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Inherited Susceptibility to Metabolic Complications of Obesity
Published in Claude Bouchard, The Genetics of Obesity, 2020
Roger R. Williams, Paul N. Hopkins, Steven C. Hunt, M. Catherine Schumacher, Barry M. Stults, Lily L. Wu, Sandra J. Hasstedt
Five different types of causal factors can contribute to such syndromes. In the first category of causal factors, single major gene effects are responsible for the predominant determination of a given trait. Major gene effects are striking, but uncommon. One example is LPL deficiency, discussed above as a predominant cause of high triglyceride and low HDL levels in heterozygous carriers.22 Another example would be heterozygous familial hypercholesterolemia, which causes twice-normal LDL cholesterol levels and very early coronary disease in males and females.24 Another example is glucocorticoid-remediable aldosteronism, a single gene leading to early serious hypertension with strokes in the mid-40s.25 In each of these disorders a single gene has a predominant effect which is modulated to some degree by other factors such as age and obesity, but the predominant expression is attributable to a single gene in heterozygous carriers.
The Li+/Na+ Countertransport in Hypertension
Published in Antonio Coca, Ricardo P. Garay, Ionic Transport in Hypertension: New Perspectives, 2019
Large samples of kindreds have been investigated to define the mode of inheritance of Li+/Na+ CT, as bimodality could be either genetic or nongenetic. The coefficients of correlation for Li+/Na+ CT in families are larger among first-degree relatives (monozygous and dizygous twins) than between genetically unrelated individuals (spouses).45 Because these data are consistent with a genetic component, various genetic models were tested. The most likely is a major gene with a polygenic component or an environmental factor.28,46
Human Genetic Variability and Susceptibility to Infectious Diseases
Published in Thomas R. O’Brien, Chemokine Receptors and AIDS, 2019
The genetic information required for this phenotype/genotype model is generally provided by segregation analysis, which uses family data to determine the mode of inheritance of a given phenotype. The aim of segregation analysis is to discriminate between factors that may cause familial resemblance in an effort to test for the existence of a major gene that affects the phenotype. The term “major gene” does not mean that only one gene is involved in the expression of the phenotype, but that, among a set of involved genes, at least one gene has an effect important enough to be distinguished from the other genes. For a binary clinical phenotype (e.g., affected or not), this effect can be expressed in terms of relative risks (e.g., the ratio of the probability of being affected given a DD genotype to the probability of being affected given a dd genotype). For a quantitative phenotype (e.g. infection levels), this effect is measured by the proportion of the phenotypic variance explained by the major gene (the heritability due to the gene).
Microanatomy of the metabolic associated fatty liver disease (MAFLD) by single-cell transcriptomics
Published in Journal of Drug Targeting, 2023
Lijun Wang, Kebing Zhou, Qing Wu, Lingping Zhu, Yang Hu, Xuefeng Yang, Duo Li
We extracted immune cell subsets (T cell, B cell, DC, Kupffer cell, Macrophage, Plasma B cell) from the single-cell dataset and analysed them with the Monocle R package to construct the trajectory of immune cell subsets in pseudo-time. The cell transfer trajectory showed one root and two branches in pseudo-time, and the pseudo-timing diagram was coloured based on three aspects: cell type (Figure 2A), cell cluster (Figure 2B) and pseudo-time process (Figure 2C). We observed that most cells at the beginning of pseudo-time (0) were clustered on two branches for the Kupffer cell, T cell and B cell, respectively. However, Macrophages, DCs, and Plasma B cells showed high invasive potential. Since the reprogramming trajectory was divided into two branches in the later stage, we try to clarify the molecular dynamics that distinguish the two branches (Figure 2D). Three major gene clusters were identified to explain these differences. GO analysis of three gene clusters showed that cluster 1 was significantly enriched in immune cell activation, such as monocyte differentiation, regulation of T cell activation and lymphocyte differentiation, and cluster 2 was significantly enriched in positive regulation of cell adhesion, cytokine-mediated signal pathway, leukocyte migration and other functions related to cell migration. Cluster 3 was significantly enriched in immune cell activation, such as B cell activation, monocyte differentiation and regulation of B cell activation (see Table 1).
Gene therapy for neurological disorders: challenges and recent advancements
Published in Journal of Drug Targeting, 2020
Stefanie A. Pena, Rahul Iyengar, Rebecca S. Eshraghi, Nicole Bencie, Jeenu Mittal, Abdulrahman Aljohani, Rahul Mittal, Adrien A. Eshraghi
The efficacy of gene therapy depends upon effective and safe vectors for the transfection of human cells with intended therapeutic genetic material. Major gene therapy advances have focussed on improved vector designs and increased safety profiles for targeted gene delivery and tangible applications of outcomes. These methodologic innovations include highly specific viral vector designs, plasmid transfection, nanoparticles, polymer-mediated gene delivery, engineered microRNA and in vivo CRISPR-based therapeutics. Viruses are naturally designed to infect human cells with viral genetic material, making them easily modifiable vectors for gene delivery. Viral transduction entails bioengineering of viruses to effectively deliver genetic sequences to human cells without associated pathogenicity. The main advantages of viral vectors are high specificity for a specific cell type and reliable transmission [69]. Limitations include size carrying capacity of therapeutic genetic material, invasive delivery and potential for adverse immune reactions or downstream genetic effects [70]. A wide variety of viruses have been employed as vectors, each with specific advantages, limitations and applications for use (Table 1). Current viral vectors include adenovirus, adeno-associated virus (AAV), Lentivirus, herpes simplex virus (HSV) and various retroviruses (Figure 7).
Promise of gene therapy to treat sickle cell disease
Published in Expert Opinion on Biological Therapy, 2018
Zulema Romero, Mark DeWitt, Mark C. Walters
The three major gene editing technologies use different site-directed nucleases (Figure 4) [71]. Zinc finger-nucleases (ZFN) are arrays of engineered zinc finger domain-containing protein modules, each binds a targeted three base pair sequence. An endonuclease covalently linked to the zinc fingers creates a DSB when the targeted DNA sequence is engaged. Widespread use of ZFN for research and development has been hindered by the difficulty of engineering effective constructs, and the proprietary nature of the technology. Related to ZFN are Transcription activator-like effector nucleases (TALENs), a more recent technology that utilizes protein modules to bind a single nucleotide base pair [74,75]. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 is another recently-developed gene editing technology that enables highly flexible targeting [76,77], controlled by a 20 nucleotide single guide RNA (sgRNA) and an adjacent NGG sequence (‘Protospacer adjacent motif’ or PAM sequence) [77]. The advent of this modular, user-friendly gene editing system has expanded gene editing research, and led to a renewed focus on SCD and β-thalassemia. Gene editing of the blood is accomplished through a procedure analogous to viral gene therapy described above: HSPC are harvested, edited ex vivo, and then re-infused after myeloablative conditioning (Figure 2).