Genetic variation in thioredoxin interacting protein (TXNIP) is associated with hypertriglyceridaemia and blood pressure in diabetes mellitus

Aims Thioredoxin interacting protein (TXNIP) is an attractive candidate gene for diabetes or diabetic dyslipidaemia, since TXNIP is the strongest glucose-responsive gene in pancreatic B-cells, TXNIP deficiency in a mouse model is associated with hyperlipidaemia and TXNIP is located in the 1q21-1q23 chromosomal Type 2 diabetes mellitus (DM) locus. We set out to investigate whether metabolic effects of TXNIP that were previously reported in a murine model are also relevant in human Type 2 DM. Methods The frequency distribution of a 3' UTR single nucleotide polymorphism (SNP) in TXNIP was investigated in subjects with normal glucose tolerance (NGT; n = 379), impaired glucose tolerance (IGT; n = 228) and Type 2 DM (n = 230). Metabolic data were used to determine the effect of this SNP on parameters associated with lipid and glucose metabolism. Results The frequency of the TXNIP variation did not differ between groups, but within the group of diabetic subjects, carriers of the TXNIP-T variant had 1.6-fold higher triglyceride concentrations (P = 0.015; n = 136) and a 5.5-mmHg higher diastolic blood pressure (P = 0.02; n = 212) than homozygous carriers of the common C-allele, whereas in non-diabetic subjects fasting glucose was 0.26 mmol/l lower (P = 0.002; n = 478) in carriers of the T-allele. Moreover, a significant interaction between plasma glucose concentrations and TXNIP polymorphism on plasma triglycerides was observed (P = 0.012; n = 544). Conclusion This is the first report to implicate TXNIP in a human disorder of energy metabolism, Type 2 diabetes. The effect of TXNIP on triglycerides is influenced by plasma glucose concentrations, suggesting that the biological relevance of TXNIP variations may be particularly relevant in recurrent episodes of hyperglycaemia

Age-related accrual of methylomic variability is linked to fundamental ageing mechanisms

Background: Epigenetic change is a hallmark of ageing but its link to ageing mechanisms in humans remains poorly understood. While DNA methylation at many CpG sites closely tracks chronological age, DNA methylation changes relevant to biological age are expected to gradually dissociate from chronological age, mirroring the increased heterogeneity in health status at older ages. Results: Here, we report on the large-scale identification of 6366 age-related variably methylated positions (aVMPs) identified in 3295 whole blood DNA methylation profiles, 2044 of which have a matching RNA-seq gene expression profile. aVMPs are enriched at polycomb repressed regions and, accordingly, methylation at those positions is associated with the expression of genes encoding components of polycomb repressive complex 2 (PRC2) in trans. Further analysis revealed trans-associations for 1816 aVMPs with an additional 854 genes. These trans-associated aVMPs are characterized by either an age-related

Blood lipids influence DNA methylation in circulating cells

Background: Cells can be primed by external stimuli to obtain a long-term epigenetic memory. We hypothesize that long-term exposure to elevated blood lipids can prime circulating immune cells through changes in DNA methylation, a process that may contribute to the development of atherosclerosis. To interrogate the causal relationship between triglyceride, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol levels and genome-wide DNA methylation while excluding confounding and pleiotropy, we perform a stepwise Mendelian randomization analysis in whole blood of 3296 individuals. Results: This analysis shows that differential methylation is the consequence of inter-individual variation in blood lipid levels and not vice versa. Specifically, we observe an effect of triglycerides on DNA methylation at three CpGs, of LDL cholesterol at one CpG, and of HDL cholesterol at two CpGs using multivariable Mendelian randomization. Using RNA-seq data available for a large subset of individuals (N = 2044), DNA methylation of these six CpGs is associated with the expression of CPT1A and SREBF1 (for triglycerides), DHCR24 (for LDL cholesterol) and

Controlling bias and inflation in epigenome- and transcriptome-wide association studies using the empirical null distribution

We show that epigenome- and transcriptome-wide association studies (EWAS and TWAS) are prone to significant inflation and bias of test statistics, an unrecognized phenomenon introducing spurious findings if left unaddressed. Neither GWAS-based methodology nor state-of-the-art confounder adjustment methods completely remove bias and inflation. We propose a Bayesian method to control bias and inflation in EWAS and TWAS based on estimation of the empirical null distribution. Using simulations and real data, we demonstrate that our method maximizes power while properly controlling the false positive rate. We illustrate the utility of our method in large-scale EWAS and TWAS meta-analyses of age and smoking

