farmers about the effect genetic-environment interaction effect of forage yield and nutritive value and the relation between morphology and yield and nutritive value would improve the uptake of lablab in mixed the farming system leading to more sustainable agricultural production.

TGF-β as Predictive Marker and Pharmacological Target in Lung Cancer Approach

Lung cancer (LC) represents the leading cause of cancer incidence and mortality worldwide. LC onset is strongly related to genetic mutations and environmental interactions, such as tobacco smoking, or pathological conditions, such as chronic inflammation. Despite advancement in knowledge of the molecular mechanisms involved in LC, this tumor is still characterized by an unfavorable prognosis, and the current therapeutic options are unsatisfactory. TGF-β is a cytokine that regulates different biological processes, particularly at the pulmonary level, and its alteration has been demonstrated to be associated with LC progression. Moreover, TGF-β is involved in promoting invasiveness and metastasis, via epithelial to mesenchymal transition (EMT) induction, where TGF-β is the major driver. Thus, a TGF-β-EMT signature may be considered a potential predictive marker in LC prognosis, and TGF-β-EMT inhibition has been demonstrated to prevent metastasis in various animal models. Concerning a LC therapeutic approach, some TGF-β and TGF-β-EMT inhibitors could be used in combination with chemo- and immunotherapy without major side effects, thereby improving cancer therapy. Overall, targeting TGF-β may be a valid possibility to fight LC, both in improving LC prognosis and cancer therapy, via a novel approach that could open up new effective strategies against this aggressive cancer.

Air pollution and cardiovascular heath in a changing climate

Air pollution and cardiovascular heath in a changing climate

Genetic-environment interactions and climatic variables effect on bean physical characteristics and chemical composition of Coffea arabica.

The effects of the environment and genotype in the coffee bean chemical composition were studied using 9 trials covering an altitudinal gradient (600-1100 m.a.s.l) with 3 genotypes of Coffea arabica in the Northwest mountainous region of Vietnam. The impacts of the climatic conditions on bean physical characteristics and chemical composition were assessed. We showed that the environment had a significant effect on the bean density and on all bean chemical compounds. The environment effect was stronger than the genotype and genotype-environment interaction effects for cafestol, kahweol, arachidic (C20:0), behenic acid (C22:0), 2,3-butanediol, 2-methyl-2-buten-1-ol, benzaldehyde, benzene ethanol, butyrolactone, decane, dodecane, ethanol, pentanoic acid, and phenylacetaldehyde bean content. A 2°C increase in temperature had more influence on bean chemical compounds than a 100 mm increase in soil water content. Temperature was positively correlated with lipids and volatile compounds. With an innovative method using iterative moving averages, we showed that correlation of temperature, VPD and rainfall with lipids and volatiles was higher between the 10th and 20th weeks after flowering highlighting this period as crucial for the synthesis of these chemicals. Genotype specific responses were evidenced and could be considered in future breeding programs to maintain coffee beverage quality in the midst of climate change. This first study of the effect of the genotype-environment interactions on chemical compounds enhances our understanding of the sensitivity of coffee quality to genotype environment interactions during bean development. This work addresses the growing concern of the effect of climate change on speciality crops and more specifically coffee. This article is protected by copyright. All rights reserved.

Physical activity as an exogenous risk factor for amyotrophic lateral sclerosis: a review of the evidence.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder. The only established epidemiological risk factors for ALS are male sex and increasing age. The role of physical activity has been debated as an environmental risk factor. Over the last decade multiple studies have attempted to delineate the architecture of ALS. These have not yet established definite risk factors, often due to low-powered studies, lack of focus on at-risk genotypes and sub-optimal methodology. We have conducted a review of all the studies published between 2009 and December 2021. The free text search terms were [(motor neuron disease) OR (MND) OR (Amyotrophic Lateral Sclerosis) OR (ALS)] AND [(Exercise) or (Physical Activity) or (PA) or (sport)]. We identified common themes, for example soccer, head injury and the physiological mechanisms that differ in ALS patients. We have analysed the relevant, available studies (n = 93), highlighting the underlying reasons for any reported discrepancies. Overall, we have found that the more highly powered studies using validated exposure methodologies, linked strenuous, anaerobic physical activity as a risk factor for ALS. Future large-scale studies focusing on specific at-risk genotypes and physical activity should be conducted to confirm this finding. This will strengthen the evidence already surrounding strenuous physical activity as an environmental risk factor for ALS and allow advice to be given to at-risk family members. Increasing our understanding of the genetic-environmental interactions in the pathophysiology of ALS will allow for the possibility of developing preventative therapeutic approaches.

