Genomics of Post-Prandial Lipidomic Phenotypes in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study

<div><p>Background</p><p>Increased postprandial lipid (PPL) response to dietary fat intake is a heritable risk factor for cardiovascular disease (CVD). Variability in postprandial lipids results from the complex interplay of dietary and genetic factors. We hypothesized that detailed lipid profiles (eg, sterols and fatty acids) may help elucidate specific genetic and dietary pathways contributing to the PPL response.</p><p>Methods and Results</p><p>We used gas chromatography mass spectrometry to quantify the change in plasma concentration of 35 fatty acids and 11 sterols between fasting and 3.5 hours after the consumption of a high-fat meal (PPL challenge) among 40 participants from the GOLDN study. Correlations between sterols, fatty acids and clinical measures were calculated. Mixed linear regression was used to evaluate associations between lipidomic profiles and genomic markers including single nucleotide polymorphisms (SNPs) and methylation markers derived from the Affymetrix 6.0 array and the Illumina Methyl450 array, respectively. After the PPL challenge, fatty acids increased as well as sterols associated with cholesterol absorption, while sterols associated with cholesterol synthesis decreased. PPL saturated fatty acids strongly correlated with triglycerides, very low-density lipoprotein, and chylomicrons. Two SNPs (rs12247017 and rs12240292) in the sorbin and SH3 domain containing 1 (<i>SORBS1</i>) gene were associated with b-Sitosterol after correction for multiple testing (<i>P</i>≤4.5*10⁻¹⁰). <i>SORBS1</i> has been linked to obesity and insulin signaling. No other markers reached the genome-wide significance threshold, yet several other biologically relevant loci are highlighted (eg, <i>PRIC285</i>, a co-activator of PPARa).</p><p>Conclusions</p><p>Integration of lipidomic and genomic data has the potential to identify new biomarkers of CVD risk.</p></div

Clinical Application of Stem/Stromal Cells in COPD

Chronic obstructive pulmonary disease (COPD) is a progressive life-threatening disease that is significantly increasing in prevalence and is predicted to become the third leading cause of death worldwide by 2030. At present, there are no true curative treatments that can stop the progression of the disease, and new therapeutic strategies are desperately needed. Advances in cell-based therapies provide a platform for the development of new therapeutic approaches in severe lung diseases such as COPD. At present, a lot of focus is on mesenchymal stem (stromal) cell (MSC)-based therapies, mainly due to their immunomodulatory properties. Despite increasing number of preclinical studies demonstrating that systemic MSC administration can prevent or treat experimental COPD and emphysema, clinical studies have not been able to reproduce the preclinical results and to date no efficacy or significantly improved lung function or quality of life has been observed in COPD patients. Importantly, the completed appropriately conducted clinical trials uniformly demonstrate that MSC treatment in COPD patients is well tolerated and no toxicities have been observed. All clinical trials performed so far, have been phase I/II studies, underpowered for the detection of potential efficacy. There are several challenges ahead for this field such as standardized isolation and culture procedures to obtain a cell product with high quality and reproducibility, administration strategies, improvement of methods to measure outcomes, and development of potency assays. Moreover, COPD is a complex pathology with a diverse spectrum of clinical phenotypes, and therefore it is essential to develop methods to select the subpopulation of patients that is most likely to potentially respond to MSC administration. In this chapter, we will discuss the current state of the art of MSC-based cell therapy for COPD and the hurdles that need to be overcome