👤 Denes Molnar

Habitual physical activity (PA) affects metabolism and homeostasis in various tissues and organs. However, detailed knowledge of associations between PA and cardiovascular disease (CVD) risk markers is limited. We sought to identify associations between accelerometer-assessed PA classes and 183 proteomic and 154 metabolomic CVD-related biomarkers. We utilized cross-sectional data from the main SCAPIS cohort (n = 4647, median age: 57.5 yrs, 50.5% female) as a discovery sample and the SCAPIS pilot cohort (n = 910, median age: 57.5 yrs, 50.3% female) as a validation sample. PA was assessed via hip-worn accelerometers, while plasma concentrations of proteomic biomarkers were measured using Olink CVD II and III panels. Metabolomic markers were assessed using the Nightingale NMR platform. We evaluated associations between four PA classes (moderate-to-vigorous PA [MVPA], low-intensity PA [LIPA], sedentary [SED], and prolonged SED [prolSED]) and biomarkers, controlling for potential confounders and applying a false discovery rate of 5% using multiple linear regressions. A total of eighty-five metabolomic markers and forty-three proteomic markers were validated and found to be significantly associated with one or more PA classes. LIPA and SED markers demonstrated significant mirroring or opposing relations to biomarkers, while prolSED mainly shared relations with SED. Notably, HDL species were predominantly negatively associated with SED, whereas LDL species were positively associated with SED and negatively associated with MVPA. Among the proteomic markers, eighteen were uniquely associated with MVPA (among those Interleukin - 6 [IL6] and Growth/differentiation factor 15 [GDF15] both negatively related), seven with SED (among those Metalloproteinase inhibitor 4 [TIMP4] and Tumor necrosis factor receptor 2 [TNFR2], both positively related), and eight were related to both SED/prolSED (among those Lipoprotein lipase [LPL] negatively related to SED and leptin [LEP] positively related to SED) and MVPA (with LPL positively related to MVPA and LEP negatively related to MVPA). Our findings suggest the existence of specific associations between PA classes and metabolomic and cardiovascular protein biomarkers in a middle-aged population. Beyond validation of previous results, we identified new associations. This multitude of connections between PA and CVD-related markers may help elucidate the previously observed relationship between PA and CVD. The identified cross-sectional associations could inform the design of future experimental studies, serving as important outcome measures. Show less

Early diagnosis of sepsis and discrimination from SIRS is crucial for clinicians to provide appropriate care, management and treatment to critically ill patients. We describe identification of mRNA biomarkers from peripheral blood leukocytes, able to identify severe, systemic inflammation (irrespective of origin) and differentiate Sepsis from SIRS, in adult patients within a multi-center clinical study. Participants were recruited in Intensive Care Units (ICUs) from multiple UK hospitals, including fifty-nine patients with abdominal sepsis, eighty-four patients with pulmonary sepsis, forty-two SIRS patients with Out-of-Hospital Cardiac Arrest (OOHCA), sampled at four time points, in addition to thirty healthy control donors. Multiple clinical parameters were measured, including SOFA score, with many differences observed between SIRS and sepsis groups. Differential gene expression analyses were performed using microarray hybridization and data analyzed using a combination of parametric and non-parametric statistical tools. Nineteen high-performance, differentially expressed mRNA biomarkers were identified between control and combined SIRS/Sepsis groups (FC>20.0, p<0.05), termed 'indicators of inflammation' (I°I), including CD177, FAM20A and OLAH. Best-performing minimal signatures e.g. FAM20A/OLAH showed good accuracy for determination of severe, systemic inflammation (AUC>0.99). Twenty entities, termed 'SIRS or Sepsis' (S°S) biomarkers, were differentially expressed between sepsis and SIRS (FC>2·0, p-value<0.05). The best performing signature for discriminating sepsis from SIRS was CMTM5/CETP/PLA2G7/MIA/MPP3 (AUC=0.9758). The I°I and S°S signatures performed variably in other independent gene expression datasets, this may be due to technical variation in the study/assay platform. Show less

Two rate-limiting enzymes in PUFA biosynthesis, Δ5- and Δ6-desaturases, are encoded by the FADS1 and FADS2 genes, respectively. Genetic variants in the FADS1-FADS2 gene cluster are associated with changes in plasma concentrations of PUFA, HDL- and LDL-cholesterol, and TG. However, little is known about whether dietary PUFA intake modulates these associations, especially in adolescents. We assessed whether dietary linoleic acid (LA) or α-linolenic acid (ALA) modulate the association between the FADS1 rs174546 polymorphism and concentrations of PUFA, other lipids, and lipoproteins in adolescents. Dietary intakes of LA and ALA, FADS1 rs174546 genotypes, PUFA levels in serum phospholipids, and serum concentrations of TG, cholesterol, and lipoproteins were determined in 573 European adolescents from the HELENA study. The sample was stratified according to the median dietary LA (≤9.4 and >9.4 g/d) and ALA (≤1.4 and >1.4 g/d) intakes. The associations between FADS1 rs174546 and concentrations of PUFA, TG, cholesterol, and lipoproteins were not affected by dietary LA intake (all P-interaction > 0.05). Similarly, the association between the FADS1 rs174546 polymorphism and serum phospholipid concentrations of ALA or EPA was not modified by dietary ALA intake (all P-interaction > 0.05). In contrast, the rs174546 minor allele was associated with lower total cholesterol concentrations (P = 0.01 under the dominant model) and non-HDL-cholesterol concentrations (P = 0.02 under the dominant model) in the high-ALA-intake group but not in the low-ALA-intake group (P-interaction = 0.01). These results suggest that dietary ALA intake modulates the association between FADS1 rs174546 and serum total and non-HDL-cholesterol concentrations at a young age. Show less

Genetic variability in the NR1H3 gene (encoding LXRα) and in several of its target genes is associated with serum HDL-cholesterol (HDL-C) concentrations. We sought to assess if these associations could be detected in adolescents. Thirty-nine polymorphisms in NR1H3, ABCA1, APOE, CETP, PLTP and LPL were analysed in the HELENA study (n = 1144 European adolescents). The minor alleles of rs11039155 in NR1H3, rs2575879 in ABCA1, rs708272, rs17231506 and rs5882 in CETP and rs328 in LPL were associated with higher serum HDL-C concentrations (p ≤ 0.0012). The minor alleles of rs12221497 in NR1H3, rs1800978 in ABCA1 and the APOE ɛ4 allele were associated with lower HDL-C concentrations (p ≤ 0.01). The combined set of associated polymorphisms accounted for ∼6.6% of the variance in HDL-C. We report for the first time that polymorphisms in NR1H3 and its target genes ABCA1, APOE, CETP and LPL contribute to the genetic variance for HDL-C concentrations in adolescence. Show less