Advancing precision medicine in medical education: Integrated, precise and data‐driven smart solutions

AbstractAdvances in “Precision Medicine” initiative, also known as “Personalized Medicine” is an emerging approach for disease treatment and prevention that has already led to innovative discoveries and has created “smart” applications and solutions tailored to a person's or a group of individuals' genetic profile, lifestyle, and environment interaction. Already many physicians as part of patient care routinely prescribe various molecular/genetic and other tests enabling them to select personalized treatments that improve the chances of survival and reduce exposure to adverse effects. This initiative should provide to medical and healthcare professionals with adequate resources and readily available solutions so that the target to specific treatments and care of the illnesses is achieved while at the same time protecting the privacy and safety of the individual is secured as well as the Electronic Health Records (EHRs) and whatever additional data is necessary within the context of Precision Medicine. This study, through a literature review mostly, and some case study analysis, examine whether personalized medicine is delivered to the patient in an “accurate” and “precise” way, as expected. This requires that Health and Human Services and other stakeholders and agencies collaborate to solicit the right input from patients while at the same time can identify and address any educational, practical, legal, and technical issues and providing smart solutions. The lack of proper medical education and advanced infrastructure are still major barriers to the adoption of Precision Medicine, therefore, the role of medical training in Precision Medicine is also examined and analyzed. Specific examples are discussed in an integrated, precise, and data‐driven manner to provide “smart” solutions.

Precision agriculture innovation focuses on sustainability using GGE biplot and AMMI analysis to evaluate GE interaction for quality essential oil yield in Eucalyptus citriodora Hook

Eucalyptus citriodora is a perennial shrub with aromatic and medicinal qualities that produces a volatile, fragrant essential oil. Its essential oil is widely used in various cosmetic and fragrance businesses, including toiletries, disinfectants, and fragrances. The essential oils had extraordinarily high citronellal, isopulegol, and citronellol. The findings also demonstrate that genetic diversity plays a role in interactions among genotypes (G), environments (E), and genetic environments (G × E) for stability, including vital oil output. The RBD design of the trials included three replications at each site. According to the GE interaction, all traits were significant, except for trait X3. The findings also showed that genetic diversity is evident in genotypes (G), environments (E), and genetic environment (GE) interactions for stability, including essential oil yield. The traits, namely X2-VS-X3, X2-VS-X5, and X3-VS-X6, displayed positive and highly significant correlations in all three locations/environments, in contrast to the negative and highly significant correlations observed between the traits X1-VS-X4. These traits either directly or indirectly control the manifestation of genotype stability. The study results indicated that the GGE biplot identifies the optimum lines over the location. The genotypes, namely Ec1, Ec2, and Ec4, were near the origin in the circle and were highly stable and able to yield high essential oils (116.20, 115.50, and 94.80 kg/ha) with high citronellal (76.80, 72.60, and 62.03%), and citronellol content (8.86, 8.70, and 8.65%). These E. citriodora genotypes are recommended for cultivation in a large area of India.

The Role of Gut Dysbiosis in the Pathophysiology of Neuropsychiatric Disorders

Mounting evidence shows that the complex gut microbial ecosystem in the human gastrointestinal (GI) tract regulates the physiology of the central nervous system (CNS) via microbiota and the gut-brain (MGB) axis. The GI microbial ecosystem communicates with the brain through the neuroendocrine, immune, and autonomic nervous systems. Recent studies have bolstered the involvement of dysfunctional MGB axis signaling in the pathophysiology of several neurodegenerative, neurodevelopmental, and neuropsychiatric disorders (NPDs). Several investigations on the dynamic microbial system and genetic-environmental interactions with the gut microbiota (GM) have shown that changes in the composition, diversity and/or functions of gut microbes (termed "gut dysbiosis" (GD)) affect neuropsychiatric health by inducing alterations in the signaling pathways of the MGB axis. Interestingly, both preclinical and clinical evidence shows a positive correlation between GD and the pathogenesis and progression of NPDs. Long-term GD leads to overstimulation of hypothalamic-pituitary-adrenal (HPA) axis and the neuroimmune system, along with altered neurotransmitter levels, resulting in dysfunctional signal transduction, inflammation, increased oxidative stress (OS), mitochondrial dysfunction, and neuronal death. Further studies on the MGB axis have highlighted the significance of GM in the development of brain regions specific to stress-related behaviors, including depression and anxiety, and the immune system in the early life. GD-mediated deregulation of the MGB axis imbalances host homeostasis significantly by disrupting the integrity of the intestinal and blood-brain barrier (BBB), mucus secretion, and gut immune and brain immune functions. This review collates evidence on the potential interaction between GD and NPDs from preclinical and clinical data. Additionally, we summarize the use of non-therapeutic modulators such as pro-, pre-, syn- and post-biotics, and specific diets or fecal microbiota transplantation (FMT), which are promising targets for the management of NPDs.

