scholarly journals The Impact of Environmental Factors on Monogenic Mendelian Diseases

2021 ◽  
Author(s):  
Anke M Tukker ◽  
Charmaine D Royal ◽  
Aaron B Bowman ◽  
Kimberly A McAllister
Keyword(s):  
Environmental Factors ◽  
Complex Disease ◽  
Health Science ◽  
Model Systems ◽  
Mendelian Disease ◽  
Disease Etiology ◽  
Mendelian Disorders ◽  
Mendelian Diseases ◽  
Gene Environment ◽  
The Impact

Abstract Environmental factors and gene-environment interactions modify the variable expressivity, progression, severity, and onset of some classic (monogenic) Mendelian-inherited genetic diseases. Cystic fibrosis, Huntington disease, Parkinson’s disease, and sickle cell disease are examples of well-known Mendelian disorders that are influenced by exogenous exposures. Environmental factors may act by direct or indirect mechanisms to modify disease severity, timing, and presentation, including through epigenomic influences, protein misfolding, miRNA alterations, transporter activity, and mitochondrial effects. Because pathological features of early-onset Mendelian diseases can mimic later onset complex diseases, we propose that studies of environmental exposure vulnerabilities using monogenic model systems of rare Mendelian diseases have high potential to provide insight into complex disease phenotypes arising from multi-genetic/multi-toxicant interactions. Mendelian disorders can be modeled by homologous mutations in animal model systems with strong recapitulation of human disease etiology and natural history, providing an important advantage for study of these diseases. Monogenic high penetrant mutations are ideal for toxicant challenge studies with a wide variety of environmental stressors, because background genetic variability may be less able to alter the relatively strong phenotype driving disease-causing mutations. These models promote mechanistic understandings of gene-environment interactions and biological pathways relevant to both Mendelian and related sporadic complex disease outcomes by creating a sensitized background for relevant environmental risk factors. Additionally, rare disease communities are motivated research participants, creating the potential of strong research allies among rare Mendelian disease advocacy groups and disease registries and providing a variety of translational opportunities that are under-utilized in genetic or environmental health science.

scholarly journals Gut-Ex-Vivo system as a model to study gluten response in celiac disease

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Mara Gagliardi ◽  
Nausicaa Clemente ◽  
Romina Monzani ◽  
Luca Fusaro ◽  
Eleonora Ferrari ◽  
...  
Keyword(s):  
Celiac Disease ◽  
Intestinal Epithelium ◽  
Complex Disease ◽  
Ex Vivo ◽  
Dynamic Condition ◽  
Model Systems ◽  
In Vivo Models ◽  
Effective Manner ◽  
Junction Protein ◽  
The Impact

AbstractCeliac disease (CD) is a complex immune-mediated chronic disease characterized by a consistent inflammation of the gastrointestinal tract induced by gluten intake in genetically predisposed individuals. Although initiated by the interaction between digestion-derived gliadin, a gluten component, peptides, and the intestinal epithelium, the disorder is highly complex and involving other components of the intestine, such as the immune system. Therefore, conventional model systems, mainly based on two- or three-dimension cell cultures and co-cultures, cannot fully recapitulate such a complex disease. The development of mouse models has facilitated the study of different interacting cell types involved in the disorder, together with the impact of environmental factors. However, such in vivo models are often expensive and time consuming. Here we propose an organ ex vivo culture (gut-ex-vivo system) based on small intestines from gluten-sensitive mice cultivated in a dynamic condition, able to fully recapitulate the biochemical and morphological features of the mouse model exposed to gliadin (4 weeks), in 16 h. Indeed, upon gliadin exposure, we observed: i) a down-regulation of cystic fibrosis transmembrane regulator (CFTR) and an up-regulation of transglutaminase 2 (TG2) at both mRNA and protein levels; ii) increased intestinal permeability associated with deregulated tight junction protein expression; iii) induction and production of pro-inflammatory cytokines such as interleukin (IL)-15, IL-17 and interferon gamma (IFNγ); and iv) consistent alteration of intestinal epithelium/villi morphology. Altogether, these data indicate that the proposed model can be efficiently used to study the pathogenesis of CD, test new or repurposed molecules to accelerate the search for new treatments, and to study the impact of the microbiome and derived metabolites, in a time- and cost- effective manner.

scholarly journals Impacts of Environmental Factors on Head and Neck Cancer Pathogenesis and Progression

