Recently, large-scale meta-analyses of genome-wide association (GWA) studies have identified a number of loci significantly associated with systolic and/or diastolic blood pressure (BP). Most of the ...GWA studies reported to date were conducted in populations of European descent. Given the appreciable ethnic differences in clinical presentation of hypertension, studies in non-European populations allow us to assess the relevance of the findings in Europeans to other ethnic groups and to potentially discover novel variants. Before the GWA scan era, the presence of racial or ethnic differences has been widely recognized for response to antihypertensive therapies, salt sensitivity and impact of obesity on developing hypertension. Despite a limited number of genetic loci that have been proven to show substantial ethnic differences, we can assume four possible genetic mechanisms--(1) absence of target variants in other ethnic groups; (2) presence of allelic heterogeneity; (3) difference in linkage disequilibrium structure; and (4) gene-gene and gene-environment interactions. Considering such a number of potential sources of heterogeneity, we should be cautious about claiming the presence of genuine ethnic differences in genetic susceptibility to BP-related traits or hypertension. Approximately a quarter of BP-associated loci that have been reported in four meta-analyses of GWA studies (i.e., 8 out of 34 loci) appear to be common across three ethnic groups--Europeans, east Asians and south Asians. 'Transethnic' BP meta-analysis will be useful not only for revealing novel susceptibility loci and pathophysiological pathways but also for facilitating the fine mapping of common causal variants.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Epigenome-wide association studies (EWAS) and differential gene expression analyses are generally performed on tissue samples, which consist of multiple cell types. Cell-type-specific effects of a ...trait, such as disease, on the omics expression are of interest but difficult or costly to measure experimentally. By measuring omics data for the bulk tissue, cell type composition of a sample can be inferred statistically. Subsequently, cell-type-specific effects are estimated by linear regression that includes terms representing the interaction between the cell type proportions and the trait. This approach involves two issues, scaling and multicollinearity.
First, although cell composition is analyzed in linear scale, differential methylation/expression is analyzed suitably in the logit/log scale. To simultaneously analyze two scales, we applied nonlinear regression. Second, we show that the interaction terms are highly collinear, which is obstructive to ordinary regression. To cope with the multicollinearity, we applied ridge regularization. In simulated data, nonlinear ridge regression attained well-balanced sensitivity, specificity and precision. Marginal model attained the lowest precision and highest sensitivity and was the only algorithm to detect weak signal in real data.
Nonlinear ridge regression performed cell-type-specific association test on bulk omics data with well-balanced performance. The omicwas package for R implements nonlinear ridge regression for cell-type-specific EWAS, differential gene expression and QTL analyses. The software is freely available from https://github.com/fumi-github/omicwas.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The addition of more than 1 wt % sodium alginate to a 7.5 wt % sodium caseinate solution induced aqueous two-phase separation (ATPS). Alginate and caseinate were effectively condensed in the upper ...and lower phases, respectively, thereby forming an alginate–casein assembly. The rigid structure of the alginate, which was formed by repeated regular hydrogen bonds between guluronic acid units, became supple when casein micelles penetrated and were adsorbed into the coiled alginate chains to weaken the diaxial linkages of the alginate hydrogen bonds. Protein–polysaccharide hybrid gel fibrils with a bundled structure were formed due to the deformation of the alginate–casein assembly in an aqueous solution by shear in a co-flow double tube, followed by cross-linking with Ca2+ supplied as the sheath fluid. The combination of ATPS and shear-induced elongation of the alginate–casein assemblies enabled the fabrication of hundreds of parallel gel filaments (φ = 1–10 μm) along the flow direction. These multiple parallel gel filaments can be applied to biomimetic chemistry for fibrous living tissues, as a biodegradable scaffold for cell engineering, and as a release carrier of physiologically active substances or drugs. Our proposed technique enables the formation of biomimetic protein–polysaccharide hybrid gel filaments with a bundled structure using Ca2+ chelation under laminar flow in a capillary, without the need for enzymatic cross-linking and multihole nozzles.
