ABSTRACT
Loss-of-function (LoF) variants in the filaggrin (FLG) gene are the strongest known genetic risk factor for atopic dermatitis (AD), but the impact of these variants on AD outcomes is poorly understood. We comprehensively identified genetic variants through targeted region sequencing of FLG in children participating in the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children cohort. Twenty FLG LoF variants were identified, including 1 novel variant and 9 variants not previously associated with AD. FLG LoF variants were found in the cohort. Among these children, the presence of 1 or more FLG LoF variants was associated with moderate/severe AD compared with those with mild AD. Children with FLG LoF variants had a higher SCORing for Atopic Dermatitis (SCORAD) and higher likelihood of food allergy within the first 2.5 years of life. LoF variants were associated with higher transepidermal water loss (TEWL) in both lesional and nonlesional skin. Collectively, our study identifies established and potentially novel AD-associated FLG LoF variants and associates FLG LoF variants with higher TEWL in lesional and nonlesional skin.
Subject(s)
Dermatitis, Atopic , Filaggrin Proteins , Intermediate Filament Proteins , Loss of Function Mutation , Phenotype , Dermatitis, Atopic/genetics , Dermatitis, Atopic/pathology , Humans , Male , Female , Child, Preschool , Prospective Studies , Infant , Intermediate Filament Proteins/genetics , Genetic Predisposition to Disease , Child , Food Hypersensitivity/geneticsABSTRACT
Artificial lipid bilayers have revolutionized biochemical and biophysical research by providing a versatile interface to study aspects of cell membranes and membrane-bound processes in a controlled environment. Artificial bilayers also play a central role in numerous biosensing applications, form the foundational interface for liposomal drug delivery, and provide a vital structure for the development of synthetic cells. But unlike the envelope in many living cells, artificial bilayers can be mechanically fragile. Here, we develop prototype scaffolds for artificial bilayers made from multiple chemically linked tiers of actin filaments that can be bonded to lipid headgroups. We call the interlinked and layered assembly a multiple minimal actin cortex (multi-MAC). Construction of multi-MACs has the potential to significantly increase the bilayer's resistance to applied stress while retaining many desirable physical and chemical properties that are characteristic of lipid bilayers. Furthermore, the linking chemistry of multi-MACs is generalizable and can be applied almost anywhere lipid bilayers are important. This work describes a filament-by-filament approach to multi-MAC assembly that produces distinct 2D and 3D architectures. The nature of the structure depends on a combination of the underlying chemical conditions. Using fluorescence imaging techniques in model planar bilayers, we explore how multi-MACs vary with electrostatic charge, assembly time, ionic strength, and type of chemical linker. We also assess how the presence of a multi-MAC alters the underlying lateral diffusion of lipids and investigate the ability of multi-MACs to withstand exposure to shear stress.
Subject(s)
Actins , Lipid Bilayers , Cell Membrane , Cytoskeleton , Actin CytoskeletonABSTRACT
The molecular processes underlying human health and disease are highly complex. Often, genetic and environmental factors contribute to a given disease or phenotype in a non-additive manner, yielding a gene-environment (G × E) interaction. In this work, we broadly review current knowledge on the impact of gene-environment interactions on human health. We first explain the independent impact of genetic variation and the environment. We next detail well-established G × E interactions that impact human health involving environmental toxicants, pollution, viruses, and sex chromosome composition. We conclude with possibilities and challenges for studying G × E interactions.