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 389
Author(s):  
Marisol Miranda-Galvis ◽  
Reid Loveless ◽  
Luiz Paulo Kowalski ◽  
Yong Teng
Keyword(s):  
Head And Neck Cancer ◽  
Environmental Factors ◽  
Head And Neck ◽  
Neck Cancer ◽  
Molecular Mechanisms ◽  
Metastatic Cancer ◽  
Environmental Drivers ◽  
Cancer Pathogenesis ◽  
Gene Environment ◽  
The Impact

Epidemiological and clinical studies over the past two decades have provided strong evidence that genetic elements interacting with environmental components can individually and collectively influence one’s susceptibility to cancer. In addition to tumorigenic properties, numerous environmental factors, such as nutrition, chemical carcinogens, and tobacco/alcohol consumption, possess pro-invasive and pro-metastatic cancer features. In contrast to traditional cancer treatment, modern therapeutics not only take into account an individual’s genetic makeup but also consider gene–environment interactions. The current review sharpens the focus by elaborating on the impact that environmental factors have on the pathogenesis and progression of head and neck cancer and the underlying molecular mechanisms involved. Recent advances, challenges, and future perspectives in this area of research are also discussed. Inhibiting key environmental drivers of tumor progression should yield survival benefits for patients at any stage of head and neck cancer.

Gene–environment interplay in the etiology of psychosis

2018 ◽  
Vol 48 (12) ◽  
pp. 1925-1936 ◽  
Author(s):  
Alyson Zwicker ◽  
Eileen M. Denovan-Wright ◽  
Rudolf Uher
Keyword(s):  
Environmental Factors ◽  
Genetic Risk ◽  
Environmental Exposures ◽  
Response To Treatment ◽  
Human Potential ◽  
Specific Gene ◽  
Environment Interaction ◽  
Gene Environment ◽  
Increased Risk ◽  
The Impact

AbstractSchizophrenia and other types of psychosis incur suffering, high health care costs and loss of human potential, due to the combination of early onset and poor response to treatment. Our ability to prevent or cure psychosis depends on knowledge of causal mechanisms. Molecular genetic studies show that thousands of common and rare variants contribute to the genetic risk for psychosis. Epidemiological studies have identified many environmental factors associated with increased risk of psychosis. However, no single genetic or environmental factor is sufficient to cause psychosis on its own. The risk of developing psychosis increases with the accumulation of many genetic risk variants and exposures to multiple adverse environmental factors. Additionally, the impact of environmental exposures likely depends on genetic factors, through gene–environment interactions. Only a few specific gene–environment combinations that lead to increased risk of psychosis have been identified to date. An example of replicable gene–environment interaction is a common polymorphism in theAKT1gene that makes its carriers sensitive to developing psychosis with regular cannabis use. A synthesis of results from twin studies, molecular genetics, and epidemiological research outlines the many genetic and environmental factors contributing to psychosis. The interplay between these factors needs to be considered to draw a complete picture of etiology. To reach a more complete explanation of psychosis that can inform preventive strategies, future research should focus on longitudinal assessments of multiple environmental exposures within large, genotyped cohorts beginning early in life.

scholarly journals How to identify gene–environment interactions in a multifactorial disease: CHD as an example

2004 ◽  
Vol 63 (1) ◽  
pp. 5-10 ◽  
Author(s):  
Philippa J. Talmud
Keyword(s):  
Environmental Factors ◽  
Context Dependency ◽  
Single Mutation ◽  
Small Contribution ◽  
Multifactorial Disease ◽  
Risk Environment ◽  
Chd Risk ◽  
Gene Environment ◽  
E4 Allele ◽  
The Impact

CHD is a multifactorial disease, caused by both genetic and environmental factors. The inherited 'defective' genes will vary from individual to individual, and any single mutation is likely to be making only a small contribution to risk. The context dependency, i.e. the importance of environmental factors in influencing genetic risk, is now becoming evident. Thus, a mutation may have a modest effect on risk in individuals who maintain a low environmental risk, but a major effect in a high-risk environment. Methods of analysing gene–environment interactions on CHD risk will be discussed and illustrated with several examples. APOE has three common alleles, ɛ2, ɛ3 and ɛ4. The ɛ4 allele has consistently been associated with CHD risk, which has been confirmed by meta-analysis. However, when the effect of genotype on risk was considered in smokers and non-smokers separately, risk in non-smokers was similar in all APOE genotypes. By comparison, in the smokers, ɛ3 homozygotes, as expected, had an approximately 2-fold higher risk, while for ɛ4 carriers there was a significantly greater than additive effect of genotype and smoking on risk (P ≫0.007). Thus, the impact of the ɛ4 allele on CHD risk appears to be confined to current smokers, an effect that has been confirmed in several studies. Another example is the interaction between the alcohol dehydrogenase 3 gene variant and alcohol consumption on CHD risk (P ≫0.001), showing the context dependency of the effect. Thus, the importance of considering environmental factors as potential genotype-risk modifiers has major public health implications.