Genome-wide identification of directed gene networks using large-scale population genomics data

Identification of causal drivers behind regulatory gene networks is crucial in understanding gene function. Here, we develop a method for the large-scale inference of gene–gene interactions in observational population genomics data that are both directed (using local genetic instruments as causal anchors, akin to Mendelian Randomization) and specific (by controlling for linkage disequilibrium and pleiotropy). Analysis of genotype and whole-blood RNA-sequencing data from 3072 individuals identified 49 genes as drivers of downstream transcriptional changes (Wald P < 7 × 10−10), among which transcription factors were overrepresented (Fisher’s P = 3.3 × 10−7). Our analysis suggests new gene functions and targets, including for SENP7 (zinc-finger genes involved in retroviral repression) and BCL2A1 (target genes possibly involved in auditory dysfunction). Our work highlights the utility of population genomics data in deriving directed gene expression networks. A resource of trans-effects for all 6600 genes with a genetic instrument can be explored individually using a web-based browser

Autosomal genetic variation is associated with DNA methylation in regions variably escaping X-chromosome inactivation

X-chromosome inactivation (XCI), i.e., the inactivation of one of the female X chromosomes, restores equal expression of X-chromosomal genes between females and males. However, ~10% of genes show variable degrees of escape from XCI between females, although little is known about the causes of variable XCI. Using a discovery data-set of 1867 females and 1398 males and a replication sample of 3351 females, we show that genetic variation at three autosomal loci is associated with female-specific changes in X-chromosome methylation. Through cis-eQTL expression analysis, we map these loci to the genes SMCHD1/METTL4, TRIM6/HBG2, and ZSCAN9. Low-expression alleles of the loci are predominantly associated with mild hypomethylation of CpG islands near genes known to variably escape XCI, implicating the autosomal genes in variable XCI. Together, these results suggest a genetic basis for variable escape from XCI and highlight the potential of a population genomics approach to identify genes involved in XCI

Skewed X-inactivation is common in the general female population

X-inactivation is a well-established dosage compensation mechanism ensuring that X-chromosomal genes are expressed at comparable levels in males and females. Skewed X-inactivation is often explained by negative selection of one of the alleles. We demonstrate that imbalanced expression of the paternal and maternal X-chromosomes is common in the general population and that the random nature of the X-inactivation mechanism can be sufficient to explain the imbalance. To this end, we analyzed blood-derived RNA and whole-genome sequencing data from 79 female children and their parents from the Genome of the Netherlands project. We calculated the median ratio of the paternal over total counts at all X-chromosomal heterozygous single-nucleotide variants with coverage ≥10. We identified two individuals where the same X-chromosome was inactivated in all cells. Imbalanced expression of the two X-chromosomes (ratios ≤0.35 or ≥0.65) was observed in nearly 50% of the population. The empirically observed skewing is explained by a theoretical model where X-inactivation takes place in an embryonic stage in which eight cells give rise to the hematopoietic compartment. Genes escaping X-inactivation are expressed from both alleles and therefore demonstrate less skewing than inactivated genes. Using this characteristic, we identified three novel escapee genes (SSR4, REPS2, and SEPT6), but did not find support for many previously reported escapee genes in blood. Our collective data suggest that skewed X-inactivation is common in the general population. This may contribute to manifestation of symptoms in carriers of recessive X-linked disorders. We recommend that X-inactivation results should not be used lightly in the interpretation of X-linked variants

Present Poise In Momentum : Embodied learning of applied aesthetics in our sense of balance – a study about sensorial cultural use of balance