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IJS, KILJ, NUK, PNG, UL, UM
Background: Tobacco smoking is a leading preventable cause of morbidity and mortality worldwide; still, the success rate of smoking cessation is low in general. From the viewpoint of public health ...and clinical care, an objective biomarker of long-term smoking behavior is sought.Methods and Results: This study assessed DNA methylation as a biomarker of smoking in a hospital setting through a combination of molecular approaches including genetic, DNA methylation and mRNA expression analyses. First, in an epigenome-wide association study involving Japanese individuals with chronic cardiovascular disease (n=94), genome-wide significant smoking association was identified at 2 CpG sites on chromosome 5, with the strongest signal at cg05575921 located in intron 3 of the aryl-hydrocarbon receptor repressor (AHRR) gene. Highly significant (P<1×10−27) smoking–cg05575921 association was validated in 2 additional panels (n=339 and n=300). For the relationship of cg05575921 methylation extent with time after smoking cessation and cumulative cigarette consumption among former smokers, smoking-related hypomethylation was found to remain for ≥20 years after smoking cessation and to be affected by multiple factors, such as cis-interaction of genetic variation. There was a significant inverse correlation (P=0.0005) between cg05575921 methylation extent and AHRR mRNA expression.Conclusions: The present study results support that reversion of AHRR hypomethylation can be a quantifiable biomarker for progress in and observance of smoking cessation, although some methodological points need to be considered.
The term "metabolic (dysfunction)-associated fatty liver disease" (MAFLD) is suggested alternative for "non-alcoholic fatty liver disease" (NAFLD), as it better reflects metabolic dysfunction. No ...study has compared outcomes of the two diagnostic criteria.
In an ongoing, community-based, cohort-study in suburban Sri Lanka, participants were randomly selected in 2007. They were reassessed in 2014 to evaluate new-onset metabolic traits (MTs) and cardiovascular-events (CVEs). Baseline characteristics, MTs and CVEs after 7-years were compared in NAFLD and MAFLD and vs. controls. Similarly, we compared these parameters in those excluded by the NAFLD definition but captured by the MAFLD definition and vice versa, and vs. controls.
Of 2985 recruited in 2007, 940 (31.5%) had NAFLD, 990 (33.1%) had MAFLD and 362 (12.1%) were controls. When compared to NAFLD, MAFLD captured an additional 2.9% and lost 1.3% individuals. At baseline, anthropometric and metabolic traits were similar in NAFLD and MAFLD. At follow-up in 7-years, the risk of having new-onset MTs and fatal/non-fatal CVEs were similar in the groups, but were significantly higher compared to controls. Those excluded by the NAFLD definition but captured by the MAFLD definition showed higher baseline MTs compared to those excluded by the MAFLD definition but captured by the NAFLD definition, and had substantially higher risk for having new-onset MTs and CVEs compared to controls.