scholarly journals Genotype-Based Bayesian Analysis of Gene-Environment Interactions with Multiple Genetic Markers and Misclassification in Environmental Factors

2012 ◽  
Vol 2012 ◽  
pp. 1-15
Author(s):  
Iryna Lobach ◽  
Ruzong Fan
Keyword(s):  
Linkage Disequilibrium ◽  
Environmental Factors ◽  
Genetic Markers ◽  
Complex Disease ◽  
Small Sample ◽  
Parameter Estimates ◽  
Simulation Experiments ◽  
Gene Environment ◽  
Small Sample Sizes ◽  
Control Study

A key component to understanding etiology of complex diseases, such as cancer, diabetes, alcohol dependence, is to investigate gene-environment interactions. This work is motivated by the following two concerns in the analysis of gene-environment interactions. First, multiple genetic markers in moderate linkage disequilibrium may be involved in susceptibility to a complex disease. Second, environmental factors may be subject to misclassification. We develop a genotype based Bayesian pseudolikelihood approach that accommodates linkage disequilibrium in genetic markers and misclassification in environmental factors. Since our approach is genotype based, it allows the observed genetic information to enter the model directly thus eliminating the need to infer haplotype phase and simplifying computations. Bayesian approach allows shrinking parameter estimates towards prior distribution to improve estimation and inference when environmental factors are subject to misclassification. Simulation experiments demonstrated that our method produced parameter estimates that are nearly unbiased even for small sample sizes. An application of our method is illustrated using a case-control study of interaction between early onset of drinking and genes involved in dopamine pathway.

Early life environment: does it have implications for predisposition to disease?

2002 ◽  
Vol 14 (6) ◽  
pp. 292-302 ◽  
Author(s):  
Nola Shanks
Keyword(s):  
Environmental Factors ◽  
Immune Function ◽  
Hpa Axis ◽  
Early Life ◽  
Inflammatory Responses ◽  
Psychiatric Disease ◽  
Disease Etiology ◽  
Increased Risk ◽  
The Impact ◽  
Postnatal Factors

Early life environmental factors have been associated with altered predisposition to a variety of pathologies. A considerable literature examines pre- and postnatal factors associated with increased risk of cardiovascular, metabolic (i.e. insulin resistance, hyperlipidemia) and psychiatric disease, and the importance of hormonal programming. The brain is exquisitely sensitive to environmental inputs during development and the stress responsiveness of the hypothalamic–pituitary–adrenal (HPA) axis has been shown to be both up- and down-regulated by early life exposure to limited nutrition, stress, altered maternal behaviors, synthetic steroids and inflammation. It has been suggested that peri-natal programming of HPA axis regulation might therefore contribute to metabolic and psychiatric disease etiology. In addition, glucocorticoids play modulatory roles regulating many aspects of immune function, notably controlling both acute and chronic inflammatory responses. Neuroendocrine–immune communication is bidirectional, and therefore it is expected that environmental factors altering HPA regulation have implications for stress effects on immune function and predisposition to inflammation. The impact of pre- and postnatal factors altering immune function, stress responsivity and predisposition to inflammatory disease are reviewed. It is also examined whether the early ‘immune environment’ might similarly influence predisposition to disease and alter neuroendocrine function. Evidence indicating a role for early life inflammation and infection as an important factor programming the neuroendocrine–immune axis and altering predisposition to disease is considered.

scholarly journals Impact of Gene–Environment Interactions on Cancer Development

2020 ◽  
Vol 17 (21) ◽  
pp. 8089
Author(s):  
Ariane Mbemi ◽  
Sunali Khanna ◽  
Sylvianne Njiki ◽  
Clement G. Yedjou ◽  
Paul B. Tchounwou
Keyword(s):  
Environmental Factors ◽  
Scientific Evidence ◽  
Critical Role ◽  
Experimental Studies ◽  
Joint Effect ◽  
Human Diseases ◽  
Nucleotide Polymorphisms ◽  
Gene Environment ◽  
Genetic And Environmental Factors ◽  
The Impact

Several epidemiological and experimental studies have demonstrated that many human diseases are not only caused by specific genetic and environmental factors but also by gene–environment interactions. Although it has been widely reported that genetic polymorphisms play a critical role in human susceptibility to cancer and other chronic disease conditions, many single nucleotide polymorphisms (SNPs) are caused by somatic mutations resulting from human exposure to environmental stressors. Scientific evidence suggests that the etiology of many chronic illnesses is caused by the joint effect between genetics and the environment. Research has also pointed out that the interactions of environmental factors with specific allelic variants highly modulate the susceptibility to diseases. Hence, many scientific discoveries on gene–environment interactions have elucidated the impact of their combined effect on the incidence and/or prevalence rate of human diseases. In this review, we provide an overview of the nature of gene–environment interactions, and discuss their role in human cancers, with special emphases on lung, colorectal, bladder, breast, ovarian, and prostate cancers.