Association of xenobiotic-metabolizing genes polymorphisms with cervical cancer risk in the Tunisian population.

Host genetic characteristics and environmental factors interactions may play a crucial role in cervical carcinogenesis. We investigated the impact of functional genetic variants of four xenobiotic-metabolizing genes (AhR, CYP1A1, GSTM1, and GSTT1) on cervical cancer development in Tunisian women. The AhR gene polymorphism was analyzed using the tetra-primer ARMS-PCR, whereas the CYP1A1 polymorphism genotypes were identified by PCR-RFLP. A multiplex ligation-dependent polymerase chain reaction approach was applied for the analysis of GSTM1 and GSTT1 polymorphisms. The homozygous A/A genotype of the AhR gene (rs2066853) and the heterozygous T/C genotype of the CYP1A1 SNP (CYP1A1-MspI) appeared to be associated with an increased risk of cervical tumorigenesis (ORa = 2.81; ORa = 5.52, respectively). Furthermore, a significantly increased risk of cervical cancer was associated with the GSTT1 null genotype (ORa = 2.65). However, the null GSTM1 genotype showed any significant association with the risk of cervical cancer compared to the wild genotype (ORa = 1.18; p = 0.784). Considering the combined effect, we noted a significantly higher association with cancer risk for individuals with at least two high-risk genotypes of CYP1A1/GSTT1 (ORa = 4.2), individuals with at least two high-risk genotypes of CYP1A1/GSTT1/AhR (ORa = 11.3) and individuals with at least two high-risk genotypes of CYP1A1/GSTM1/GSTT1/AhR exploitation low-risk genotype as a reference. This study indicated that the single-gene contribution and the combined effect of xenobiotic-metabolizing gene polymorphisms (AhR, CYP1A1-MspI, GSTM1, and GSTT1) may have a considerable association with increased cervical cancer risk.

Glucocorticoids unmask silent non-coding genetic risk variants for common diseases.

Understanding the function of non-coding genomic sequence variants represents a challenge for biomedicine. Many diseases are products of gene-by-environment interactions with complex mechanisms. This study addresses these themes by mechanistic characterization of non-coding variants that influence gene expression only after drug or hormone exposure. Using glucocorticoid signaling as a model system, we integrated genomic, transcriptomic, and epigenomic approaches to unravel mechanisms by which variant function could be revealed by hormones or drugs. Specifically, we identified cis-regulatory elements and 3D interactions underlying ligand-dependent associations between variants and gene expression. One-quarter of the glucocorticoid-modulated variants that we identified had already been associated with clinical phenotypes. However, their affected genes were 'unmasked' only after glucocorticoid exposure and often with function relevant to the disease phenotypes. These diseases involved glucocorticoids as risk factors or therapeutic agents and included autoimmunity, metabolic and mood disorders, osteoporosis and cancer. For example, we identified a novel breast cancer risk gene, MAST4, with expression that was repressed by glucocorticoids in cells carrying the risk genotype, repression that correlated with MAST4 expression in breast cancer and treatment outcomes. These observations provide a mechanistic framework for understanding non-coding genetic variant-chemical environment interactions and their role in disease risk and drug response.

Btg2 mutation induces renal injury and impairs blood pressure control in female rats.

Hypertension (HTN) is a complex disease influenced by heritable genetic elements and environmental interactions. Dietary salt is among the most influential modifiable factors contributing to increased blood pressure (BP). It is well established that men and women develop BP impairment in different patterns and a recent emphasis has been placed on identifying mechanisms leading to the differences observed between the sexes in HTN development. The current work reported here builds on an extensive genetic mapping experiment that sought to identify genetic determinants of salt-sensitive (SS) HTN using the Dahl SS rat. BTG antiproliferation factor 2 (Btg2) was previously identified by our group as a candidate gene contributing to SS HTN in female rats. In the current study, Btg2 was mutated using transcription activator-like effector nuclease (TALEN)-targeted gene disruption on the SSBN congenic rat background. The Btg2 mutated rats exhibited impaired BP and proteinuria responses to a high-salt diet compared with wild-type rats. Differences in body weight, mutant pup viability, skeletal morphology, and adult nephron density suggest a potential role for Btg2 in developmental signaling pathways. Subsequent cell cycle gene expression assessment provides several additional signaling pathways that Btg2 may function through during salt handling in the kidney. The expression analysis also identified several potential upstream targets that can be explored to further isolate therapeutic approaches for SS HTN.