The purpose of this study lies in investigating the embodied learning of applied aesthetics in our sense of balance in the educational space and how it can contribute to change one of a present major public health related problem, the problem of sedentary behaviour in school and society. The investigation is not an effect study, but aims to question our sensorial cultural practice of applied aesthetics, by looking at how we use our ability to balance in the educational space.  Introducing and including elements from the field of art, the aesthetics field of knowledge and life science, the question of acknowledging embodied learning is explored mainly in the sensorial cultural praxis of our ability to balance. Embodied praxis is represented by the Alexander Technique and Elsa Gindler’s concept, with relation to modern neuromechanics. An educational view of knowledge that unilaterally enhances and rewards abstraction as well as theoretical thinking, by validating matrices and merit points, creates unbalance. Treating this unbalance solely with physical exercises enhances the conflict of how to use learning time in school and seems not to lead to a solution. By seeing the educational space as a space of embodied practice the investigation is built around participants’ sense of balance in embodied learning during a school day. The established sensorial cultural practice of how we are using our sense of balance in movement responses is observed during a school day and in a complementary inquiry explored and discussed with the children. Also the time of sitting is measured. The qualitative analysis or reading in this research of embodied learning is done by analysing directions or pointing in poise in momentum for finding inclusive or exclusive corresponsive sensorial tendencies in relation to sensorial cultural practice, including individual, social and regulative aspects. The minor quantitative part in this investigation is looking at the time spent sitting during the school day in the given conditions for defining the pupils’ sedimentary behaviour. The found embodied learning was not noticably acknowledged and not commented by the teacher.  The learning sessions were varying in space, form and in their content. In spite of the attempt of the teacher to create moveability, the children were sitting 54%  or more of the day in school. Inclusive dynamic responsiveness gave ability to balance and promoted embodied learning. Isolated or excluded responsiveness did not noticably engage the sense of balance and did not promote embodied learning. It resulted into pointing or directing downwards and leaning forward, backward or inwards into supportive furniture in accordance with gravitation. The study finds that inclusive responsiveness increases aligned balancing in poise in momentum. In its conclusion the study recognizes the value and effect of physical activity, but argues that moving to be healthy is not effectively changing sedentary behaviour. It argues instead for embodied health sufficient moving on a general sensorial level.  To be able to use our sense of balance as function of intelligence, we still need to increase acknowledgment of our evolutionary inherited skill further.Studiens syfte ligger i att undersöka möjligheten, att med embodied learning, lärandet genom estetisk sensorisk kommunikation och förtrogen inlärning, finna möjligheter att påverka ett av de stora folkhälsoproblemen, stillasittande beteende i skolan och i samhället. Arbetet utgör ingen effektstudie, utan syftar till att ifrågasätta vår sensoriska kulturella praxis och estetik, genom att undersöka hur vi använder oss av vårt balanssinne i skolan.  En pedagogisk syn på kunskap som ensidigt främjar och belönar abstraktion liksom teoretisk konception, genom meritpoäng och bedömningsmatriser, skapar obalans. Att genom enbart fysisk aktivitet försöka lösa denna obalans, förstärker konflikten om hur tiden i skolan ska fördelas och verkar inte leda till en tillfredsställande lösning av problemet.  Studien har en tvärvetenskaplig karaktär, där utbildningsvetenskapliga aspekter, konstnärlig forskning och naturvetenskap först presenteras och sedan inkluderas i frågan om hur embodied learning i relation till vår färdighet att balansera är igenkänd i skolans sensoriska kulturella praxis och estetik. Embodied praxis och dess användning, representerad genom Alexandertekniken och Elsa Gindlers koncept, är sedan närmare diskuterad, samt dess relation till modern neuromekanik. Genom att se skolan som en plats för embodied praxis, estetisk sensorisk praktik och förtrogenhetspraktik, bygger undersökningen på deltagarnas användning av balanssinnet, sett i hållningen i ögonblicket under en skoldag. Etablerad sensorisk kulturell praxis om hur vi använder vår förmåga att vara i balans observeras från ett intersubjektivt perspektiv. Detta kompletteras med samtal och enstaka explorationer, som utgör endast en mindre del i undersökningen. Även tiden för stillasittande mäts.  Den framtagna empirin av embodied learning analyseras kvalitativt. Detta sker genom att analysera riktningar i hållningen i ögonblicket, för att hitta inkluderande eller exkluderande motsvarande sensoriska tendenser i relation till individuell, social och reglerande sensorisk kulturell praxis. Den mindre kvantitativa delen i denna undersökning består av att mäta tiden som eleverna sitter under skoldagen, för att kunna analysera elevernas sedimentära beteende.   Resultaten visar att embodied learning inte var märkbart igenkänd och inte kommenterad av läraren. Undervisningspassen var varierande i rum, form och innehåll. Trots lärarens ihållande försök att skapa rörlighet, satt barnen minst 54 % av skoldagen. Inkluderande dynamisk sensorisk korrespondens resulterade i en väl fungerande funktionell användning av balanssinnet och främjade embodied learning. Isolerande eller uteslutande respons främjade inte den funktionella användningen av balanssinnet eller embodied learning märkbart. Resultatet visar också att elevernas hållningar största delen av tiden, visade riktningar som pekade nedåt, de lutade sig framåt, bakåt eller inåt och sjönk ner i möblerna i enlighet med tyngdlagen. Visade de en inkluderande korrespondens, ökade balanssinnets fungerande i hållningen i ögonblicket. Studien tillstår i sin slutsats att fysisk aktivitet är nödvändig och har effekt, men argumenterar, att röra sig för att vara frisk är inget effektivt sätt för att förändra stillasittande beteende. Resonemanget i studien leder i stället till att vi behöver röra oss generellt på ett införlivat hälsofrämjande sätt. För att kunna använda oss av vårt balanssinne på ett intelligent sätt, behöver vi fortfarande fördjupa förståelsen av vår evolutionärt nedärvda färdighet ytterligare.    This interdisciplinary study in educational science includes elements from the field of art and aesthetics as well as life science.  The investigation is not an effect study. It is about our sensorial cultural use of balance, from the perspective of an embodied practitioner.</p