Using Full Genomic Information to Predict Disease: Breaking Down the Barriers Between Complex and Mendelian Diseases

2018 ◽  
Vol 19 (1) ◽  
pp. 289-301 ◽  
Author(s):  
Daniel M. Jordan ◽  
Ron Do
Keyword(s):  
Complex Disease ◽  
Disease Risk ◽  
Wide Spectrum ◽  
Mendelian Disease ◽  
Genomic Information ◽  
Mendelian Diseases ◽  
Genome Wide ◽  
Whole Exome ◽  
Large Populations ◽  
Genomic Studies

While sequence-based genetic tests have long been available for specific loci, especially for Mendelian disease, the rapidly falling costs of genome-wide genotyping arrays, whole-exome sequencing, and whole-genome sequencing are moving us toward a future where full genomic information might inform the prognosis and treatment of a variety of diseases, including complex disease. Similarly, the availability of large populations with full genomic information has enabled new insights about the etiology and genetic architecture of complex disease. Insights from the latest generation of genomic studies suggest that our categorization of diseases as complex may conceal a wide spectrum of genetic architectures and causal mechanisms that ranges from Mendelian forms of complex disease to complex regulatory structures underlying Mendelian disease. Here, we review these insights, along with advances in the prediction of disease risk and outcomes from full genomic information.

scholarly journals Changing Public Demand in the Genetic Counseling during the Past Decades

2011 ◽  
Vol 5 (2) ◽  
pp. 175-185
Author(s):  
Zoltan Papp
Keyword(s):  
Genetic Counseling ◽  
Environmental Factors ◽  
Genetic Epidemiology ◽  
Genetic Screening ◽  
Predictive Testing ◽  
Mendelian Disease ◽  
Mendelian Disorders ◽  
The Past ◽  
Genetic And Environmental Factors ◽  
Public Demand

ABSTRACT Before discovering genetic rules, genetic counseling was based on empirical observations. In this process, it was important to recognize that certain diagnoses were more frequent in certain couples’ descendants. The 20th century witnessed revolutionary progress in the science of genetics that coincided with increasing societal demands and therefore became an integral part of modern genetic counseling. Genetic screening is changing from Mendelian disease ascertainment to predictive testing. We are also learning that the phenotypes of even simple Mendelian disorders are influenced by complex genetic and environmental factors. Moreover, developing knowledge about genotype/phenotype associations and many other aspects of genetic epidemiology will increasingly require referral to clinical geneticists.

scholarly journals Genetic and environmental factors in the etiology of schizophrenia - towards mainstreaming

2016 ◽  
Vol 17 (4) ◽  
pp. 243-249 ◽  
Author(s):  
Agnieszka Łaba-Stefanek ◽  
Ewelina Dziwota ◽  
Marcin Olajossy
Keyword(s):  
Environmental Factors ◽  
Social Factors ◽  
Complex Disease ◽  
Point Mutations ◽  
Schizophrenia Spectrum Disorders ◽  
Biological Mechanisms ◽  
Schizophrenia Spectrum ◽  
Spectrum Disorders ◽  
Genetic And Environmental Factors ◽  
The Impact

AbstractThe prevalence of schizophrenia in a population is about 1%. Many efforts are constantly made to find the cause of this mental illness. Authors of this article provide groups of factors influencing the development of the disease. Among these factors, genetics seems to be an interesting and reasonable trend of exploration. GWAS research studies allow not only determining the point mutations in the genome, but also try to give an answer to the question about the biological mechanisms of disease. A microRNA MIR137, which is involved in neurogenesis and maturation of neurons may be an example. However, the genetic component may not always be sufficient to trigger symptoms. Definitely, a large group of environmental factors has an important role. Schizophrenia is a complex disease in which many genes interact with the environment. This article is a presentation of genes and the impact of various external environmental factors, leading to the onset of schizophrenia. Interrelationship between polygenic determinant of disease and the impact of both environmental and social factors in future will certainly become the field of interest for research concerning the etiology and course of schizophrenia-spectrum disorders.

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