👤 Tom H Karlsen

We investigated the relationship between heart failure etiology and lipoprotein subfractions, and to explore their associations with left ventricular dimension and function in heart failure with reduced ejection fraction (HFrEF) patients. Cross-sectional investigation of serum lipoprotein subfractions from 205 HFrEF patients in the SMARTEX heart failure study. Serum levels of triglycerides, cholesterol, free cholesterol, phospholipids, lipoproteins (Apolipoproteins; A-1, A-2, and B), very-low-density (VLDL), intermediate-density (IDL), low-density (LDL), and high-density lipoprotein (HDL) were determined using Stable HFrEF patients [left ventricular ejection fraction (LVEF) ≤ 35%, NYHA class II-III], with ischemic (ICM, n = 119) or non-ischemic (NICM, n = 86) cardiomyopathy were studied. NICM patients had higher levels of 48 lipoproteins compared to ICM patients, including 29 LDL, 13 VLDL, and 6 HDL subfractions [p <0.05]. NICM patients had 22% higher cholesterol and 27% higher remnant cholesterol levels, with 24% more atherogenic ApoB containing subfractions (VLDL, IDL, LDL) (p <0.05). Heart failure etiology and statin treatment explained 23-24% of the variability in cholesterol, free cholesterol, and ApoB (p <0.001). Triglyceride content in some VLDL and LDL subfractions was weakly associated with left ventricular end-diastolic volume, end-diastolic diameter, ejection fraction, and S'. NICM patients had the highest atherosclerotic lipoprotein burden, attributed to elevated ApoB particles and partly due to less statin treatment. The triglyceride content of some VLDL and LDL subfractions was weakly associated with left ventricular structure and function. However, further research is needed to determine their prognostic significance before implementation into strategies for prevention and treatment. Show less

Recent genome-wide association studies (GWAS) and pathway analyses supported long-standing observations of an association between immune-mediated diseases and Parkinson disease (PD). The post-GWAS era provides an opportunity for cross-phenotype analyses between different complex phenotypes. To test the hypothesis that there are common genetic risk variants conveying risk of both PD and autoimmune diseases (ie, pleiotropy) and to identify new shared genetic variants and their pathways by applying a novel statistical framework in a genome-wide approach. Using the conjunction false discovery rate method, this study analyzed GWAS data from a selection of archetypal autoimmune diseases among 138 511 individuals of European ancestry and systemically investigated pleiotropy between PD and type 1 diabetes, Crohn disease, ulcerative colitis, rheumatoid arthritis, celiac disease, psoriasis, and multiple sclerosis. NeuroX data (6927 PD cases and 6108 controls) were used for replication. The study investigated the biological correlation between the top loci through protein-protein interaction and changes in the gene expression and methylation levels. The dates of the analysis were June 10, 2015, to March 4, 2017. The primary outcome was a list of novel loci and their pathways involved in PD and autoimmune diseases. Genome-wide conjunctional analysis identified 17 novel loci at false discovery rate less than 0.05 with overlap between PD and autoimmune diseases, including known PD loci adjacent to GAK, HLA-DRB5, LRRK2, and MAPT for rheumatoid arthritis, ulcerative colitis and Crohn disease. Replication confirmed the involvement of HLA, LRRK2, MAPT, TRIM10, and SETD1A in PD. Among the novel genes discovered, WNT3, KANSL1, CRHR1, BOLA2, and GUCY1A3 are within a protein-protein interaction network with known PD genes. A subset of novel loci was significantly associated with changes in methylation or expression levels of adjacent genes. The study findings provide novel mechanistic insights into PD and autoimmune diseases and identify a common genetic pathway between these phenotypes. The results may have implications for future therapeutic trials involving anti-inflammatory agents. Show less

Stromal fibroblasts are important determinants of tumor cell behavior. They act to condition the tumor microenvironment, influence tumor growth, support tumor angiogenesis and affect tumor metastasis. Heparan sulfate proteoglycans, present both on tumor and stromal cells, interact with a large number of ligands including growth factors, their receptors, and structural components of the extracellular matrix. Being ubiquitously expressed in the tumor microenvironment heparan sulfate proteoglycans are candidates for playing central roles in tumor-stroma interactions. The objective of this work was to investigate the role of heparan sulfate expressed by stromal fibroblasts in modulating the growth of tumor cells and in controlling the interstitial fluid pressure in a 3-D model. We generated spheroids composed of fibroblasts alone, or composite spheroids, composed of fibroblasts and tumor cells. Here we show that stromal fibroblasts with a mutation in the heparan sulfate elongating enzyme Ext1 and thus a low heparan sulfate content, formed composite fibroblast/tumor cell spheroids with a significant lower interstitial fluid pressure than corresponding wild-type fibroblast/tumor cell composite spheroids. Furthermore, immunohistochemistry of composite spheroids revealed that the cells segregated, so that after 6 days in culture, the wild-type fibroblasts formed an inner core and the tumor cells an outer layer of cells. For composite spheroids containing Ext1-mutated fibroblasts this segregation was less obvious, indicating impaired cell migration. Analysis of tumor cells expressing the firefly luciferase gene revealed that the changes in tumor cell migration in mutant fibroblast/tumor cell composite spheroids coincided with a lower proliferation rate. This is the first demonstration that stromal Ext1-levels modulate tumor cell proliferation and affect the interstitial fluid pressure in a 3-D spheroid model. Learning how structural changes in stromal heparan sulfate influence tumor cells is essential for our understanding how non-malignant cells of the tumor microenvironment influence tumor cell progression. Show less