Biology subjects

Willems van Dijk, K.

Publications and source records attributed to Willems van Dijk, K..

5 recordsLinked to original sources

bioRxiv2020

Soluble mannose receptor induces pro-inflammatory macrophage activation andobesity-associated metaflammation

Pro-inflammatory activation of macrophages in metabolic tissues is critically important in induction of obesity-induced metaflammation. Here, we demonstrate that the soluble mannose receptor (sMR) plays a direct, functional role in both macrophage activation and metaflammation. We show that sMR binds CD45 on macrophages and inhibits its phosphatase activity, leading to a Src/Akt/NF-{kappa}B-mediated cellular reprogramming towards an inflammatory phenotype both in vitro and in vivo. Remarkably, increased serum sMR levels were observed in obese mice and humans and directly correlated with body weight. Additionally, MR deficiency lowers pro-inflammatory macrophages in metabolic tissues and protects against hepatic steatosis and whole-body metabolic dysfunctions in high-fat diet-induced obese mice. Conversely, administration of sMR in lean mice increases serum pro-inflammatory cytokines, activates tissue macrophages and promotes insulin resistance. Altogether, our results reveal sMR as novel regulator of pro-inflammatory macrophage activation which could constitute a new therapeutic target for metaflammation and other hyperinflammatory diseases.

immunology↗

bioRxiv2019

Associations between outdoor temperature and bright sunlight with metabolites in two population-based European cohorts

Context: Outdoor temperature and bright sunlight may directly and/or indirectly modulate systemic metabolism. Objective: We assessed the associations between outdoor temperature and bright sunlight duration with metabolomics. Design: meta-analysis of two cross-sectional studies. Setting: Two population-based European cohort studies. Patients or other participants: Non-diabetic individuals from the Oxford BioBank (OBB; N=6,368; mean age 47.0 years, males 44%) and the Netherlands Epidemiology of Obesity (NEO; N=5,916; mean age 55.6 years, males 43%) studies. Intervention(s): Data on mean outdoor bright sunlight and temperature collected from local weather stations in the week prior to blood sampling. Main Outcome Measure(s): Serum levels of 148 metabolites measured using NMR spectroscopy, including 14 lipoprotein subclasses. Statistical analyses: Multivariable linear regression analyses adjusted for age, sex, body mass index, season and either outdoor temperature or bright sunlight. Summary statistics from the OBB and NEO cohorts were combined using fixed-effect meta-analyses. Results: A higher mean outdoor temperature was associated with increased concentrations of lipoprotein (sub)particles and certain amino acids such as phenylalanine and leucine. In contrast, longer mean hours of bright sunlight were specifically associated with lower concentrations of very low density lipoprotein (sub)particles. The direction of effects was consistent between the OBB and NEO, although effect sizes were generally larger in the OBB. Conclusions: Increased bright sunlight duration is associated with an improved metabolic profile whilst higher outdoor temperature may adversely impact cardiometabolic health.

physiology↗

bioRxiv2019

The genomic architecture of blood metabolites based on a decade of genome-wide analyses

Metabolomics examines the small molecules involved in cellular metabolism. Approximately 50% of total phenotypic differences in metabolite levels is due to genetic variance, but heritability estimates differ across metabolite classes and lipid species. We performed a review of all genetic association studies, and identified > 800 class-specific metabolite loci that influence metabolite levels. In a twin-family cohort (N = 5,117), these metabolite loci were leveraged to simultaneously estimate total heritability (h2total), and the proportion of heritability captured by known metabolite loci (h2Metabolite-hits) for 309 lipids and 52 organic acids. Our study revealed significant differences in h2Metabolite-hits among different classes of lipids and organic acids. Furthermore, phosphatidylcholines with a high degree of unsaturation had higher h2Metabolite-hits estimates than phosphatidylcholines with a low degree of unsaturation. This study highlights the importance of common genetic variants for metabolite levels, and elucidates the genetic architecture of metabolite classes and lipid species.