Although NAFLD and MAFLD had similar MTs at baseline, and similar outcomes after 7-years, those who were excluded by the NAFLD definition but captured by the MAFLD definition seem at higher risk of adverse outcomes than those excluded by the MAFLD definition but captured by the NAFLD definition. Although the increase in the index population was small, redefining NAFLD as MAFLD seemed to improve clinical utility.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cholesteryl ester transfer protein (CETP) mediates a step in reverse cholesterol transport, which channels cholesterol from peripheral tissues back to the liver. Mice and rats are CETP-deficient ...species, which assumedly contribute to rodent atherosclerosis resistance. Both pro- and anti-atherogenic effects have been shown in studies of CETP-transgenic rodent models thus far. As the results of pharmacological studies of CETP modification are largely controversial in humans, further knowledge about the impact of CETP on atherogenic phenotypes is required to evaluate its clinical utility for the prevention of cardiovascular and other organ damage associated with metabolic syndrome. Therefore, we newly generated a human CETP-transgenic (TghCETP) strain on the genetic background of spontaneously hypertensive rats (SHRs), which are characterized by the spontaneous occurrence of hypertension and insulin resistance. This allowed us to assess the in vivo role of CETP on cardiometabolic phenotypes in combination with hypertension. In TghCETP SHRs fed normal rat chow, systolic blood pressure was markedly elevated by 20-37 mmHg throughout the study period, and the development of fatty liver was accelerated with appreciable changes in the plasma lipid profile (HDL cholesterol reduction and triglyceride elevation). These phenotypic changes are in accordance with the assumption of proatherogenic effects inducible by the overexpression of CETP. However, with plasma LDL cholesterol levels concomitantly reduced, no apparent progression of atherosclerosis was detected in either the aorta or coronary arteries of TghCETP SHRs fed a high-fat, high-cholesterol diet. Our data provide new insight into the multifaceted regulation of cardiometabolic phenotypes via the modification of CETP.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
A rigid assembly of alginates is formed in aqueous media primarily via hydrogen bonding between guluronic units. A flow of aqueous alginate solution in a co‐flow capillary can form alginate gel ...fibers by contact with Ca2+ ions in sheath flow. Mixing with polyols e.g., polyethylene glycol (PEG) facilitates the shaping of the alginate assembly because PEG disrupts the assembly of the extended alginate chains to instead form alginate–PEG complexes that exhibit shear‐thinning behavior. The shear‐induced fibrous domains of the globular alginate–PEG complexes can be partitioned by a PEG‐rich phase, resulting in multiple parallel alginate gel filaments when the strong ionic‐field‐induced PEG‐rich phase is adjusted and an alginate–PEG complex phase is used as the aqueous two‐phase separation system.
Shear‐induced shaping of alginate–polyethylene glycol assembly enables the fabrication of thousands of parallel alginate domains without the need for a spinneret. The aligned continuous gel filaments appear when the fluid containing filamentous domains contacts Ca2+ ions acting as a cross‐linker using a co‐flow capillary. The filamentous domains are partitioned by polyethylene glycol, which is not responsive to Ca2+ ions.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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•A two-phase sodium-alginate/hydroxypropyl-cellulose system was prepared.•A hydrogel of thermosensitive HPC bearing PMA graft chains was formed.•The filamentous HPC-PMA-domain ...structure was instantly fixed on contact with PEI.•Unlike other systems, gel self-assembly is induced by electrostatic interactions.
Assemblies of carbohydrate polymers are important in a number of applications and improved methods for their fabrication are increasingly sought after. Herein, we report that an aqueous two-phase system of alginate (Alg) and hydroxypropyl cellulose with poly(methacrylic acid) graft chains (HPC-PMA) facilitated the assembly of Alg/HPC-PMA in both phases. Dynamically formed filamentous domains in a flow field were gelled by rapid complexation with cationic polyethyleneimine (PEI). The fabricated HPC-PMA gel filament morphologies can be switched between the bundled and dissociated gel filaments using a co-flow microfluidic device in response to the amount of supplied PEI crosslinker. Excess complexation of PEI contributes to the fabrication of cationic gel filaments; this contribution results in a dissociated structure due to electrostatic repulsion. In contrast, an appropriate amount of PEI resulted in a bundle structure. The proposed spinning method avoids the risk of nozzle clogging, and enables the one-step spinning of multiple gel filaments.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder of the vasculature, characterized by epistaxis, telangiectasia and arteriovenous malformations in multiple organs. We herein report a ...49-year-old woman with a history of early-onset myocardial infarction and intracranial aneurysms, in whom we incidentally detected multiple hepatic vascular abnormalities. We subsequently diagnosed her with HHT after discovering gastrointestinal telangiectases and a pulmonary arteriovenous fistula along with a history of recurrent epistaxis. Whole-exome sequencing revealed a novel pathogenic variant in SMAD4, a relatively rare causative gene for HHT. This case highlights the fact that HHT patients may present with asymptomatic liver lesions.
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