Plant stanol supplementation decreases serum triacylglycerols in subjects with overt hypertriglyceridemia.

Evidence is accumulating that high serum concentrations of triacylglycerols (TAG) are, like LDL cholesterol, causally related to cardiovascular disease. A recent meta-analysis has indicated that plant stanol ester (PSE) intake not only lowered LDL cholesterol, but also serum TAG concentrations, especially in subjects with high baseline TAG concentrations. We therefore evaluated the effects of PSE supplementation on lipid metabolism in a population with elevated fasting TAG concentrations. In a randomized, placebo-controlled, parallel study, 28 subjects with elevated TAG concentrations (>1.7 mmol/L) were studied. After a 1-week run-in period during which a control margarine was used, subjects consumed for 3 weeks either control or PSE-enriched margarine (2.5 g/day of plant stanols). Serum plant stanol concentrations increased in all subjects receiving the PSE-enriched margarines, demonstrating good compliance. PSE supplementation significantly decreased serum total (6.7%, P = 0.015) and LDL cholesterol (9.5%, P = 0.041). A significant interaction between baseline TAG concentrations and PSE intake was found; PSE intake lowered TAG concentrations, particularly in subjects with high baseline TAG concentrations (>2.3 mmol/L; P = 0.009). Additionally, a significant interaction between baseline total number of LDL particles (LDL-P) and PSE intake was found (P = 0.020). PSE consumption lowered LDL-P, primarily in subjects with elevated baseline values; this was mainly due to a non-significant decrease in the number of atherogenic small LDL-P. Circulating levels of hs-CRP, glucose, and insulin were not changed after PSE intake. Taken together, PSE supplementation not only lowered LDL cholesterol, but also serum TAG concentrations, especially in subjects with overt hypertriglyceridemia

Corrigendum to “Quantification of dicarbonyl compounds in commonly consumed foods and drinks; presentation of a food composition database for dicarbonyls” [Food Chemistry, 339 (2020) 128063]

Dicarbonyls are reactive precursors of advanced glycation endproducts. They are formed endogenously and during food processing. Currently, a comprehensive database on dicarbonyls in foods that covers the entire range of food groups is lacking, limiting knowledge about the amount of dicarbonyls that is ingested via food. The aim of this study was to analyze the dicarbonyls methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG) in commonly-consumed products in a Western diet. We validated a UHPLC-MS/MS method to quantify MGO, GO, and 3-DG. We present a dietary dicarbonyl database of 223 foods and drinks. Total dicarbonyl concentrations were highest in dried fruit, Dutch spiced cake, and candy bars (> 400 mg/kg). Total dicarbonyl concentrations were lowest in tea, dairy, light soft drinks, and rice (<10 mg/kg). The presented database of MGO, GO, and 3-DG opens the possibility to accurately estimate dietary exposure to these dicarbonyls, and explore their physiological impact on human health