genetics↗

bioRxiv2019

Genome-wide association study of plasma lipids

There is continuous interest in the genetic determinants of plasma triglycerides (TGs) and phospholipids and their role in the etiology of cardiovascular disease (CVD). Here, we report the results of a Dutch genome wide association study (GWAS) of an in-house developed lipidomics platform, focusing on 90 plasma lipids. Lipids were assessed by liquid chromatography mass spectrometry in participants from the Leiden Longevity Study, the Netherlands Twin Register and the Erasmus Rucphen Family (ERF) study and meta-analysed, resulting in a sample size of 5537 participants. In addition, we performed genetic correlation analyses between the 90 plasma lipids and markers of metabolic health, as well as vascular pathology and CVD combining our GWAS results with publicly available GWAS outputs. We replicated previously known associations between 34 lipids and 10 lipid quantitative trait loci (lipQTL) (GCKR, APOA1, FADS1, SGPP1,TMEM229B, LIPC, PDXDC1, CETP, CERS4 and SPTLC3) with metabolome-wide (P < 1.61 x 10-9) significance. Moreover, we report 6 novel phospholipid-related and 5 triglyceride (TG)-related loci: SGGP1 (SM21:0), SPTLC3 (SM21:0 and SM25:1), FADS1 (LPCO16:1, PC38:2, PEO36:5, PEO38:5, TG56:5, TG56:6, and TG56:7), TMEM229 (LPCO16:1), GCKR (TG50:2), and APOA1 (TG54:4). In addition, we report suggestively significant (P < 5 x 10-8) associations mapping to eleven novel lipid quantitative trait loci (lipQTLs), three of which are supported by mining previous GWAS data: MAU (PC34:4), LDLR (SM16:0), and MLXIPL (TG48:1 and TG50:1)). Genetic correlation analysis indicates that one specific specific sphingomyelin, SM22:0, shares common genetic background with CVD. Levels of SM22:0 also positively associate with carotid artery intima-media thickness in the ERF study, and this observation is independent of LDL-C level. Our findings yield higher resolution of plasma lipid species and new insights in the biology of circulating phosholipids and their relation to CVD risk.

epidemiology↗

bioRxiv2019

Role of Rare and Low Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels

BackgroundAlcohol intake influences plasma lipid levels and such effects may be modulated by genetic variants. ObjectiveWe aimed to characterize the role of aggregated rare and low-frequency variants in gene by alcohol consumption interactions associated with fasting plasma lipid levels. DesignIn the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, fasting plasma triglycerides (TG), and high- and low-density lipoprotein cholesterol (HDL-c and LDL-c) were measured in 34,153 European Americans from five discovery studies and 32,275 individuals from six replication studies. Rare and low-frequency protein coding variants (minor allele frequency [≤] 5%) measured by an exome array were aggregated by genes and evaluated by a gene-environment interaction (GxE) test and a joint test of genetic main and GxE interaction effects. Two dichotomous self-reported alcohol consumption variables, current drinker, defined as any recurrent drinking behavior, and regular drinker, defined as the subset of current drinkers who consume at least two drinks per week, were considered. ResultsWe discovered and replicated 21 gene-lipid associations at 13 known lipid loci through the joint test. Eight loci (PCSK9, LPA, LPL, LIPG, ANGPTL4, APOB, APOC3 and CD300LG) remained significant after conditioning on the common index single nucleotide polymorphism (SNP) identified by previous genome-wide association studies, suggesting an independent role for rare and low-frequency variants at these loci. One significant gene-alcohol interaction on TG was discovered at a Bonferroni corrected significance level (p-value <5x10-5) and replicated (p-value <0.013 for the interaction test) in SMC5. ConclusionsIn conclusion, this study applied new gene-based statistical approaches to uncover the role of rare and low-frequency variants in gene-alcohol consumption interactions on lipid levels.

epidemiology↗